bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–03–29
eighty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. The complexities of respiratory chain biogenesis and maintenance in yeast mitochondria.
  2. Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
  3. A structure-selective endonuclease drives uniparental mitochondrial DNA inheritance.
  4. Cell biology: Killing the prisoner escaping from mitochondria.
  5. Heart-Specific and Conditional Deletion of the Immt Gene Reveals Its Role in Regulating Mitochondrial Structure and Total Heart Metabolism.
  6. Mitochondrial NADP(H) integrates redox and metabolism.
  7. Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication.
  8. From the cytosol to the inner membrane: biogenesis of the mitochondrial carrier family.
  9. Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.
  10. Wernicke Encephalopathy Complicating a Distinctive POLG Phenotype With MNGIE-Like Features.
  11. Expanding the Phenotype of TUFM-Related Combined Oxidative Phosphorylation Deficiency 4.
  12. DCTPP1 orchestrates dCTP pool dynamics and mtDNA stability in quiescent cells.
  13. Chronic cold exposure induces plasticity of mitochondrial calcium uptake in beige and brown fat of UCP1-deficient mice.
  14. Quantitative analysis of oligonucleotide delivery into isolated mitochondria: a proof-of-concept method.
  15. No Correlation Between Interferon Signaling and Cytosolic Mitochondrial DNA/RNA Leakage in Cultured Skin Fibroblasts of Patients With Mitochondrial Diseases.
  16. Protein domain characterization reveals human MIC60 tolerates loss of helical bundle domain.
  17. A molecular switch in NAC prevents mitochondrial protein mistargeting by SRP.
  18. How strong is a mitochondrial targeting signal?
  19. Mitochondrial lactate venting limits oxidative stress.
  20. mtDNA-Depleted Mitochondria Form Sites of Contact with the Nucleus and Alter the Cellular Epigenome.
  21. Dysfunction of α2δ4 leads to photoreceptor degeneration through disrupted synaptic mitochondria and calcium crosstalk.
  22. Expanding the AFG3L2 Spectrum: A Link to Axonal Neuropathy.
  23. Age-Dependent Decline in Plasmalogen Biosynthesis Impairs Stress-Induced Mitochondrial Fission in Drosophila.
  24. Using image classifiers to predict CMT2A disease-relevant mitochondrial motility phenotypes in iPSC motor neurons.
  25. Mitochondrial DNA Modification in Assisted Reproduction: Concept to Practice-A Narrative Review.
  26. Transplantation of Saccharomyces cerevisiae Rmd9p peptide into mammalian mitochondrial IF2 substitutes for the IF1 function in Escherichia coli.
  27. Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.
  28. MitoGEx: An Integrated Platform for Streamlined Human Mitochondrial Genome Analysis.
  29. UFMylation of Pyruvate Dehydrogenase Regulates Mitochondrial Metabolism.
  30. A small-molecule stabilizer of the calpastatin-calpain-2 complex restores mitochondrial function and mitigates neurodegeneration.
  31. Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity.
  32. Sirt1 coordinates the mitochondrial UPR and myocellular proteostasis to preserve muscle integrity during muscle atrophy in zebrafish.
  33. Regulation of skeletal muscle mitochondrial fuel utilization during exercise.
  34. Intracellular mitochondrial transfer in ischemic stroke: Mechanisms and therapeutic application.
  35. Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.
  36. Mitochondrial Dynamic Proteins MiD49 and MiD51 as Novel Targets of Cardioprotection.
  37. PLIN5 phosphorylation orchestrates mitochondria lipid-droplet coupling to control hepatic lipid flux and steatosis.
  38. Age-dependent H3K9 trimethylation by dSetdb1 impairs mitochondrial UPR leading to degeneration of olfactory neurons and loss of olfactory function in Drosophila.
  39. Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows.
  40. Massive-scale single-nucleus multi-omics identifies novel rare noncoding drivers of Parkinson's disease.
  41. UV irradiation alters TFAM binding specificity and compaction of DNA.
  42. Mitochondrial interplay with membrane organelles in health and disease.
  43. Cancer mtDNA mutations: metabolic plasticity and therapeutic promise?
  44. A multistage cost-effective strategy for the molecular diagnosis of unexplained vision loss patients: practice in inherited ocular fundus disease.
  45. CRISPR and Beyond: Genome-Editing Strategies in Retinal Stem Cell Research.
  46. TSPO-PET highlights an atypical mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype.
  47. Structural Analysis of Human LonP1 Protease Bound with the Native Substrate.
  48. Mitochondrial metabolic imbalance drives diploidization in mouse haploid embryonic stem cells via NADPH overload.
  49. Functional and metabolomic analyses of brown adipose tissue during cold-deacclimation reveal rapid N-acetylated amino acid adaptations.
  50. A Mysterious Case of Diffuse Severe Hepatic Steatosis in a Thin Teenager.
  51. NCBoost v2: a classifier for non-coding single nucleotide variants in Mendelian diseases.
  52. Moonlighting cytosolic function of ACAD9: suppression of TRAF6-mediated osteoclastogenesis and protection against osteoporosis.
  53. WiNGS-API: a federated genome/phenome data sharing platform enabling gene discovery and variant classification for rare diseases.
  54. Structure and Substrate Specificity of Human Short-Chain Acyl-CoA Dehydrogenase and Insights into Pathogenicity of Disease-Associated Mutations.
  55. Strand-seq and the future of personalized genomics.
  56. An ARVC-5 Drosophila knock-in model reveals new functions of Tmem43 in lipid homeostasis.
  57. HADHA in Cardiovascular Disease: From Mitochondrial Dysfunction to Therapeutic Targets.
  58. Multi-omics liquid biopsy identifies mitochondrial dysfunction in geographic atrophy and supports the longevity-associated metabolite α-ketoglutarate as a therapeutic strategy.
  59. The E3-ome gene-centric compendium reveals the human E3 ligase landscape.
  60. Integrative Insights Into Mitochondrial Dysfunction and Organelle Crosstalk in Diabetic Kidney Disease.
  61. Structure/function relationships of mitochondrial protein carrier (SLC25A20) for carnitine/acylcarnitine: A review.
  62. Mitochondrial Impairment in Unloaded Postural Muscle: Mechanisms Driving Loss of Muscle Function and Mass.
  63. Modeling cis -regulatory variation in human brain enhancers across a large Parkinson's Disease cohort.
  64. BLOC1S1 variants cause lysosomal and autophagic defects resulting in a hypomyelinating leukodystrophy with epileptic encephalopathy.
  65. TaoChongBao: a large-scale C. elegans missense variant database bridging worm and human genomes.
  66. Restoring Mitochondrial Homeostasis: Therapeutic Strategies for Metabolic Dysfunction-Associated Fatty Liver Disease.
  67. Often forgotten but essential: long-chain acyl-CoAs in metabolic control.
  68. The ATF3-DRP1 Axis Coordinates Mitochondrial Homeostasis and Suppresses Early Apoptosis in Zinc-Deficient Cardiomyocytes.
  69. Atypical subacute sclerosing panencephalitis mimicking mitochondrial encephalopathy, lactic acidosis and stroke-like episodes.
  70. Lifestyle interventions for Parkinson's disease.
  71. Challenges and opportunities for the use of telehealth in rare disease diagnosis, treatment, research, and education: key opinion leader interviews by the IRDiRC telehealth task force.
  72. Gcn2 deficiency triggers anemia and hypoxic intolerance in zebrafish.
  73. Knockdown of RNF128 attenuated Parkinson's-induced mitochondrial dysfunction in neurons by stabilizing the SIRT1 protein.
  74. Generation of Friedreich's ataxia induced pluripotent stem cells carrying the FXN c.165 + 5G>C splicing mutation.
  75. Miratul Muqit: leading an alliance to decode Parkinson's disease.
  76. TEM-based Study of the Phenotype of Astrocytes Differentiated from Induced Pluripotent Stem Cells from a Healthy Donor and a Patient with Parkinson's Disease.
  77. Atlas of one-carbon metabolism in conventional and germ-free mice reveals folate as a key determinant of biochemical pathways.
  78. Mitochondrial Dysfunction in Renal Aging: A Vicious Cycle Driving Kidney Disease Progression.
  79. Mitochondrial Ultrastructure, Fission Proteins, Activity, and Motor Dysfunctions in the Innovative Parkinson's Disease Model Induced by Manganese Inhalation.
  80. A supramolecular fluorescent probe targeting mitochondrial iron for assisting early Parkinson's disease diagnosis.
  1. Protein Sci. 2026 Apr;35(4): e70545
    The complexities of respiratory chain biogenesis and maintenance in yeast mitochondria.
    Andreas Carlström, Carmela Vazquez-Calvo, Martin Ott.
      Mitochondrial oxidative phosphorylation is the most efficient way of energy conversion for eukaryotic cells. It is executed by a series of high-molecular weight enzyme complexes in the inner mitochondrial membrane that were acquired during endosymbiosis at the root of eukaryotic evolution. Biogenesis of this machinery depends not only on nuclear gene expression and protein import, but also on an organelle-specific system to express a handful of proteins encoded in mitochondrial DNA. These two genetic systems cooperate for the biogenesis and maintenance of oxidative phosphorylation complexes. Here, we use the respiratory chain complex III as an example to highlight the complexities of this process. Specifically, we will describe the intricate mechanisms by which respiratory chain complexes are assembled, how the two genetic systems are coordinated and how biogenesis and function are physically separated within the inner mitochondrial membrane. To do so, we will primarily discuss findings from baker's yeast, where a wealth of recent data revealed exciting insights into these processes.
    Keywords:  OXPHOS; assembly; biogenesis; complex III; mitochondria; proteostasis; quality control; regulation; respiratory chain; translation
    DOI:  https://doi.org/10.1002/pro.70545
  2. Autophagy. 2026 Mar 22. 1-2
    Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
    Julia A Thayer, Derek P Narendra.
      Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, whether diverse forms of mitochondrial damage activate the PINK1-PRKN pathway through a unified mechanism. Recently, we demonstrated that loss of mitochondrial membrane potential (MMP) leads to the stabilization and activation of PINK1 under a wide range of mitochondrial stressors, including mitochondrial protein misfolding. Mechanistically, we suggest that the MMP is required at a key step of PINK1 import into mitochondria, in which PINK1 is transferred between the translocases of the outer and inner mitochondrial membranes. Consistent with this model, retention of active PINK1 of the outer membrane requires the translocase of the outer mitochondrial membrane (TOMM) complex, whereas import of PINK1 from the outer to inner membrane requires the TIMM23 (translocase of inner mitochondrial membrane 23) complex. Notably, chronic disruption of the TIMM23 complex is sufficient to stabilize active PINK1 in the TOMM complex, phenocopying MMP loss. Together, our findings suggest PINK1 primarily senses catastrophic drops in a mitochondrion's MMP: a dead-end for the mitochondrion's continued biogenesis.
    Keywords:  Autophagy; PARK2; PARK6; mitochondria unfolded protein response; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2646238
  3. bioRxiv. 2026 Mar 20. pii: 2026.03.19.713005. [Epub ahead of print]
    A structure-selective endonuclease drives uniparental mitochondrial DNA inheritance.
    Mayu Shimomura, Hwa Young Yun, Philip C Zuzarte, Jared T Simpson, Haley D M Wyatt, Thomas R Hurd.
      Maternal inheritance of mitochondrial DNA (mtDNA) is a near-universal feature of eukaryotes 1 , yet the mechanisms that ensure this by preventing paternal mtDNA inheritance have remained unclear. In both Drosophila and humans, mtDNA is actively eliminated from sperm during spermatogenesis, producing mature sperm whose mitochondria lack their genomes 2-5 . Here we identify Hotaru, a previously uncharacterized, testis-specific GIY-YIG endonuclease, as a central player in this process. We find that Hotaru is expressed in elongated spermatids, localizes to the mitochondrial matrix, and is required for paternal mtDNA elimination. In hotaru mutants, sperm retain mtDNA at levels comparable to those present before the elimination process. Genetic and biochemical analyses show that Hotaru selectively recognizes and cleaves cruciform DNA structures within the mtDNA control region. Together, these findings identify a dedicated nuclease that enforces mitochondrial genome elimination in the animal male germline and reveal that an unexpected structural feature of mtDNA serves as the molecular determinant of its destruction. By recognizing DNA structure rather than specific sequence motifs, this mechanism is inherently robust to the high mutation rate of mitochondrial genomes.
    DOI:  https://doi.org/10.64898/2026.03.19.713005
  4. Curr Biol. 2026 Mar 23. pii: S0960-9822(26)00166-1. [Epub ahead of print]36(6): R259-R261
    Cell biology: Killing the prisoner escaping from mitochondria.
    Arun Kumar Kondadi, Andreas S Reichert.
      Mitochondria contain their own DNA (mtDNA), which can be released via multiple routes and cause inflammation and disease. A recent study revealed the unexpected role of a mitochondrial nuclease, present in the intermembrane space, in preventing mtDNA escape via mitophagy.
    DOI:  https://doi.org/10.1016/j.cub.2026.02.016
  5. Cells. 2026 Mar 12. pii: 505. [Epub ahead of print]15(6):
    Heart-Specific and Conditional Deletion of the Immt Gene Reveals Its Role in Regulating Mitochondrial Structure and Total Heart Metabolism.
    Yasuhide Kuwabara, Caitlin Keezer, Suh-Chin J Lin, Akanksha Rajput, Jeffery D Molkentin.
      Mitochondria comprise ~1/3rd of the volume of an adult ventricular cardiomyocyte. The gene Immt encodes the Mic60/Mitofilin protein that is hypothesized to organize the mitochondrial contact site and cristae organization system (MICOS) complex that generates mitochondrial cristae junctions between the inner and outer membranes. To investigate the function of the Immt gene in the mouse heart, we generated and characterized mice in which this gene was specifically deleted in the mouse heart using a loxP-targeted allele (Immtfl/fl) and either the constitutive heart-specific Myh6-Cre transgene or the conditional Myh6-MerCreMer transgene, each of which showed lethality in several weeks. Hearts from these mice showed progressive hypertrophic cardiomyopathy and failure with lost contractility and lung edema. At the ultrastructural level, hearts from these mice showed extreme abnormalities in mitochondrial architecture characterized by lost cristae junctions, stacking of the inner mitochondrial membranes, mitophagy and areas with complete absence of mitochondria. Analysis of mitochondria showed loss of the MICOS complex of proteins as well as loss of mitochondrial membrane potential (Δψ) and increased expression of mitophagy proteins and mitochondrial biogenesis transcription factors. Hearts from these mice also showed widespread cardiomyocyte necrosis and induction of the universal mitochondrial stress response at the mRNA level, as well as major alterations in cardiac metabolites, suggesting greater use of glucose, ketones and amino acids. We conclude that the Immt gene is required for cardiac mitochondrial structure and function, although the ensuing mitochondrial stress response provides molecular clues as to how the heart can compensate metabolically and maintain viability for weeks after mitochondria are absent or unfunctional.
    Keywords:  cardiac hypertrophy; cardiomyocyte; metabolism; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/cells15060505
  6. Trends Endocrinol Metab. 2026 Mar 25. pii: S1043-2760(25)00267-X. [Epub ahead of print]
    Mitochondrial NADP(H) integrates redox and metabolism.
    Ren Zhang, Kezhong Zhang.
      The compartmentalization of NAD(H) and NADP(H) is fundamental to cellular metabolism, enabling precise coordination of redox balance, biosynthetic reactions, and energy homeostasis. Within mitochondria, NADP(H) has long been viewed as a redox buffer supporting antioxidant defense and reductive biosynthesis. Emerging evidence, however, reveals that mitochondrial NADP(H) also drives oxidative metabolism and metabolic flexibility. Loss of the mitochondrial NAD kinase, which phosphorylates NAD(H) to generate mitochondrial NADP(H), disrupts NADP(H)-dependent pathways that sustain oxidative metabolism and systemic energy balance. These advances reposition mitochondrial NADP(H) as an integrative regulator that links redox homeostasis with energy metabolism across cellular and systemic levels, with broad implications for metabolic disease.
    Keywords:  NAD(H); NADK2; NADP(H); fatty acid oxidation; mitochondria; redox
    DOI:  https://doi.org/10.1016/j.tem.2025.12.003
  7. bioRxiv. 2026 Mar 04. pii: 2026.03.04.709625. [Epub ahead of print]
    Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication.
    Amber Crabtree, Suraj Thapliyal, Mohd Mabood Khan, Edgar Garza Lopez, Andrea Marshall, Calixto Pablo Hernandez Perez, Oleg Kovtun, Jenny C Schafer, Dea Pulatani, Yuho Kim, Sepiso K Masenga, Annet Kirabo, Jeremiah Afolabi, Melanie McReynolds, Renata O Pereira, Prasanna Venkhatesh, Prasanna Katti, Brian Glancy, Antentor Hinton.
      Mitochondrial structural plasticity is a critical adaptive response to cellular stress, yet the transcriptional networks governing the formation of specialized mitochondrial architectures remain poorly defined. Here, we identified and demonstrated that activating transcription factor 4 (ATF4), the master regulator of the integrated stress response, directly regulates mitochondrial morphological remodeling through a novel ATF4-NRF1/Nrf2-MFN2 signaling axis. Using serial block-face scanning electron microscopy and three-dimensional reconstruction in Drosophila flight muscle, primary myotubes, and human skeletal muscle, we show that overexpression of ATF4 promotes significant mitochondrial elongation, increased cristae concentration, enhanced mitochondrial-endoplasmic reticulum contact site (MERC) formation, and the initiation of Mitochondrial Nanotunnels. In contrast, loss of ATF4 results in mitochondrial fragmentation and impaired aerobic capacity. Chromatin immunoprecipitation sequencing reveals direct ATF4 binding at the promoters of the genes encoding NRF1 and Nrf2, which in turn regulate MFN2 expression. Small-molecule inhibition studies further establish that activation of this hierarchical pathway is both necessary and sufficient for stress-induced mitochondrial structural adaptation. Together, these findings position ATF4 as a master regulator of mitochondrial architectural plasticity, providing a direct mechanistic link between cellular stress signaling and organelle remodeling.
    DOI:  https://doi.org/10.64898/2026.03.04.709625
  8. Protein Sci. 2026 Apr;35(4): e70537
    From the cytosol to the inner membrane: biogenesis of the mitochondrial carrier family.
    Catherine S Palmer, Phoebe J Leeming, Diana Stojanovski.
      Mitochondrial carrier proteins are essential for cellular physiology as they are active in a wide range of metabolic pathways including production of cellular energy, amino acid synthesis, redox balance and ion homeostasis. The double membrane of mitochondria provides a tightly gated environment through which carrier proteins facilitate the exchange of substrates including nucleotides, ions, metabolites, cofactors and vitamins. The biogenesis of the carrier family relies on the coordinated action of the TOM and TIM22 complexes, which direct the translocation of nuclear-encoded precursors across the outer membrane (TOM) and their integration into the mitochondrial inner membrane (TIM22). Due to the intrinsic hydrophobicity of the carrier precursors, their import pathway requires chaperones in both the cytosol and intermembrane space to maintain solubility and prevent aggregation during transit. Given their central role in metabolism, dysfunction of the biogenesis machinery or the carrier proteins has serious consequences to human health. In this review we summarize the current understanding of carrier protein biogenesis in human cells and highlight how perturbations to this pathway influence human health.
    Keywords:  SLC25; TIM; TOM; citrin deficiency; mitochondrial carrier protein; protein biogenesis
    DOI:  https://doi.org/10.1002/pro.70537
  9. EMBO J. 2026 Mar 24.
    Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.
    Mitsuhiro Nishigori, Serina Hirata, Hidetaka Kosako, Takeshi Ichinohe, Hendrik Nolte, Jan Riemer, Thomas Langer, Takumi Koshiba.
      Mitochondrial proteases regulate dynamic properties of organelle morphology and ensure functional plasticity at the cellular level. The metalloprotease OMA1 mediates constitutive and stress-inducible processing of its mitochondrial substrates, although only a few of its direct functional targets have been characterized. Using in vitro and in vivo multiproteomic and biochemical approaches, we here demonstrate that the membrane-anchored intermembrane space (IMS) protein AIFM1 serves as a mitochondrial stress-responsive OMA1 substrate. Under stress conditions, OMA1 cleaves AIFM1 in the IMS with slower kinetics than its conventional substrate, the dynamin-like GTPase OPA1. OMA1-mediated dislocation of cleaved AIFM1 from the mitochondrial inner membrane reduces its interaction with oxidative phosphorylation subunits, thereby decreasing respiratory activity and impairing cell growth. Furthermore, we reveal that under steady-state conditions AIFM1 broadly safeguards the mitochondrial proteome by mediating the import of proteins, particularly respiratory complex I subunits, via the TIM23 complex. Similar changes to the mitochondrial proteome occur in the lungs of virally infected mice, accompanied by stress-inducible AIFM1 processing. These findings identify OMA1 as a key integrator of mitochondrial stress and cellular energetics through AIFM1 remodeling.
    Keywords:  AIFM1; Mitochondrial Stress; OMA1; OXPHOS Activity; Proteolysis
    DOI:  https://doi.org/10.1038/s44318-026-00734-y
  10. Eur J Neurol. 2026 Mar;33(3): e70554
    Wernicke Encephalopathy Complicating a Distinctive POLG Phenotype With MNGIE-Like Features.
    Giuliana Capece, Luca Caumo, Sara Volta, Pietro Riguzzi, Elena Sogus, Angela Petrosino, Sara Vianello, Daniele Sabbatini, Leonardo Salviati, Renzo Manara, Carlo Viscomi, Gianni Sorarù, Luca Bello, Elena Pegoraro.
       BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare autosomal recessive disease caused by variants in the thymidine phosphorylase gene (TYMP), primarily characterized by severe gastrointestinal and neurological symptoms. The complete phenotype of MNGIE has not been linked to any gene other than TYMP.
    METHODS: We describe two identical twins who exhibited delayed psychomotor development, infantile bilateral cataract, congenital demyelinating polyneuropathy, and severe progressive gastrointestinal dysmotility with recurrent pseudo-obstruction episodes, along with diffuse supratentorial leukoencephalopathy that mainly overlaps with classic TYMP-related MNGIE. During the course of the disease, one patient developed Wernicke encephalopathy, triggered by chronic malnutrition related to recurrent gastrointestinal pseudo-obstruction. This patient later suffered from a catastrophic stroke-like episode, resulting in massive cerebral edema and brain death at the age of 38.
    RESULTS: Next-generation sequencing (NGS) using a custom-targeted mitochondrial gene panel identified two compound heterozygous variants in the POLG gene: the paternal variants p.Thr251Ile and p.Pro587Leu, occurring in cis, and the novel maternal variant p.Arg853Gly. Quantification of mtDNA by real-time PCR on skeletal muscle DNA detected significant depletion, but no multiple deletions were detected with mtDNA analysis by long-range PCR and Nanopore sequencing.
    CONCLUSIONS: These cases showed a very distinctive POLG phenotype, with some MNGIE-like features, expanding the clinical and genetic spectrum of the POLG-related diseases. Additionally, they highlighted the importance of monitoring for thiamine deficiency in mitochondrial patients with severe gastrointestinal dysmotility who experience sudden clinical deterioration.
    Keywords:  central nervous system diseases; malabsorption syndromes; mitochondrial diseases; mitochondrial encephalomyopathies
    DOI:  https://doi.org/10.1111/ene.70554
  11. Am J Med Genet A. 2026 Mar 22.
    Expanding the Phenotype of TUFM-Related Combined Oxidative Phosphorylation Deficiency 4.
    Noémie Villeneuve-Cloutier, Jodi Warman-Chardon, Danielle K Bourque.
      Combined oxidative phosphorylation deficiency 4 (COXPD4) is a rare mitochondrial condition caused by biallelic deleterious variants in the nuclear-encoded gene TUFM. To date, most individuals with COXPD4 have presented with encephalopathy, hypotonia, and abnormal brain imaging. Many of the reported individuals died in infancy. We aim to expand the clinical and biochemical phenotype of COXPD4 by reporting on an adult with this condition. Our proband has a homozygous TUFM c.1025T>G, p.(Val342Gly) variant. He has sensorineural hearing loss, hyperlactatemia with mild illness, and reduced activity in mitochondrial complexes I, III, and IV on endomyocardial biopsy. He presents with hypertrophic cardiomyopathy and chronic kidney failure, which have not previously been reported in this condition. Our findings suggest not all individuals with COXPD4 present with significant neurological involvement and highlight the importance of considering COXPD4 as part of the differential diagnosis of hypertrophic cardiomyopathy.
    Keywords:   TUFM ; cardiomyopathy; combined oxidative phosphorylation deficiency 4; lactic acidosis; mitochondrial disorder
    DOI:  https://doi.org/10.1002/ajmg.a.70136
  12. Cell Death Dis. 2026 Mar 26.
    DCTPP1 orchestrates dCTP pool dynamics and mtDNA stability in quiescent cells.
    Belén Fernández, Guiomar Pérez-Moreno, Blanca Martínez-Arribas, Antonio E Vidal, Luis Miguel Ruiz-Pérez, Dolores González-Pacanowska.
      Defects in nucleotide metabolism and imbalances in deoxynucleotide triphosphate (dNTP) pools are associated with several human diseases, including cancer and mitochondrial disorders. In non-replicative cells, while DNA synthesis is reduced, a continuous supply of nucleotides is essential to sustain mitochondrial DNA (mtDNA) replication and repair. Human all-α dCTP pyrophosphatase 1 (DCTPP1), a nucleotido hydrolase with high specificity for dCTP, plays a critical role in maintaining nucleotide homeostasis, however its participation in mtDNA stability remains unexplored. In this study we performed a detailed analysis of pyrimidine metabolism enzymes in non-dividing cells. We found that during quiescence, DCTPP1 is predominantly localized to mitochondria. Depletion of the enzyme leads to upregulation of the de novo thymidylate synthesis pathway and expansion of both the dCTP and dGTP pools, highlighting its pivotal role in regulating the dNTP balance. To explore the potential therapeutic relevance of these observations, we used an in vitro model of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare mitochondrial disorder caused by thymidine phosphorylase (TP) deficiency and characterized by dCTP depletion and mtDNA loss. Long-term thymidine overloading in quiescent cells (a model mimicking TP deficiency) led to reduced dCTP levels and the depletion of mtDNA, effects that were reversed upon DCTPP1 knockdown. Hence, reduced DCTPP1 levels restored dCTP availability and increased mtDNA copy number. These findings suggest that DCTPP1 plays a critical role in regulating mitochondrial dNTP pools and that down-regulation of the enzyme may serve as a compensatory mechanism in disorders marked by secondary dCTP depletion. DCTPP1 may therefore represent a promising therapeutic target for mitochondrial DNA depletion syndromes such as MNGIE.
    DOI:  https://doi.org/10.1038/s41419-026-08632-1
  13. bioRxiv. 2026 Mar 18. pii: 2026.03.16.712209. [Epub ahead of print]
    Chronic cold exposure induces plasticity of mitochondrial calcium uptake in beige and brown fat of UCP1-deficient mice.
    Casandra G Chamorro, Sachin Pathuri, Rebeca Acin-Perez, Michael Chhan, Madeleine G Milner, Natalia Ermolova, Anthony E Jones, Ajit S Divakaruni, Linsey Stiles, Andrea L Hevener, Zhenqi Zhou, Orian S Shirihai, Yuriy Kirichok, Ambre M Bertholet.
      Brown adipose tissue (BAT) is a unique tissue with mitochondria specialized for thermogenesis via the BAT-specific uncoupling protein 1 (UCP1). Ucp1 -/- mice cannot tolerate acute exposure to cold, illustrating the necessity of UCP1 for efficient mitochondrial thermogenesis. However, these mice adapt to low temperatures through a gradual acclimation process, suggesting a high degree of mitochondrial plasticity in brown and beige fat cells. This phenomenon, which remains to be fully elucidated, indicates the potential for these mitochondria to implement effective thermogenic mechanisms in the absence of uncoupling protein 1 (UCP1). Here, we investigated mitochondrial remodeling in beige and brown fat of Ucp1 -/- mice to determine how they fulfill their thermogenic role. Upon gradual acclimation to a cold environment, Ucp 1 -/- mice exhibited body metabolic parameters and temperatures in the interscapular region similar to those of wild-type mice of BAT, highlighting effective thermogenesis. Interestingly, mitochondrial patch-clamp analysis and a mitochondrial Ca 2+ swelling assay revealed a dramatic increase in Ca 2+ uptake depending on the mitochondrial calcium uniporter (MCU) in BAT mitochondria from Ucp1 -/- mice when robust thermogenesis was required. Mitochondrial remodeling was accompanied by markedly increased tethering between mitochondria and the endoplasmic reticulum (ER) in Ucp1 -/- mice, confirming a significant restructuring of the contact sites between the ER and mitochondria, likely to adapt to a new Ca 2+ homeostasis. Respiratory complexes also underwent significant reorganization, which partly led to a reduction in their assembly. Levels of ATP synthase and its F1 subcomplex increased, suggesting a major source of ATP consumption and energy expenditure. We propose a new role for MCU as a key regulator of mitochondrial plasticity, enabling efficient thermogenesis in beige and brown adipose tissues in the absence of UCP1.
    DOI:  https://doi.org/10.64898/2026.03.16.712209
  14. Biotechniques. 2026 Jan-Dec;78(1-12):78(1-12): 1-11
    Quantitative analysis of oligonucleotide delivery into isolated mitochondria: a proof-of-concept method.
    Joshua McHale, Veronica Bazzani, Abdechakour Elkihel, Jing Wu, Ling Peng, Carlo Vascotto.
      Mitochondria, with their own DNA, Represent a potential target for nucleic acid-based precision therapies. However, effective delivery of therapeutic oligonucleotides remains challenging due to the dual mitochondrial membranes and the localization of mitochondrial DNA within nucleoid complexes in the matrix. To understand the delivery process and assess the delivery efficiency of potential vectors, such as dendrimers, it is essential to effectively quantify the oligonucleotides that are successfully delivered to and remain within mitochondria. Currently, there are only limited yet inconvenient methods available for this purpose. Here, we describe a method for quantifying the delivery of fluorescent oligonucleotide cargos in isolated mitochondria using a microfiltration apparatus for reliable fluorescent analysis. By working within a range of dilutions, we are able to safeguard the concentration limits. The quantification protocol also enables the visualization of specific localization within mitochondria, allowing for the determination of whether delivery can occur across both membranes. This is particularly useful, as it offers a key insight into improving vectors as they must deliver the cargoes within the mitochondrial matrix. We validate this method in this proof-of-concept study, providing biological data to assess the difference between two amphiphilic dendrimer vectors for oligonucleotide delivery in mitochondria.
    Keywords:  Oligonucleotide delivery; dendrimers; microfiltration; mitochondria; subcellular localization
    DOI:  https://doi.org/10.1080/07366205.2026.2635461
  15. Eur J Immunol. 2026 Apr;56(4): e70176
    No Correlation Between Interferon Signaling and Cytosolic Mitochondrial DNA/RNA Leakage in Cultured Skin Fibroblasts of Patients With Mitochondrial Diseases.
    Manon Marchais, Alessandra Pennisi, Alexandre Pierga, Alice Lepelley, Nicolas Cagnard, Christine Bole, Patrick Nitschke, Mohamed Hamici, Frédéric Rieux-Laucat, Manuel Schiff, Arnold Munnich, Agnès Rötig.
      Mitochondria have long been known to be involved in the regulation of innate immune response. We questioned whether cultured skin fibroblasts of patients suffering from mitochondrial diseases are valuable biological resources for the study of interferon signaling. Expression of interferon-stimulated genes was measured in control cells supplemented with interferon and in cultured fibroblasts of patients carrying pathogenic variants in mitochondrial disease-causing genes. Control fibroblasts showed a strong expression of interferon-stimulated genes in response to interferon, but only 43% of patients' fibroblasts displayed increased interferon stimulated genes scores. Cytosolic mitochondrial DNA and RNA were quantified by immunofluorescence and confocal microscopy. No correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA release could be established. We found that cultured skin fibroblasts represent a valuable biological resource for the investigation of interferon signaling, but that abnormal interferon signaling is not always observed in patients with mitochondrial diseases. At variance to gene silencing in control fibroblasts, the lack of correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA leakage in patients' fibroblasts questions the relevance of cellular models as illustrators of pathological situations in humans.
    DOI:  https://doi.org/10.1002/eji.70176
  16. bioRxiv. 2026 Mar 22. pii: 2026.03.19.713006. [Epub ahead of print]
    Protein domain characterization reveals human MIC60 tolerates loss of helical bundle domain.
    Stephanie M Rockfield, Krishnan Venkataraman, Chih-Hsuan Wu, Randall Wakefield, Alan Wu, Amit Budhraja, Ricardo Rodriguez-Enriquez, Ali Khalighifar, Camenzind G Robinson, Cai Li, Alexandre F Carisey, Joseph Thomas Opferman.
      The mitochondrial contact site and cristae organizing system (MICOS) is essential for cristae junction formation and inner mitochondrial membrane architecture. To define how MICOS integrity is established and maintained, we generated conditional deletion models of Immt (encoding MIC60), a core MICOS subunit, in tissue-specific settings and in cultured cells. Liver-specific deletion of Immt in mice induced profound defects in mitochondrial ultrastructure and function, establishing MIC60 as essential for mitochondrial integrity. Notably, despite the severity of the defects, we did not detect increased apoptosis in liver tissue or in cells. To directly link MIC60 structure to its function, we performed a systemic structure-function analysis of human MIC60 using domain-specific deletion mutants expressed in Immt-deleted cells. We identified that the transmembrane, coiled-coil, and mitofilin domains are required for MICOS assembly, mitochondrial morphology, and respiratory function. Unexpectedly, deletion of the predicted helical bundle (a region spanning 229 amino acids) substantially restored mitochondrial structure and function, nearly matching full-length MIC60. A mutation (K299E) associated with human disease within this domain similarly preserved most MIC60-dependent functions. Together, these results establish MIC60 as a non-redundant regulator of mitochondrial architecture while revealing that a large predicted structural domain is largely dispensable for MIC60s core functions, refining current models of MICOS organization and uncovering unexpected modularity within MIC60.
    DOI:  https://doi.org/10.64898/2026.03.19.713006
  17. Nat Commun. 2026 Mar 27.
    A molecular switch in NAC prevents mitochondrial protein mistargeting by SRP.
    Emir Maldosevic, Radoslaw Jakub Gora, Liangguang Leo Lin, Linyao Elina Zhou, Zexin Jason Li, Yelena Peskova, Ling Qi, Shu-Ou Shan, Ahmad Jomaa.
      The nascent polypeptide-associated complex (NAC) co-translationally screens all nascent proteins and regulates their access to signal recognition particle (SRP) to ensure the fidelity of protein targeting to the endoplasmic reticulum (ER). However, the mechanism by which NAC prevents the mistargeting of nascent mitochondrial proteins remains unclear. Here, we identify a molecular switch in NAC that allows its central barrel domain to adopt a stabilized conformation on ribosomes exposing a mitochondrial targeting sequence (MTS). Mutations of the MTS on the nascent chain or in the NAC switch region increase NAC barrel dynamics and reduce its binding to the ribosome. This impairs the ability of NAC to prevent mistargeting by SRP and causes ER stress in human cells. Our work reveals how NAC detects nascent mitochondrial proteins early in translation and prevents their promiscuous access to SRP, elucidating the structural basis that underlies this role and providing mechanistic insights into protein targeting fidelity with broader implications for cellular proteostasis.
    DOI:  https://doi.org/10.1038/s41467-026-71061-3
  18. J Cell Biol. 2026 Apr 06. pii: e202603036. [Epub ahead of print]225(4):
    How strong is a mitochondrial targeting signal?
    Carlotta Peselj, F-Nora Vögtle.
      In this issue, Yan et al. show that mitochondrial targeting signals (presequences) vary widely in import strength. Using the quantitative MitoLuc and PotLuc assays, they dissect multiple parameters of protein import and reveal how presequence features influence mitochondrial targeting efficiency and stress sensitivity.
    DOI:  https://doi.org/10.1083/jcb.202603036
  19. Cell Metab. 2026 Mar 24. pii: S1550-4131(26)00093-8. [Epub ahead of print]
    Mitochondrial lactate venting limits oxidative stress.
    Daniela Rauseo, Yasna Contreras-Baeza, Mildreth Salazar, Abigail J Galarza, Sebastián Holtheuer-Gallardo, Hugo Faurand, Natali Cárcamo-Lemus, Raibel Suárez, Joel L Asenjo, Alexandra von Faber-Castell, Franco Silva, Valentina Mora-González, Jan Dernic, Luca Ravotto, Matthias T Wyss, Felipe Baeza-Lehnert, Iván Ruminot, Carlos Alvarez-Navarro, Alejandro San Martín, Bruno Weber, Pamela Y Sandoval, L Felipe Barros.
      Lactate has been proposed to enter mitochondria and fuel respiration, but this "intracellular lactate shuttle" remains controversial. Using genetically encoded lactate and redox sensors in cultured cells and neurons in vivo, we identify a dynamic lactate pool within the mitochondrial matrix that tracks extracellular and blood lactate and promotes lactylation of mitochondrial proteins. Lactate crosses the inner mitochondrial membrane through a saturable pathway that is partly sensitive to pharmacologic and genetic inhibition of the mitochondrial pyruvate carrier (MPC). Despite transport and matrix lactate dehydrogenase activity, lactate does not measurably energize the electron transport chain under the conditions tested. Instead, energized mitochondria can produce lactate from pyruvate, a response enhanced by hypoxia. Blocking MPC causes matrix lactate and H₂O₂ accumulation, revealing a rapid lactate-based "vent" that modulates matrix energy and reactive oxygen species.
    Keywords:  genetically encoded fluorescent indicator; hypoxia; lactate; lactate dehydrogenase; membrane transport; metabolism; mitochondrial pyruvate carrier; monocarboxylate transporter; pyruvate; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.020
  20. Contact (Thousand Oaks). 2026 Jan-Dec;9:9 25152564261428840
    mtDNA-Depleted Mitochondria Form Sites of Contact with the Nucleus and Alter the Cellular Epigenome.
    Richard Boulton-McDonald, Eva Sidlauskaite, Jiri Neuzil, Michelangelo Campanella.
      Mitochondrial sites of contact with the nucleus, hereafter referred to as Nucleus-Associated Mitochondria (NAM), are specialised domains that enable communication, influencing cellular function. Previous studies have shown that these contacts can be stabilised by protein scaffolds acting as tethers to promote retrograde signalling, particularly during apoptotic stress. This is facilitated via the mitochondrial protein TSPO. In this study, we have investigated a mitochondrial DNA (mtDNA)-depleted (ρ0) 4T1 cell model to further inform the role of NAM in retrograde communication between corrupted mitochondria and the nucleus. Our data report an increase in NAM frequency in mtDNA-depleted cells compared to the mtDNA-retaining parental 4T1 line. Using a combination of cellular assays, transmission electron microscopy, and epigenetic profiling, we have found that under conditions of mtDNA loss, mitochondria become enriched in TSPO, evading mitophagic clearance and are prone to forming stable contacts with the nucleus. This coincides with an extreme reduction in DNA methylation, as well as histone modifications associated with chromatin decondensation.
    Keywords:  NAM; TSPO; VDAC; contact sites; mitochondria
    DOI:  https://doi.org/10.1177/25152564261428840
  21. Cell Death Dis. 2026 Mar 23.
    Dysfunction of α2δ4 leads to photoreceptor degeneration through disrupted synaptic mitochondria and calcium crosstalk.
    Choice I Amieghemen, Trong Thuan Ung, Gillian N Huskin, James A Mobley, Melissa F Chimento, Mai Nguyen, James Fortenberry, Timothy W Kraft, Steven J Pittler, Yuchen Wang.
      Synaptic deficit has emerged as a key early hallmark for neurodegeneration in the visual pathway. The molecular pathway connecting local synaptic deficit with global cell dysfunction and death remains unclear. We have previously shown that α2δ4, an auxiliary subunit of the voltage-gated calcium channel, is targeted to photoreceptor synapses and required for their formation and function. Notably, α2δ4 mutations have been identified in patients with retinal dystrophy. However, how loss of synaptic α2δ4 leads to overall photoreceptor degeneration remains unknown. Here, we showed that α2δ4 loss in mice leads to a late onset photoreceptor degeneration around 7 months. Consistent with clinical observation, the progression of degeneration is minimal until 17 months, as supported by ERG, OCT imaging and histology. We found that Cav1.4 KO mice, where the calcium channel is missing, display an earlier degeneration onset than α2δ4 KO mice, where calcium channel is partially preserved. Proteomic studies revealed that tricarboxylic acid (TCA) cycle is significantly downregulated in the young α2δ4 KO retinas prior to degeneration. Transmission electron microscopy study demonstrated significant reduction in mitochondrial size and number in photoreceptor synaptic terminals, but not in the inner segment (IS), of the young α2δ4 KO retinas. Consistently, immunohistochemistry (IHC) studies showed significant reduction of mitochondrial proteins in the outer plexiform layer (OPL). IHC studies on ER and mitochondrial proteins revealed that ryanodine receptor (RyR2) and mitochondrial calcium uniporter (MCU) are downregulated in the OPL, but not in the IS. Together, our results propose a model where α2δ4 dysfunction impairs Cav1.4 channel activity, leading to disrupted calcium crosstalk among the plasma membrane, ER, and mitochondria, as well as mitochondrial damage and metabolic deficits. Importantly, our study underscores the critical role of synaptic calcium homeostasis and mitochondrial integrity in connecting the early stages of synaptic dysfunction with the later stages of cell degeneration.
    DOI:  https://doi.org/10.1038/s41419-026-08587-3
  22. Neurol Genet. 2026 Apr;12(2): e200368
    Expanding the AFG3L2 Spectrum: A Link to Axonal Neuropathy.
    Alessandra Rocco, Christian Laurini, Yuri Matteo Falzone, Silvia Calzavara, Ubaldo Del Carro, Stefano Carlo Previtali, Francesca Maltecca.
       Objectives: The AFG3L2 gene encodes a mitochondrial AAA-protease involved in inner mitochondrial membrane (IMM) proteostasis. Heterozygous variants in the AFG3L2 proteolytic domain cause Spinocerebellar Ataxia type 28, heterozygous variants in the AFG3L2 ATPase domain cause Optic Atrophy type 12, while biallelic variants lead to recessive Spastic Ataxia type 5. In this study, we aimed to investigate the link between AFG3L2 haploinsufficiency and Charcot-Marie-Tooth (CMT) phenotypes.
    Methods: We performed clinical evaluation, genetic analyses, electrophysiology, and functional studies in 1 patient's fibroblasts.
    Results: In this study, we report a patient presenting with progressive symmetric distal muscle atrophy, weakness, pes cavus, and sensory deficits at lower limbs, in the absence of cerebellar or pyramidal signs. Electrophysiologic studies confirmed axonal sensorimotor neuropathy. After excluding common CMT-related genes, clinical exome sequencing revealed a heterozygous truncating variant in AFG3L2 [NM_006793.3:c.121C > T; p.(Arg41*)]. In patient's fibroblasts, we observed ∼50% reduction in AFG3L2 protein levels, which is sufficient to hyperactivate the stress-sensitive IMM protease OMA1. Consequently, we detected increased OPA1 processing, mitochondrial shortening, and activation of the integrated stress response.
    Discussion: These findings suggest that AFG3L2 haploinsufficiency can underlie axonal CMT, expanding the clinical spectrum of AFG3L2-related diseases and emphasizing its potential inclusion in CMT diagnostic panels.
    DOI:  https://doi.org/10.1212/NXG.0000000000200368
  23. Exp Cell Res. 2026 Mar 20. pii: S0014-4827(26)00091-1. [Epub ahead of print] 114974
    Age-Dependent Decline in Plasmalogen Biosynthesis Impairs Stress-Induced Mitochondrial Fission in Drosophila.
    Ankur Kumar, Anurag Das, Tracey Stewart, Fong-Fu Hsu, Ping Kang, Hua Bai.
      Mitochondrial dynamics, maintained by balanced fission and fusion, are essential for organelle quality control and cellular homeostasis, yet this process becomes disrupted during aging. The upstream cues underlying age-associated fission defects remain poorly defined. Here, using Drosophila oenocytes (hepatocyte-like cells), we show that aging drives progressive mitochondrial enlargement and morphological abnormalities. Live-cell imaging analysis demonstrated that young oenocytes rapidly undergo mitochondrial fission in response to paraquat-induced oxidative stress, whereas aged oenocytes fail to fragment, resulting in persistently enlarged mitochondria. This age-dependent fission defect correlates with a marked decline in mitochondrial plasmalogen levels, a class of ether phospholipids enriched in mitochondrial membranes. In addition, genetic disruption of plasmalogen biosynthesis using a hypomorphic mutation in the plasmanylethanolamine desaturase Kua (TMEM189) recapitulated the aging phenotype. These findings establish that an age-dependent decline in plasmalogen biosynthesis impairs mitochondrial fission, leading to persistent mitochondrial enlargement. Thus, loss of plasmalogen-dependent membrane dynamics represents a novel mechanism driving mitochondrial dysfunction during aging in metabolic tissues.
    Keywords:  Aging; Drosophila oenocytes; Drp1; Mitochondrial fission; Plasmalogens
    DOI:  https://doi.org/10.1016/j.yexcr.2026.114974
  24. bioRxiv. 2026 Mar 17. pii: 2026.03.16.712192. [Epub ahead of print]
    Using image classifiers to predict CMT2A disease-relevant mitochondrial motility phenotypes in iPSC motor neurons.
    Leo Epstein, Adam C Weiner, Bria L Macklin, Kaitlin R Kelly, Bruce R Conklin, Barbara E Engelhardt.
      Charcot-Marie-Tooth disease type 2A (CMT2A) is a genetic disease characterized by autosomal dominant MFN2 mutations and dysregulated mitochondrial trafficking. While there is currently no FDA-approved CMT2A therapy, the recent development of iPSC motor neuron model systems, high-throughput imaging platforms, and CRISPR-based gene editing technologies holds promise for screening new therapies at scale in vitro . A critical roadblock for therapeutic screening is the development of scalable and robust computational methods to assess the mitochondrial trafficking phenotypes, healthy or diseased, of each iPSC motor neuron sample. To address this gap, we developed a vision transformer (ViT) based classification framework that predicts disease phenotypes using kymographs, an image transformation that captures particle movement along a prespecified path, such as mitochondrial movement along axons. We show that our classification approach more accurately discriminates healthy MFN2 wild-type (WT) from diseased MFN2 R364W-mutant (R364W) iPSCs than alternative summary statistics, such as mitochondrial speed and fraction of stationary mitochondria that are directly extracted from kymographs. Furthermore, we show that our model maintains high accuracy when deployed on a biological replicate holdout dataset. An analysis of ViT patch embeddings of the kymographs shows that mitochondria with highly variable sizes and many intersection events most strongly associate with R364W diseased kymographs. The computational approach demonstrated in this paper has broad applicability for future high-throughput screens where organelle trafficking along axons plays a key role in disease pathogenesis.
    DOI:  https://doi.org/10.64898/2026.03.16.712192
  25. Int J Mol Sci. 2026 Mar 23. pii: 2890. [Epub ahead of print]27(6):
    Mitochondrial DNA Modification in Assisted Reproduction: Concept to Practice-A Narrative Review.
    Mariam Mehwish Mohsin, Misbah Azher, Fatima Asghar, Hiba Habeebu Rahiman, Rajani Dube, Subhranshu Sekhar Kar, Shadha Nasser Mohammed Bahutair, Bellary Kuruba Manjunatha Goud, Swayam Siddha Kar.
      Mitochondria play a fundamental role in human reproduction by supplying the energy required for key early reproductive processes. As mitochondrial Deoxyribonucleic acid (mtDNA) is maternally inherited, pathogenic mutations can lead to multisystem disorders that are transmitted to offspring. Mitochondrial replacement therapy (MRT) has emerged as a promising assisted reproductive approach to prevent the transmission of pathogenic mtDNA by replacing defective mitochondria with healthy donor mitochondria. There have been recent reports of successful MRT in humans. However, MRT remains a relatively new procedure and needs further experiments to establish its long-term safety and effectiveness. Overall, mitochondrial replacement therapy holds significant promise in helping families build healthier futures. This review explores the evolution of mitochondrial DNA modification in reproductive cells and addresses the associated ethical considerations, including acceptable clinical indications, reproductive choices, and long-term considerations for affected children.
    Keywords:  DNA modification; assisted reproductive technique; mitochondria; mitochondrial diseases; mitochondrial replacement therapy
    DOI:  https://doi.org/10.3390/ijms27062890
  26. Microbiology (Reading). 2026 Mar;172(3):
    Transplantation of Saccharomyces cerevisiae Rmd9p peptide into mammalian mitochondrial IF2 substitutes for the IF1 function in Escherichia coli.
    Jitendra Singh, Amit Kumar Sahu, Umesh Varshney.
      Mitochondrial translation machinery exhibits similarities with the bacterial translation apparatus. Of the three bacterial translation initiation factors (IF1, IF2 and IF3), two (IF2 and IF3) have homologues in mitochondria (mtIF2 and mtIF3). A high conservation of decoding nucleotides in the ribosomal A-site suggests relevance of IF1-like proteins in mitochondria. The mitochondrial translation machineries have evolved with different solutions for the IF1 function. However, in Saccharomyces cerevisiae, the identity of such a protein remains unknown. Here, based on sequence alignment with human mtIF2, we deduced that Rmd9p may contribute to an IF1-like function in S. cerevisiae. Our genetic analyses show that Rmd9p is required for mitochondrial translation. In addition, we show that a sequence from Rmd9p, pivotal for its mitochondrial function, when inserted into mtIF2, substitutes for both the IF2 and IF1 functions in an established model of Escherichia coli. Interestingly, while the mutations at the critical residues in the Rmd9p peptide compromise the IF1 function, the mutant peptide is still able to support E. coli growth, suggesting that the structure (rather than the precise sequence) of the IF1-like insert domain in mitochondrial IF2 plays a major role in the recognition of the decoding nucleotides in the ribosomal A-site.
    Keywords:   mitochondrial IF2; translation initiation factors; IF1; Rmd9p
    DOI:  https://doi.org/10.1099/mic.0.001689
  27. bioRxiv. 2026 Mar 04. pii: 2026.03.03.709381. [Epub ahead of print]
    Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.
    Sadia Ahmed, Namratha Javvaji, Katherine L Hammond, Kevin M Casin, John W Elrod, Paul M Holloway, Yvonne Couch, Jillian N Simon.
      Mitochondrial Ca 2+ uptake governs metabolism and cell fate, yet how signals from other organelles shape this remains incompletely defined. Although lysosomes are relatively small Ca 2+ stores, their strategic positioning at organelle contact sites suggests they may amplify Ca 2+ transfer within nanodomains. Here, we show that activation of the lysosomal Two-pore channel 2 (TPC2) initiates rapid mitochondrial Ca 2+ uptake through an endoplasmic reticulum-dependent relay requiring IP₃ receptors and the mitochondrial calcium uniporter channel. The extent of mitochondrial Ca 2+ accumulation scales with TPC2 activity without affecting global Ca 2+ responses, identifying TPC2 as a specific amplifier of lysosome-mitochondria Ca 2+ exchange. Moderate TPC2 activation transiently enhances oxidative phosphorylation, whereas sustained enhancement increases susceptibility to Ca 2+ -induced mitochondrial permeability transition. In stroke models, hyperactivation of TPC2 exacerbates injury, while acute pharmacological inhibition at reperfusion confers neuroprotection, including in human iPSC-derived neurons. Thus, lysosomal Ca 2+ release acts as an upstream regulator of mitochondrial energetic resilience under stress.
    DOI:  https://doi.org/10.64898/2026.03.03.709381
  28. Genes (Basel). 2026 Mar 18. pii: 338. [Epub ahead of print]17(3):
    MitoGEx: An Integrated Platform for Streamlined Human Mitochondrial Genome Analysis.
    Kongpop Jeenkeawpiam, Pemikar Srifa, Natakorn Nokchan, Natthapon Khongcharoen, Anas Binkasem, Surasak Sangkhathat.
      Background/Objectives: Mitochondrial DNA (mtDNA) is an important resource for understanding human ancestry, population diversity, and the molecular mechanisms of mitochondrial diseases. However, analyzing mtDNA thoroughly often requires advanced bioinformatics skills and command-line knowledge. To address this challenge, we created Mitochondrial Genome Explorer (MitoGEx), a user-friendly computational pipeline optimized for human mtDNA analysis that combines multiple mtDNA analysis modules within a single graphical user interface. Methods: The platform simplifies key analytical steps, such as quality control, sequence alignment, alignment quality assessment, variant detection, haplogroup classification, and phylogenetic reconstruction. Users can choose between Quick and Advanced modes, which offer default settings or customizable options based on their analysis needs. To demonstrate its effectiveness, we analyzed 15 whole-exome sequencing (WES) samples from Songklanagarind Hospital using MitoGEx. Results: The sequencing data were of high quality, with over 92 percent of bases scoring above a Phred score and consistent GC content across all samples. Variant detection using the GATK mitochondrial pipeline and annotation with ANNOVAR and the MitImpact database revealed multiple high-confidence variants. Haplogroup classification with Haplogrep 3 and phylogenetic analysis with IQ-TREE 2 confirmed diverse maternal lineages within the cohort. Conclusions: Taken together, MitoGEx facilitates mitochondrial genome analysis in a reproducible and accessible manner for both research and clinical bioinformatics applications. The analytical results produced by MitoGEx are concordant with those obtained using standalone bioinformatic tools, demonstrating analytical correctness. By integrating all analysis steps into a single automated workflow, MitoGEx reduces execution time and limits human error inherent to manual, multi-step pipelines.
    Keywords:  MitoGEx; bioinformatics; computational tools; mitochondrial DNA; mitochondrial diseases; mitochondrial genome analysis
    DOI:  https://doi.org/10.3390/genes17030338
  29. bioRxiv. 2026 Mar 18. pii: 2026.03.18.712693. [Epub ahead of print]
    UFMylation of Pyruvate Dehydrogenase Regulates Mitochondrial Metabolism.
    Phong T Nguyen, Zheng Wu, Dohun Kim, Tamaratare Ogu, Siyu Yin, Varun Sondhi, Feng Cai, Trevor S Tippetts, Annie Jen, Evgenia Shishkova, Ling Cai, Dennis Dumesnil, Margaret Cervantes, Hongli Chen, Prashant Mishra, Joshua J Coon, Gerta Hoxhaj, Min Ni, Ralph J DeBerardinis.
      The ubiquitin-fold modifier 1 (UFM1) post-translational modification (PTM), or UFMylation, regulates protein homeostasis and is essential for human development. Yet the roles of the de-UFMylase, UFM1-specific peptidase 2 (UFSP2), which removes UFM1 from UFMylated proteins, remain poorly characterized. Here, we demonstrate that UFMylation and UFSP2 regulate mitochondrial metabolism. Quantitative proteomics in UFSP2-deficient cells revealed the accumulation of many proteins previously unknown to be impacted by UFMylation. These included components of the mitochondrial ribosome, electron transport chain (ETC), and pyruvate dehydrogenase (PDH) complex. Functional analyses demonstrated that excessive UFMylation in UFSP2-deficient cells increases mitochondrial respiration, glucose oxidation in the tricarboxylic acid (TCA) cycle, and PDH enzymatic activity. We identified dihydrolipoamide S-acetyltransferase (DLAT), the E2 component of PDH, as a direct UFMylation substrate, with lysine 118 (K118) as the primary conjugation site. Mutating K118 to arginine (K118R) abolished DLAT UFMylation and reduced pyruvate oxidation, identifying this modification as an activator of PDH. These findings reveal a UFMylation-based regulatory mechanism that controls mitochondrial function by inducing utilization of pyruvate as a TCA cycle fuel.
    DOI:  https://doi.org/10.64898/2026.03.18.712693
  30. Sci Adv. 2026 Mar 27. 12(13): eaeb1174
    A small-molecule stabilizer of the calpastatin-calpain-2 complex restores mitochondrial function and mitigates neurodegeneration.
    Di Hu, Xiaoyan Sun, Yutong Shang, Kathleen Lundberg, Drew J Adams, Xin Qi.
      Mitochondrial dysfunction and dysregulated proteolysis drive Huntington's disease (HD), tauopathy, and related neurodegenerative disorders. Calpain-2, a Ca2+-activated protease restrained by calpastatin (CAST), is pathologically overactivated, yet no therapies directly target this axis. We identify A36, a brain-penetrant small molecule derived from CHIR99021 that selectively stabilizes the CAST-calpain-2 complex without inhibiting GSK3. A36 acts as a protein-protein interaction stabilizer, enhancing CAST-calpain-2 binding, preventing CAST degradation, and thereby limiting calpain-2 activation and mitochondrial damage. In patients with HD induced pluripotent stem cell-derived neurons and mutant mouse striatal neurons, A36 normalized mitochondrial morphology and membrane potential, reduced oxidative stress, and improved survival. In vivo, A36 displayed favorable pharmacokinetics and central nervous system exposure; treatment reduced striatal neurodegeneration, mutant huntingtin aggregation, and motor deficits in HD R6/2 mice, and lowered phosphorylated tau, neuroinflammation, and cognitive decline in tauopathy PS19 mice. These findings establish pharmacological stabilization of CAST-calpain-2 as a therapeutic strategy and position A36 as a mechanism-selective modulator with broad neurodegenerative disease potential.
    DOI:  https://doi.org/10.1126/sciadv.aeb1174
  31. Mol Genet Metab. 2026 Mar 17. pii: S1096-7192(26)00189-7. [Epub ahead of print]148(2): 109906
    Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity.
    André B P van Kuilenburg, Hanna Mandel, Tameemi Abdalla Moady, Ronen Sloma, Ayalla Fedida, René Leen, Judith Jansen-Meijer, Tamar Paperna, Vered Fleisher Sheffer, Doreen Dobritzsch, Ori Hochwald, Nicole N van der Wel, Anita E Grootemaat, Semyon Chulsky, Mika S Rootman, Ayelet Eran, Maha A Yousef, April Dinwiddie, Joshua Manor, Clara D M Van Karnebeek, Limor Kalfon, Tova Hershkovitz, Galit Tal, Tzipora C Falik Zaccai.
      Glutaminase deficiency has recently been identified as a novel inherited metabolic disorder with a broad phenotypic spectrum ranging from early-onset global developmental delay to lethal early neonatal encephalopathy. We describe three infants from two unrelated families who presented clinically with neonatal onset refractory burst-suppression epileptic encephalopathy and respiratory failure, progressing to either a persistent vegetative state or early death. One patient remains alive at the age of six years. Metabolic investigations demonstrated elevated glutamine concentrations in cerebrospinal fluid and increased serum alanine and glutamine levels, biochemical features characteristic of urea cycle disorders, while ammonia levels remained within the normal range. Notably, brain magnetic resonance imaging revealed cystic lesions resembling the neuroimaging findings typically observed in patients with urea cycle defects. Exome sequencing identified a homozygous, unreported missense variant in GLS (NM_014905.5:c.1174G > A; p.Gly392Arg) in both siblings from family 1, and a novel homozygous missense variant (NM_014905.5:c.1031 T > C; p.Leu344Pro) in the proband from family 2. Functional studies of patient fibroblasts and recombinantly expressed mutant glutaminase protein, demonstrated a complete glutaminase deficiency. In addition, patient-derived fibroblasts exhibited pronounced ultrastructural abnormalities, including nuclear dysmorphisms, lysosomal dysfunction with glycogen accumulation, ER stress, Golgi disruption, and mitochondrial fragmentation, along with altered cellular bioenergetics characterized by impaired mitochondrial respiratory function. The biochemical and clinical findings in our patients support a key role for elevated glutamine in the neuropathogenesis of both glutaminase-deficient patients and individuals with hepatic encephalopathy and/or urea cycle defects.
    Keywords:  Encephalopathy; GLS; Glutaminase deficiency; Glutamine; Hyperammonemia
    DOI:  https://doi.org/10.1016/j.ymgme.2026.109906
  32. Front Cell Dev Biol. 2026 ;14 1761278
    Sirt1 coordinates the mitochondrial UPR and myocellular proteostasis to preserve muscle integrity during muscle atrophy in zebrafish.
    Qing Chen, Yu-Lun Chang, Miao-Wen Hung, Po-Lin Lee, Chen Hsin, Yi-Fan Lin.
       Introduction: The decline of mitochondrial homeostasis and proteostasis, the two key cell quality control mechanisms, is the hallmark of aging and age-related diseases. One of the most notable examples is the age-related progressive loss of muscle mass, quality, and strength --a condition known as sarcopenia. In atrophic muscle, mitochondrial dysfunction and proteostasis impairment frequently occur together, indicating a potential association between the decline of mitochondrial homeostasis and proteostasis. However, the mechanism by which these two modes of cell quality control are coordinated remains poorly understood.
    Methods: We employed dexamethasone-induced muscle atrophy models in both larval and adult zebrafish to investigate the role of cell stress responses in muscle maintenance. Mitochondrial stress was assessed by measuring the mitochondrial unfolded protein response (UPRmt) activity using qRT-PCR and reporter analyses. Proteostasis impairment was evaluated by detecting insoluble polyubiquitinated protein aggregates via Western blotting. Muscle integrity was examined histologically in larval and adult tissues. We performed these assays in sirt1 loss of function conditions (genetic mutation and pharmacological inhibition). Furthermore, to elucidate the mechanism by which Sirt1 regulates proteostasis and muscle preservation, we inhibited the mitochondrial fatty acid oxidation (mFAO) using etomoxir.
    Results: Inhibition of Sirt1 markedly exacerbated muscle deterioration and proteostasis impairment under dexamethasone-induced muscle atrophy in zebrafish. Mechanistically, Sirt1 is required for activation of the UPRmt, which in turn promotes expression of the mFAO gene cpt1b. Pharmacological inhibition of Cpt1 using etomoxir phenocopied the defects in muscle integrity and proteotoxic stress observed following Sirt1 inhibition. Importantly, enhancement of proteostasis via hormetic heat shock partially rescued the etomoxir-induced muscle defects.
    Discussion: We have demonstrated that muscle atrophic stress induced by dexamethasone treatment activates the UPRmt in zebrafish. The UPRmt is part of the activity of a cell stress regulator, Sirt1, to promote mitochondrial function and preserve muscle integrity during muscle atrophy. Notably, suppressing the UPRmt via Sirt1 inhibition leads to protein aggregation and the ultimate loss of muscle mass, indicating a link between mitochondrial function and proteostasis. We have further shown that mitochondrial metabolism plays a role in proteostasis regulation, as pharmacological inhibition of the mFAO exacerbates dexamethasone-induced proteotoxicity. Collectively, our findings have uncovered a previously uncharacterized regulatory mechanism linking UPRmt signaling to myocellular proteostasis, and highlight the activity of Sirt1, which coordinates these two key cell quality control mechanisms, in muscle preservation during muscle atrophy.
    Keywords:  SIRT1; UPRmt; mitochondrial dysfunction; mitochondrial homeostasis; muscle atrophy; myocellular proteostasis; proteostasis
    DOI:  https://doi.org/10.3389/fcell.2026.1761278
  33. Trends Endocrinol Metab. 2026 Mar 24. pii: S1043-2760(26)00014-7. [Epub ahead of print]
    Regulation of skeletal muscle mitochondrial fuel utilization during exercise.
    Likun Yang, Tingting Fu, Hao Yu, Yujing Yin, Zhenji Gan.
      Skeletal muscle exhibits remarkable metabolic plasticity, with mitochondria playing a central role in adapting to energy demands during exercise. These organelles form a dynamic and specialized system capable of remodeling to meet metabolic challenges. Recent studies demonstrate that exercise not only stimulates mitochondrial biogenesis but also engages finely tuned quality-control mechanisms to sustain energy efficiency and performance. A key adaptation is mitochondrial fuel flexibility, the capacity to switch between lipid and carbohydrate oxidation, which underlies endurance and metabolic health. Importantly, efficient lipid utilization, rather than low lipid content, explains why trained muscle can accumulate lipids while remaining insulin sensitive. Here, we review emerging insights into how exercise reprograms skeletal muscle mitochondria to optimize fuel use and highlight implications for metabolic disease.
    Keywords:  biogenesis; exercise; fuel utilization; mitochondria; mitochondrial quality control; skeletal muscle
    DOI:  https://doi.org/10.1016/j.tem.2026.01.014
  34. J Adv Res. 2026 Mar 20. pii: S2090-1232(26)00257-2. [Epub ahead of print]
    Intracellular mitochondrial transfer in ischemic stroke: Mechanisms and therapeutic application.
    Rong Fu, Yang Zhao, Yayi Li, Yuliang Zhang, Meidan Wang, Zhuo Wang, Ming-Sheng Zhou, Yueyang Liu.
       BACKGROUND: Current therapeutic models for ischemic stroke (IS) are shifting from a narrow focus on neuroprotection to a broader concept of cytoprotection. This new paradigm emphasizes rescuing damaged brain cells and maintaining their structural and functional integrity through organelle transfer between healthy and damaged cells. Mounting evidence have supported that intracellular mitochondrial transfer is an intrinsic response to IS, playing a critical role in mitigating neural damage. Consequently, mitochondrial transplantation from stem cell is emerging as a therapeutic avenue for IS.
    AIM OF REVIEW: This article reviews the IS-induced mitochondrial dysfunction, the modes and mechanisms of endogenous intracellular mitochondrial transfer, and recent advances in using stem cell-derived mitochondrial transplantation to treat IS.
    KEY SCIENTIFIC CONCEPTS: This review emphasizes the dual roles of mitochondrial transfer in determining neural cells fate and neurological function recovery following IS. On one hand, health cells can donate intact mitochondria to damaged cells, to revitalize them by restoring cell metabolic function. On the other hand, damaged cell may expel dysfunction mitochondria, which can be cleared by healthy neighbors or, alternatively propagate injury. We discuss the current challenges in this field and propose that enhancing healthy mitochondrial transfer or preventing damaged mitochondrial release may hold great potential for alleviating IS injury.
    Keywords:  Cell to cell communication; Ischemic stroke; Mitochondrial transfer; Preserving neuronal function; Stem cell therapy
    DOI:  https://doi.org/10.1016/j.jare.2026.03.037
  35. Blood. 2026 Mar 24. pii: blood.2025031552. [Epub ahead of print]
    Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.
    Silvia Sighinolfi, Laura Cassina, Maria Rosa Lidonnici, Stefano Beretta, Davide Stefanoni, Mariangela Storto, Christina Mayerhofer, Trine A Kristiansen, David T Scadden, Ivan Merelli, Alessandra Boletta, Annamaria Aprile, Giuliana Ferrari.
      Iron is an essential element for most cellular processes and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). Abnormal iron levels impact HSC quiescence and self-renewal, however, the mechanism by which iron overload (IO) influences HSC function is still unknown. Here, we show that intracellular IO impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring. In thalassemic mice, as a model of chronic IO, HSCs accumulate mitochondria with elevated reactive oxygen species (mtROS), low membrane potential and reduced oxidative phosphorylation (OXPHOS). Mitochondrial defects are confirmed in other two models of IO, sickle cell disease and iron-loaded wild-type mice, and in vivo iron reduction rescues HSC mitochondria. IO HSCs are highly proliferating and in presence of damaged mitochondria rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo mtROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS and mitochondrial activity in HSCs, revealing that IO shapes HSC metabolic programs.
    DOI:  https://doi.org/10.1182/blood.2025031552
  36. Cells. 2026 Mar 20. pii: 559. [Epub ahead of print]15(6):
    Mitochondrial Dynamic Proteins MiD49 and MiD51 as Novel Targets of Cardioprotection.
    Parisa Samangouei, Gustavo E Crespo-Avilan, Andrew R Hall, Sauri Hernandez-Resendiz, J Maeve Elder, Laura D Osellame, Nicole G Z Tee, Khairunnisa Katwadi, Sang-Bing Ong, Xiu-Yi Kwek, Siavash Beikoghli Kalkhoran, Niall Burke, Derek M Yellon, Derek J Hausenloy.
      Novel therapeutic strategies are required to protect the heart from acute ischaemia-reperfusion injury (IRI) and improve outcomes in patients with acute myocardial infarction (AMI). Mitochondria play a critical role in determining cardiomyocyte fate following acute IRI, with genetic and pharmacological inhibition of Drp1-mediated mitochondrial fission limiting cardiomyocyte death. We investigated the role of the mitochondrial Drp1 receptors, MiD49 and MiD51, as novel targets for cardioprotection. In cardiac cell lines subjected to simulated IRI, dual genetic knockdown of both MiD49 and MiD51 reduced cell death, inhibited mitochondrial fission, prevented mitochondrial permeability transition pore opening, and attenuated mitochondrial calcium overload compared with wild-type cells. However, individual knockdown of either MiD49 or MiD51 did not induce mitochondrial elongation or inhibit MPTP opening. Whole-body genetic ablation of MiD49 in adult mice modestly altered mitochondrial morphology but did not affect myocardial infarct size or cardiac function following AMI. Together with the in vitro protection seen with dual MiD49/51 knockdown, these findings suggest that MiD49 deficiency alone is insufficient and that coordinated inhibition of MiD49 and MiD51 may be required for cardioprotection.
    Keywords:  MiD49; MiD51; cardioprotection; ischaemia-reperfusion injury; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial permeability transition pore
    DOI:  https://doi.org/10.3390/cells15060559
  37. Nat Metab. 2026 Mar;8(3): 587-603
    PLIN5 phosphorylation orchestrates mitochondria lipid-droplet coupling to control hepatic lipid flux and steatosis.
    Sun Woo Sophie Kang, Lauryn A Brown, Colin B Miller, Katherine M Barrows, Jihye L Golino, Hanyang Liu, Constance M Cultraro, Daniel Feliciano, Mercedes B Cornelius-Muwanuzi, Kirsten Remmert, Jonathan M Hernandez, Andy D Tran, Michael Kruhlak, Alexei Lobanov, Maggie Cam, Natalie Porat-Shliom.
      Steatotic liver disease is common, yet the mechanisms by which hepatocytes cope with surges in dietary fatty acids remain unclear. Here we use single-cell tissue imaging (scPhenomics) and spatial proteomics to map lipid handling across dietary states. Fasting remodeled mitochondria and lipid droplets (LDs), increasing mitochondria-LD contacts, whereas contacts were infrequent in Western diet (WD)-fed male mice. Fasting also elevated perilipin-5 (PLIN5), a mediator of mitochondria-LD tethering. PLIN5 overexpression modulated contact formation in a phosphorylation-dependent manner: the S155A variant enhanced organelle contacts and LD expansion, whereas the S155E variant reduced contacts and yielded fewer, smaller LDs. Overexpression of the S155A variant in WD reduced lipotoxicity. These data reveal an adaptive organelle-interaction program that channels lipids during nutrient stress and is attenuated by an obesogenic diet. Our work establishes scPhenomics for spatially resolved cell-state analysis and identifies PLIN5 phosphorylation as a lever to tune hepatocyte lipid flux, suggesting therapeutic potential for targeting mitochondria-LD coupling.
    DOI:  https://doi.org/10.1038/s42255-026-01476-1
  38. Elife. 2026 Mar 26. pii: e103118. [Epub ahead of print]15
    Age-dependent H3K9 trimethylation by dSetdb1 impairs mitochondrial UPR leading to degeneration of olfactory neurons and loss of olfactory function in Drosophila.
    Francisco Muñoz-Carvajal, Nicole Sanhueza, Mario Sanhueza, Felipe A Court.
      Aging is characterized by a decline in essential sensory functions, including olfaction, which is crucial for environmental interaction and survival. This decline is often paralleled by the cellular accumulation of dysfunctional mitochondria, particularly detrimental in post-mitotic cells such as neurons. Mitochondrial stress triggers the mitochondrial unfolded protein response (UPRMT), a pathway that activates mitochondrial chaperones and antioxidant enzymes. Critical to the efficacy of the UPRMT is the cellular chromatin state, influenced by the methylation of lysine 9 on histone 3 (H3K9). While it has been observed that the UPRMT response can diminish with an increase in H3K9 methylation, its direct impact on age-related neurodegenerative processes, especially in the context of olfactory function, has not been clearly established. Using Drosophila, we demonstrate that an age-dependent increase in H3K9 trimethylation by the methyltransferase dSetdb1 reduces the activation capacity of the UPRMT in olfactory projection neurons leading to neurodegeneration and loss of olfactory function. Age-related neuronal degeneration was associated with morphological alterations in mitochondria and an increase in reactive oxygen species levels. Importantly, forced demethylation of H3K9 through knockdown of dSetdb1 in olfactory projection neurons restored the UPRMT activation capacity in aged flies, and suppressed age-related mitochondrial morphological abnormalities. This in turn prevented age-associated neuronal degeneration and rescued age-dependent loss of olfactory function. Our findings highlight the effect of age-related epigenetic changes on the response capacity of the UPRMT, impacting neuronal integrity and function. Moreover, they suggest a potential therapeutic role for UPRMT regulators in age-related neurodegeneration and loss of olfactory function.
    Keywords:  D. melanogaster; cell biology; neuroscience
    DOI:  https://doi.org/10.7554/eLife.103118
  39. Biomolecules. 2026 03 16. pii: 445. [Epub ahead of print]16(3):
    Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows.
    Snježana Kaštelan, Antonela Gverović Antunica, Suzana Konjevoda, Zora Tomić, Ana Sarić, Marjan Kulaš, Lorena Kulaš, Emina Kujundžić Begović, Samir Čanović, Petra Kovačević, Mira Ivanković.
      Mitochondrial reactive oxygen species (mtROS) play a dual role in retinal physiology, acting as essential redox signalling mediators under homeostatic conditions but driving oxidative damage and neurodegeneration once regulatory thresholds are exceeded. Owing to the exceptionally high energetic demands of retinal neurons and supporting cells, even subtle perturbations in mitochondrial redox balance can precipitate progressive retinal dysfunction. Increasing evidence indicates that retinal neurodegenerative diseases, including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), and inherited optic neuropathies, are characterised not by uniform oxidative stress, but by disease- and stage-specific mtROS signatures shaped by mitochondrial quality control capacity. This review synthesises current insights into the sources, regulation, and signalling functions of mtROS in the retina, with particular emphasis on threshold-dependent redox transitions, reverse electron transport, and the progressive failure of mitochondrial quality control mechanisms, including mitophagy, mitochondrial dynamics, and redox-responsive transcriptional networks. The limitations of non-selective antioxidant strategies are critically examined, highlighting why indiscriminate ROS suppression has yielded limited clinical benefit. In contrast, emerging therapeutic approaches aimed at recalibrating mitochondrial redox homeostasis, rather than abolishing physiological signalling, are discussed in the context of disease stage, metabolic state, and mitochondrial competence. By integrating redox biology with mitochondrial quality control and precision medicine concepts, this review proposes a unifying framework in which retinal neurodegeneration is governed by regulated mtROS signalling and the progressive exhaustion of mitochondrial resilience. This model defines critical therapeutic windows for mitochondria-targeted intervention and provides a framework for biomarker-guided patient stratification.
    Keywords:  mitochondria-targeted intervention; mitochondrial quality control; mitochondrial reactive oxygen species (mtROS); mitophagy; precision medicine; redox signalling; retinal ganglion cells; retinal neurodegeneration; reverse electron transport
    DOI:  https://doi.org/10.3390/biom16030445
  40. bioRxiv. 2026 Mar 05. pii: 2026.03.05.709922. [Epub ahead of print]
    Massive-scale single-nucleus multi-omics identifies novel rare noncoding drivers of Parkinson's disease.
    Global Parkinson’s Genetic Program (GP2)
      Most genetic variants contributing to complex diseases reside in the noncoding genome. While common variants uncovered by genome-wide association studies often fail to explain much of the observed heritability of these diseases, rare variants often have higher effect sizes and cumulatively explain a larger portion of heritability. However, rare variants, particularly rare noncoding variants, have remained under-characterized largely due to the difficulties of accurately predicting variant functionality at scale, given that each individual carries an average of ∼10,000 rare variants. Here, we generated multi-omic data from >3.3 million nuclei sampled from five brain regions across a cohort of 80 individuals with Parkinson's disease (PD) and 21 neurologically normal control individuals with matched 30x whole-genome sequencing. We use this data to identify cell type-specific features of PD, map cell type-specific chromatin accessibility and expression quantitative trait loci, and train machine learning models to predict the effect of variants on gene regulation. We identify rare noncoding variants statistically associated with sporadic PD and extend our approaches to predict drivers of familial PD of unknown genetic origin. Our results underscore the significance of rare noncoding variants in complex diseases and provide a roadmap for applying similar approaches in other disease systems.
    DOI:  https://doi.org/10.64898/2026.03.05.709922
  41. Elife. 2026 Mar 25. pii: RP108862. [Epub ahead of print]14
    UV irradiation alters TFAM binding specificity and compaction of DNA.
    Dillon E King, Emily E Beard, Matthew J Satusky, Alex George, Ian Ryde, Caitlin Johnson, Emma L Dolan, Yuning Zhang, Wei Zhu, Hunter Wilkins, Evan Corden, Susan K Murphy, Dorothy A Erie, Raluca Gordân, Joel Meyer.
      Mitochondria lack nucleotide excision repair; however, mitochondrial DNA (mtDNA) is resistant to mutation accumulation following DNA damage. These observations suggest additional damage sensing or protection mechanisms. Transcription Factor A, Mitochondrial (TFAM) compacts mtDNA into nucleoids and binds differentially to certain forms of DNA damage. As such, TFAM has emerged as a candidate for protecting mtDNA or sensing damage. To examine the possibilities that TFAM might protect DNA from damage or act as a damage sensing protein for irreparable forms of mtDNA damage, we used live-cell imaging and HeLa cell-based assays, atomic force microscopy (AFM), and high-throughput protein-DNA binding assays to characterize the binding properties of human TFAM to ultraviolet-C (UVC) irradiated DNA and the cellular consequences of UVC irradiation. Our cell data show increased TFAM mRNA after exposure and suggest an increase in mtDNA degradation without a loss in mitochondrial membrane potential that might trigger mitophagy. Our protein-DNA binding assays indicate a reduction in sequence specificity of TFAM following UVC irradiation and a redistribution of TFAM binding throughout the mitochondrial genome. Our AFM data show increased compaction of DNA by TFAM in the presence of damage. Despite the TFAM-mediated compaction of mtDNA in vitro, we do not observe any protective effect of increased TFAM protein on DNA damage formation in cells or in vitro. Increased TFAM protein did not alter levels of mtDNA damage over time after UVC exposure in vivo, but knockdown of TFAM did alter mtDNA damage levels in HeLa cells both at baseline and after UVC exposure. Taken together, these studies indicate that UVC-induced DNA damage alters TFAM binding and promotes compaction by TFAM in vitro. We hypothesize that TFAM may act as a damage sensing protein in vivo, sequestering damaged genomes to prevent mutagenesis by facilitating removal or suppression of replication.
    Keywords:  DNA damage; TFAM; chromosomes; gene expression; mtDNA; none
    DOI:  https://doi.org/10.7554/eLife.108862
  42. Cell Commun Signal. 2026 Mar 27.
    Mitochondrial interplay with membrane organelles in health and disease.
    Shao-Hong Liu, Yong Wang, Chao Tong, Xiao-Man Liu.
      
    Keywords:  ERMCS; Endoplasmic reticulum (ER); Endosomes; Lipid droplets; Lysosomes; Mitochondria
    DOI:  https://doi.org/10.1186/s12964-026-02843-x
  43. Trends Mol Med. 2026 Mar 24. pii: S1471-4914(26)00033-X. [Epub ahead of print]
    Cancer mtDNA mutations: metabolic plasticity and therapeutic promise?
    Ersong Shang, Omar Aftab, Abbienaya Dayanamby, Laura C Greaves.
      Mitochondria, once viewed mainly as cellular powerhouses, are now recognised as key regulators of cancer metabolism, redox balance, and immune interactions. While early models emphasised a switch to aerobic glycolysis, many tumours exhibit metabolic plasticity and retain oxidative phosphorylation capacity. Mitochondrial DNA (mtDNA) mutations are common across cancers, yet their roles in carcinogenesis and therapy response remain unclear. Emerging base-editing technologies now enable modelling of these mutations, allowing the exploration of their impact on tumourigenesis, which may differ depending on mutation type, heteroplasmy, and tissue origin. mtDNA alterations also shape immune responses within the tumour microenvironment and therefore may influence treatment sensitivity. This review integrates recent advances on mtDNA's role in cancer biology and explores therapeutic opportunities for targeting mitochondrial metabolism.
    Keywords:  DNA, mitochondrial; genes, neoplasm; neoplasms; oxidative phosphorylation; tumour microenvironment
    DOI:  https://doi.org/10.1016/j.molmed.2026.02.003
  44. Mol Genet Genomics. 2026 Mar 21. pii: 78. [Epub ahead of print]301(1):
    A multistage cost-effective strategy for the molecular diagnosis of unexplained vision loss patients: practice in inherited ocular fundus disease.
    Junyi Wang, Jia Li, Limeng Dai, Xintong Zhu, Yanling Long, Xiaohong Meng, Shiying Li, Xiaoyong Huang, Hong Guo.
      Inherited ocular fundus diseases are the most common causes of blindness with high heterogeneity. We established a tiered strategy for the molecular diagnosis of unexplained vision loss patients. Patients were screened with ophthalmological examinations followed by a tiered genetic diagnosis, including mitochondrial genome sequencing, multigene panel and whole exome sequencing. A total of 146 individuals with unexplained vision loss were enrolled, including 103 individuals with abnormal pattern visual evoked potential and 43 individuals with abnormal optic coherence tomography. Based on our tiered strategy for molecular diagnosis, 33 cases were diagnosed with Leber's hereditary optic neuropathy, with common or very rare mitochondrial variants. Moreover, 22 cases with monogenic disorders were diagnosed with 15 novel and 16 reported mutations. Our study reveals the genetic etiology of unexplained vision loss and expands the genetic variation spectrum. The tiered cost-effective strategy for molecular diagnosis improves genetic detection rates and is expected to be applied to future clinical practice.
    Keywords:  Inherited ocular fundus disease; Macular disease; Molecular diagnosis; Optic neuropathy; Retinopathy
    DOI:  https://doi.org/10.1007/s00438-025-02321-y
  45. Cells. 2026 Mar 10. pii: 489. [Epub ahead of print]15(6):
    CRISPR and Beyond: Genome-Editing Strategies in Retinal Stem Cell Research.
    Małgorzata Woronkowicz, Maya Natasha Thomas, Sarah Jacqueline Saram, Amanda-Jayne F Carr, Ana Alonso-Carriazo Fernandez, Zaynab Butt, Piotr Skopiński, Conor M Ramsden.
      Genome editing has emerged as a transformative approach for understanding and treating retinal degenerative diseases. Combining this technology with pluripotent stem cells provides an ideal platform for modeling human development and disease, and investigating emerging therapeutic strategies ultimately aimed towards in vivo correction. This approach enables both functional studies to understand retinal degeneration and the early development of targeted therapies for inherited disease. This review offers a comprehensive overview of genome-editing techniques and the ability to create new clinically relevant models to understand human disease in retinal research, focusing on the use of the CRISPR-Cas9 system in induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), as well as highlighting recent advancements in base and prime editing. Gene editing in various retinal diseases is discussed in context of studies focusing on disease modeling or developing therapeutic strategies. Continued refinement of these techniques will be essential for advancing translational applications in retinal disease treatment.
    Keywords:  CRISPR-Cas9; ESCs; TALENs; ZFNs; base editing; iPSCs; prime editing; retina; stem cells
    DOI:  https://doi.org/10.3390/cells15060489
  46. Neurol Sci. 2026 Mar 26. pii: 372. [Epub ahead of print]47(4):
    TSPO-PET highlights an atypical mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype.
    Yang Zeng, Yingxue Yang, Wei Wang, Qing Peng, Yuye Bai, Xiaoling Yu, Shen Yang, Liankun Ren.
      
    Keywords:  MELAS; Mitochondrial gene; Neuroinflammation; TSPO-PET; m.10158T>C
    DOI:  https://doi.org/10.1007/s10072-026-08998-2
  47. Life (Basel). 2026 Mar 16. pii: 478. [Epub ahead of print]16(3):
    Structural Analysis of Human LonP1 Protease Bound with the Native Substrate.
    Ming Li, Hongwei Liu, Shengchun Zhang, Qijun Gao, Shanshan Li, Junfeng Wang, Kaiming Zhang.
      The human mitochondrial Lon protease (LonP1) is a central regulator of mitochondrial DNA copy number and metabolic reprogramming. However, the structural basis for how LonP1 recognizes native physiological substrates remains elusive. Here, we present the high-resolution cryo-EM structure of the human LonP1 hexamer actively engaging its native substrate, TFAM. The reconstruction reveals a distinct bipartite search-and-shred mechanism. Unlike its bacterial homologs, the human N-terminal domain (NTD) adopts a compact architecture acting as a selective vestibule to recruit and initially unfold the substrate tertiary structure. Subsequently, the polypeptide is threaded through the central channel via a hand-over-hand mechanism driven by a spiral array of aromatic pore-loops. This structural framework provides a mechanistic rationale for the spatial segregation of LonP1 and offers a template for targeting mitochondrial proteostasis in human diseases.
    Keywords:  Lon protease; cryo-EM; native substrate
    DOI:  https://doi.org/10.3390/life16030478
  48. Nat Commun. 2026 Mar 24.
    Mitochondrial metabolic imbalance drives diploidization in mouse haploid embryonic stem cells via NADPH overload.
    Giulio Di Minin, Anna B Rüegg, Kevin Halter, Tobias Fuhrer, Tatjana Kleele, Nicola Zamboni, Anton Wutz.
      A hallmark of mammals is a diploid genome. Despite constraints from dosage compensation and imprinting, haploid embryonic stem cells can be established. However, rapid diploidization is observed in such cultures from mice, rats, and humans, limiting their use and indicating counterselection of a haploid genome. Here, we use metabolic profiling to discover that diploidization is triggered by an imbalance that arises from a smaller cytoplasmic volume and increased mitochondrial density. Reduced respiration causes a change in redox potential, leading to increased NADPH. Conversely, we demonstrate that NADPH oxidation in the mitochondria is sufficient to stabilize the haploid genome. We further show that the redox change leads to reduced AURORA kinase activation on chromosomes, connecting metabolic state to mitotic regulation. Our data, therefore, identify a mitochondrial metabolic imbalance as the root cause of diploidization and connect redox dysregulation to karyotypic instability.
    DOI:  https://doi.org/10.1038/s41467-026-70939-6
  49. iScience. 2026 Apr 17. 29(4): 115146
    Functional and metabolomic analyses of brown adipose tissue during cold-deacclimation reveal rapid N-acetylated amino acid adaptations.
    Chantal A Pileggi, Ella McIlroy, Lauren M K Hamilton, Nidhi Kuksal, Luke S Kennedy, Valeria Vasilyeva, Michel N Kanaan, Ziyad El Hankouri, Yan Burelle, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.
      Non-shivering thermogenesis (NST) in brown adipose tissue (BAT) is rapidly activated in the cold but inactive at warm ambient temperatures. To elucidate the metabolic remodeling in BAT during recovery from cold exposure, mice were acclimated to 4°C for 7 days, then deacclimated at thermoneutrality (30°C) for 3-48 h. Cold-acclimated mice demonstrated high metabolic rates and food intake, which decreased immediately by ∼40% upon deacclimation. Uncoupled respiration decreased by 24 h, corresponding with gradual declines in mitochondrial protein content and UCP1 gene expression. Decreases in BAT mitochondrial content paralleled declines in protein content by 48 h of cold deacclimation. Metabolomic profiling revealed major alterations in amino acid, TCA cycle, glutathione, and purine metabolism pathways. Marked decreases in the abundance of N-acetylated amino acids in cold deacclimated mice corresponded with increased aminoacylase 1 (Acy1) expression. Together, results highlight the coordinated structural and metabolic remodeling of BAT mitochondria during thermogenesis and deactivation.
    Keywords:  physiology
    DOI:  https://doi.org/10.1016/j.isci.2026.115146
  50. Gastroenterology. 2026 Mar 23. pii: S0016-5085(26)00255-6. [Epub ahead of print]
    A Mysterious Case of Diffuse Severe Hepatic Steatosis in a Thin Teenager.
    Xuemei Tao, Wei Jiang, Hong Tang.
      
    Keywords:  Hepatic Steatosis; Mitochondrial disease; Whole-exome sequencing
    DOI:  https://doi.org/10.1053/j.gastro.2026.02.043
  51. Bioinformatics. 2026 Mar 25. pii: btag138. [Epub ahead of print]
    NCBoost v2: a classifier for non-coding single nucleotide variants in Mendelian diseases.
    Barthélémy Caron, Antonio Rausell.
       MOTIVATION: The current diagnostic rate of rare diseases through whole-genome sequencing has stabilized at around 30% on average, highlighting the need for improved computational scores to identify pathogenic variants. In 2019, we developed NCBoost, a supervised-learning approach that mined a comprehensive set of sequence constraint features and proved particularly well suited to identifying high-effect pathogenic non-coding variants in genetic diseases. Since its first release, the substantial increase in the number of variants available for training, as well as the enhanced capacity to detect purifying selection signals from large-scale genome sequencing projects, motivated an update of NCBoost.
    RESULTS: We implemented NCBoost v2, a pathogenicity score for non-coding single-nucleotide variants, trained on the largest set of curated pathogenic variants in monogenic Mendelian diseases available to date. It leverages conservation features computed from recent large-scale genomic consortia such as Zoonomia and gnomAD, and incorporates recent splice-altering predictive scores. NCBoost v2 outperformed alternative state-of-the-art methods in a variety of scenarii, providing more consistent scores across non-coding genomic regions and fine-tuning the scoring of pathogenic splice-altering variants in Mendelian disease genes.
    AVAILABILITY: NCBoost v2 software is implemented in Python 3.10 and is freely available under the GNU General Public License Version 3 at https://doi.org/10.5281/zenodo.16029049 and https://github.com/RausellLab/NCBoost-2, together with precomputed scores for the human genome assembly GRCh38.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btag138
  52. Cell Death Dis. 2026 Mar 26.
    Moonlighting cytosolic function of ACAD9: suppression of TRAF6-mediated osteoclastogenesis and protection against osteoporosis.
    Mimi Wang, Chao Yuan, Yi Zhang, Mengmeng Peng, Yundie Liu, Ruolin Liu, Zhaode Feng, Zhiwei Yang, Hao Li, Zhongbo Liu, Ying Cheng.
      Acyl-CoA dehydrogenase-9 (ACAD9) is classically known for its role in mitochondrial fatty acid β-oxidation and complex I assembly. Here, we identify ACAD9 deficiency as a clinically relevant risk factor for fragility fractures and reveal a previously unrecognized cytosolic function of ACAD9 in suppressing osteoclast differentiation, thereby protecting against osteoporosis. Mechanistically, while preserving its canonical mitochondrial role in complex I assembly, we find that ACAD9 also facilitates the formation of respiratory chain supercomplexes. Notably, in the cytosol, ACAD9 competitively binds to TRAF6, preventing its interaction with the E2 ubiquitin-conjugating complex UBC13/UEV1A, and thereby blocking K63-linked polyubiquitination and downstream activation of the RANK/TRAF6/TAK1/NFATc1 signaling cascade. Additionally, ACAD9 promotes K48-linked polyubiquitination of TRAF6, leading to its proteasomal degradation. Osteoclast-specific Acad9 knockout mice exhibit increased osteoclast numbers and decreased bone mass. These findings uncover a novel extramitochondrial function of ACAD9 in regulating osteoclast differentiation and maturation, and offer potential therapeutic insights for targeting osteoclast hyperactivity in osteoporosis.
    DOI:  https://doi.org/10.1038/s41419-026-08626-z
  53. Genome Med. 2026 Mar 26.
    WiNGS-API: a federated genome/phenome data sharing platform enabling gene discovery and variant classification for rare diseases.
    Nishkala Sattanathan, Benjamin Huremagic, Joris Robert Vermeesch, Yves Moreau, Geert Vandeweyer.
      
    Keywords:  Clinical genomics; Federated querying; Rare diseases; Variant filtering; Variant-level data sharing
    DOI:  https://doi.org/10.1186/s13073-026-01627-9
  54. Int J Mol Sci. 2026 Mar 14. pii: 2657. [Epub ahead of print]27(6):
    Structure and Substrate Specificity of Human Short-Chain Acyl-CoA Dehydrogenase and Insights into Pathogenicity of Disease-Associated Mutations.
    Fang Bai, Xinru Li, Kaide Ju, Xijiang Pan, Ye Jin, Zhijing You, Lili Zhang, Zhaoxia Liu, Shuyang Zhang, Xiaodong Luan.
      Short-chain acyl-CoA dehydrogenase (SCAD) is a critical enzyme in mitochondrial fatty acid β-oxidation, catalyzing the initial dehydrogenation of short-chain acyl-CoAs. Mutations in the ACADS gene cause SCAD deficiency (SCADD), a disorder with remarkably heterogeneous clinical presentation. However, the molecular mechanisms underlying substrate specificity and the pathogenicity of most ACADS variants remain poorly understood. Here, we present high-resolution cryo-EM structures of human SCAD in complex with its physiological substrate butyryl-CoA (C4) and the longer substrate hexanoyl-CoA (C6). The butyryl-CoA-bound structure at 2.1 Å resolution details a pre-catalytic geometry ideal for hydride transfer, with Glu392 positioned as the catalytic base. We systematically characterized nineteen disease-associated mutations, which we classify into three functional categories: those disrupting FAD binding, those impairing substrate binding, and those compromising protein folding and stability. In addition, using the W177R mutant as a representative model, we demonstrate that folding-defective mutations provoke protein aggregation, leading to proteotoxicity, oxidative stress, and apoptosis, revealing a pathogenic mechanism beyond mere catalytic loss. In brief, our integrated findings elucidate the structural determinants of substrate specificity and catalytic mechanism in SCAD, and provide mechanistic insights into the functional impairments caused by mutations linked to SCADD.
    Keywords:  SCAD; SCADD; cryo-EM; gene mutation; mechanisms of disease
    DOI:  https://doi.org/10.3390/ijms27062657
  55. Nat Genet. 2026 Mar 25.
    Strand-seq and the future of personalized genomics.
    Vincent C T Hanlon, Peter M Lansdorp.
      Sequencing the human genome came with the promise of refined risk assessment for heritable diseases, drug responses and other applications of personalized genomics. Genome-wide association studies that linked thousands of genetic alterations to heritable disorders have partially delivered on this promise. However, many patients with rare diseases remain undiagnosed after genome sequencing, in part because conventional sequencing studies struggle to characterize and phase all genomic variation. Chromosome-length phasing, enabled by the single-cell Strand-seq technique in combination with long-read data, has done much to improve the situation. For example, new diploid assembly analyses for personal genomes allow nearly complete descriptions of genomic variation. Moreover, a new Strand-seq-based phasing method can leverage DNA methylation to assign genetic variants not just to haplotypes but to maternally or paternally inherited homologous chromosomes, representing a new frontier in personalized genomics. Here we review the principles and application of Strand-seq, a key enabler of these developments.
    DOI:  https://doi.org/10.1038/s41588-026-02548-4
  56. Biol Open. 2026 Mar 24. pii: bio.062326. [Epub ahead of print]
    An ARVC-5 Drosophila knock-in model reveals new functions of Tmem43 in lipid homeostasis.
    Kai Jürgens, Lena Menzel, Nora Klinke, Lisa Schäper, Sandra Ratnavadivel, Stefan Walter, Hendrik Milting, Heiko Meyer, Achim Paululat.
      Arrhythmogenic right ventricular cardiomyopathy type 5 is caused by the missense mutation S358L in the gene TMEM43 in humans. To date, the molecular mechanisms underlying the disease remain poorly understood. We established a CRISPR/Cas9 knock-in Drosophila model carrying the orthologous Tmem43p.S333L mutation to investigate these mechanisms in vivo. The resulting flies were viable but displayed reduced lifespan, smaller body size, lipid droplet accumulation, and mitochondrial defects. Proteomic and lipidomic profiling revealed a dosage-dependent misregulation of the energy metabolism, concomitant with reduced fatty acid synthesis and ß-oxidation rates, altered peroxisomal pathways, and changes in membrane phospholipid composition. Notably, phosphatidylethanolamine (PE) and phosphatidylinositol (PI) levels were elevated, while triacylglycerols were reduced. Ultrastructural analyses confirmed mitochondrial degradation in the muscle tissue of corresponding mutants. These findings establish Tmem43p.S333L knock-in flies as a robust in vivo model of ARVC-5, and support a role for TMEM43 in linking lipid homeostasis to mitochondrial energy metabolism and integrity. Mutation-derived impairments in these processes result in cardiomyopathy.
    Keywords:  ARVC5; Cardiomyopathy; Drosophila; ER-mitochondrial contact site; Mitochondria
    DOI:  https://doi.org/10.1242/bio.062326
  57. Ageing Res Rev. 2026 Mar 19. pii: S1568-1637(26)00098-X. [Epub ahead of print] 103106
    HADHA in Cardiovascular Disease: From Mitochondrial Dysfunction to Therapeutic Targets.
    Yichen Qi, Siyu Guo, Xinming Cai, Chen Liu, Yugang Dong, Xi Chen, Yili Chen, Wengen Zhu.
      HADHA, encoding the α-subunit of MTP, plays a pivotal role in long-chain fatty acid β-oxidation and mitochondrial energy homeostasis. HADHA dysfunction disrupts energy balance by causing toxic metabolite buildup, impairing oxidative phosphorylation, and aberrant cardiolipin remodeling. These disturbances contribute to metabolic dysfunction and the development of cardiovascular diseases. This review summarizes the structural biology, metabolic functions, and regulatory mechanism of HADHA. We further explore its role in cardiac metabolic remodeling, underscoring its involvement in various cardiovascular diseases. In addition, we discuss emerging therapeutic strategies targeting HADHA-related pathways, including molecular interventions and metabolic modulation. By integrating molecular insights with clinical applications, this review highlights HADHA as a promising target in cardiovascular precision medicine and offers new approaches for diagnosing and treating fatty acid oxidation disorders.
    Keywords:  Cardiovascular Disease; Fatty Acid Oxidation; HADHA; Mitochondrial Metabolism
    DOI:  https://doi.org/10.1016/j.arr.2026.103106
  58. medRxiv. 2026 Mar 19. pii: 2026.03.12.26347263. [Epub ahead of print]
    Multi-omics liquid biopsy identifies mitochondrial dysfunction in geographic atrophy and supports the longevity-associated metabolite α-ketoglutarate as a therapeutic strategy.
    Tsai-Chu Yeh, Gabriel Velez, Architesh Prasad, Soo Hyeon Lee, Ditte K Rasmussen, Aarushi Kumar, Madhumeeta Chadha, Mohamed Ziad Dabaja, Aneal M Singh, Steven Sanislo, Stephen Smith, Prithvi Mryuthyunjaya, Artis Montague, Alexander G Bassuk, David Almeida, Antoine Dufour, Vinit B Mahajan.
       Background: Mitochondrial dysfunction is an emerging metabolic hallmark of age-related diseases, yet tools to directly profile mitochondrial pathways and test metabolic interventions in the living human eye remain limited. Multi-omics ocular liquid biopsy enables real-time proteomic and metabolomic profiling of the intraocular microenvironment, complementing systemic biomarkers and imaging surrogates. Here, we used this approach to define mitochondrial and tricarboxylic acid (TCA) cycle dysregulation in geographic atrophy (GA) and to assess whether oral α-ketoglutarate (α-KG) supplementation can modulate mitochondrial metabolites within the eye.
    Methods: Mitochondrial and TCA cycle-related proteins were profiled in aqueous humor (AH) samples from patients with GA using DNA-aptamer-based proteomics. In a phase 0 study, a second cohort undergoing sequential cataract surgery provided paired AH samples collected at first-eye surgery and at second-eye surgery after interim α-KG supplementation. These samples underwent targeted metabolomic profiling using hydrophilic interaction liquid chromatography coupled with mass spectrometry.
    Results: In GA, 64 mitochondrial proteins were differentially expressed, including coordinated TCA-cycle deficiencies marked by reduced expression of enzymes regulating TCA entry and flux, including PDHB and DLST. In the phase 0 cohort, oral α-KG supplementation significantly increased intraocular α-KG levels and the α-KG-to-succinate ratio (P < 0.05), with coordinated shifts across TCA intermediates consistent with enhanced TCA cycle flux.
    Conclusions: AH proteomics demonstrated mitochondrial pathway depletion in GA, consistent with reduced oxidative bioenergetic capacity. AH metabolomics provided first-in-human in vivo evidence that systemic α-KG supplementation can modify intraocular metabolites and may enhance intraocular energy metabolism. These findings support ocular liquid biopsy as a precision-health framework for per-patient biomarker-guided metabolic trials in GA.
    Plain Language Summary: Geographic atrophy (GA) is an advanced form of age-related macular degeneration and a major cause of irreversible vision loss. To better understand the biology of GA, we studied proteins and small molecules in aqueous humor, the fluid inside the eye. We found that eyes with GA showed clear signs of mitochondrial dysfunction, including disruptions in the tricarboxylic acid (TCA) cycle, a key pathway for energy production. This suggests that impaired cellular metabolism is an important feature of the disease. We then tested whether oral α-ketoglutarate (α-KG), a metabolite involved in mitochondrial function and previously shown to have life-extending effects in preclinical studies, could alter these metabolic pathways in the human eye. We found that α-KG supplementation not only increased intraocular α-KG levels but changed metabolic markers linked to mitochondrial activity, providing the first direct evidence that oral supplementation can reach the eye and measurably modify metabolism inside the living human eye. Together, these findings show that liquid biopsy can provide a direct molecular snapshot of the living human eye and may help accelerate the development of biomarker-guided therapies for ocular diseases.
    Key Points: Questions: What specific mitochondrial and TCA-cycle dysfunctions occur in the aqueous humor (AH) of patients with geographic atrophy (GA), and can oral α-ketoglutarate (α-KG) supplementation measurably remodel these metabolic pathways in the living human eye?Findings: AH proteomics in GA patients revealed significant mitochondrial disruption and a coordinated depletion of TCA-cycle enzymes. In a paired-eye interventional metabolomics study, oral α-KG significantly increased intraocular α-KG levels and the α-KG-to-succinate ratio, proving that systemic therapy can drive measurable metabolic modulation within the human eye.Meaning: Multi-omics liquid biopsy provides a direct, eye-specific readout of mitochondrial metabolism in GA and offers early human proof-of-concept that a systemic metabolic therapy can successfully reach and modify intraocular pathways, paving the way for biomarker-guided clinical trials in AMD.
    DOI:  https://doi.org/10.64898/2026.03.12.26347263
  59. Cell. 2026 Mar 20. pii: S0092-8674(26)00116-9. [Epub ahead of print]
    The E3-ome gene-centric compendium reveals the human E3 ligase landscape.
    Ngee Kiat Chua, Tania J González-Robles, Cameron J Reddington, Jane Dudley-Fraser, Richard W Birkinshaw, Jiru Han, Ashleigh Solano, Soon Wei Wong, Tomasz Kochańczyk, Joshua J Peter, Mark A Nakasone, Florian Aust, Jacob Munro, Yeh Huei Tong, Julie Iskander, Waruni Abeysekera, Alex Garnham, Hannah Huckstep, Matthew E Ritchie, Ingrid Wertz, Sarah Hymowitz, Sharad Kumar, Ron C Conaway, Gilbert G Privé, Alex N Bullock, Jeffrey J Babon, Rachel E Klevit, Sonja Lorenz, Alessio Ciulli, Eric S Fischer, Nicolas H Thomä, Radosław P Nowak, Brenda A Schulman, Michael Rapé, Katrin Rittinger, Julia K Pagan, Melanie Bahlo, Joel P Mackay, Peter D Mace, Christopher D Lima, Ronald T Hay, David Komander, Bernhard C Lechtenberg, Claudio A P Joazeiro, Michele Pagano, Kay Hofmann, Rebecca Feltham.
      To define and systematically characterize the human E3 ubiquitin ligase (E3) landscape, we generated the E3-ome, a compendium of E3s encoded by the human genome. The E3-ome integrates experimental data, bioinformatics, and published research, revealing 672 high-confidence E3s. We standardized E3 classifications to create a unified framework for annotation and comparative analysis. The E3-ome identified several previously unrecognized domains, motifs, E3 candidates, and relationships, expanding the diversity of E3s. Furthermore, the E3-ome mapped the spatial and physiological organization of E3s across human tissues and cell types, revealing context-dependent E3s. Genetic analyses identified disease-associated variants across the E3-ome, linking E3s to diverse human pathologies. Together, these analyses define the human E3 landscape at high resolution and deliver a foundational resource to drive mechanistic and therapeutic discovery.
    DOI:  https://doi.org/10.1016/j.cell.2026.01.029
  60. FASEB J. 2026 Mar 31. 40(6): e71692
    Integrative Insights Into Mitochondrial Dysfunction and Organelle Crosstalk in Diabetic Kidney Disease.
    Wanyu Cao, Guoding Cao, Qingtai Meng, Dingfei Li, Jie Zhang, Tianhui Wu, Fengmin Zhang.
      Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease and is driven in large part by early, sustained mitochondrial dysfunction, which promotes metabolic reprogramming, oxidative stress and inflammation that accelerate glomerular and tubular injury. We review recent mechanistic and translational advances linking mitochondrial dysfunction and organelle crosstalk to DKD progression. We synthesize evidence across four interrelated mitochondrial axes-metabolic reprogramming, altered fission-fusion dynamics, defective mitophagy, and mtDNA release-and highlight mitochondria-ER contacts (MAMs) as a nexus integrating redox signaling and calcium homeostasis. Preclinical studies indicate that interventions restoring mitochondrial biogenesis, rebalancing dynamics, enhancing selective mitophagy and preserving mtDNA attenuate glomerular and tubular injury. Clinically, several approved agents (metformin, SGLT2 inhibitors, finerenone, GLP-1RAs) exert renoprotective effects involving mitochondrial pathways; deconvolution of multi-component formulations, targeted antioxidants, metabolic activators and fission inhibitors expand therapeutic options, while organelle-level approaches such as mitochondrial transplantation are emergent. We propose a translational framework that links redox-centered mitochondrial mechanisms to actionable therapeutic strategies for DKD.
    Keywords:  diabetic kidney disease; metabolism reprogramming; mitochondrial dynamics; mitochondria‐associated membranes; mitophagy; mtDNA
    DOI:  https://doi.org/10.1096/fj.202504735R
  61. Biochim Biophys Acta Biomembr. 2026 Mar 22. pii: S0005-2736(26)00027-1. [Epub ahead of print] 184524
    Structure/function relationships of mitochondrial protein carrier (SLC25A20) for carnitine/acylcarnitine: A review.
    Nicola Giangregorio, Annamaria Tonazzi, Lara Console, Cesare Indiveri.
      The mitochondrial carnitine/acylcarnitine carrier (CAC) is a member of the mitochondrial carrier (MC) family. It facilitates the import of acylcarnitines into the mitochondrial matrix in exchange for carnitine, playing a crucial role in the carnitine shuttle, being essential for fatty acid oxidation and ATP production. This review summarizes three decades of progress in our research on the structural features of CAC. Although the crystallized structure of CAC has not yet been determined, several in vitro and in silico studies, many of which utilized the three-dimensional structures of the ADP/ATP carrier in both its cytosolic and matrix conformations, offers valuable insights for shed light on the molecular mechanism of substrate transport, supporting the hypothesis of a common single-binding centered-gated pore mechanism shared by all mitochondrial carriers. In addition, we discuss the transient dimerization of CAC and the formation of a supramolecular complex with a channeling function. Finally, the mechanistic analysis of CAC reported in this review could lay the basis for the development of new therapeutic strategies for patients with impaired CAC function.
    Keywords:  Carnitine/acylcarnitine carrier; Dimer; Salt bridges; Site-directed mutagenesis; Transport; c-State conformation; m-State conformation
    DOI:  https://doi.org/10.1016/j.bbamem.2026.184524
  62. Antioxidants (Basel). 2026 Feb 24. pii: 277. [Epub ahead of print]15(3):
    Mitochondrial Impairment in Unloaded Postural Muscle: Mechanisms Driving Loss of Muscle Function and Mass.
    Kristina A Sharlo, Timur M Mirzoev, Boris S Shenkman.
      Mechanical unloading of skeletal muscle triggers various signaling alterations that result in muscle atrophy and weakness. Mitochondria are essential to muscle health, acting not only as energy suppliers but also as central mediators of molecular regulation. Mitochondrial activity, content, and dynamics are tightly controlled by multiple signaling pathways; conversely, mitochondria-derived messengers, such as reactive oxygen species (ROS), ATP, and mitokines, are involved in the regulation of nearly all aspects of muscle signaling. During mechanical unloading, altered muscle activity leads to mitochondrial dysfunction. However, the initial triggers, underlying mechanisms, and full consequences of this dysfunction remain poorly understood. Nevertheless, mitochondria-targeted therapies have emerged as a promising strategy for mitigating unloading-induced muscle impairments. In this review, we summarize current data regarding the characteristics, causes, and outcomes of unloading-induced mitochondrial dysfunction, specifically focusing on muscle atrophy and functional decline. We highlight novel findings regarding the roles of mitokines and mitochondrial calcium overload, propose a new hypothesis to explain the biphasic dynamics of ATP accumulation during slow-type muscle unloading, and describe emerging therapeutic strategies to counteract these mitochondrial impairments.
    Keywords:  ATP; ROS; calcium handling; dry immersion; hindlimb suspension; mechanical unloading; mitochondria; mitokines; muscle atrophy; skeletal muscle
    DOI:  https://doi.org/10.3390/antiox15030277
  63. bioRxiv. 2026 Mar 18. pii: 2026.03.15.711881. [Epub ahead of print]
    Modeling cis -regulatory variation in human brain enhancers across a large Parkinson's Disease cohort.
    Olga M Sigalova, Alexandra Pančíková, Julie De Man, Koen Theunis, Gert J Hulselmans, Vasileios Konstantakos, Bram Stuyven, Anton De Brabandere, Jarne Geurts, Antonina Mikorska, Shinjini Mukherjee, Sara Abouelasrar Salama, Katy Vandereyken, Kristofer Davie, Lukas Mahieu, Charles H Adler, Thomas G Beach, Geidy E Serrano, Thierry Voet, Jonas Demeulemeester, Stein Aerts.
      Genome-wide association studies (GWAS) have linked more than hundred non-coding genomic loci to Parkinson's disease (PD) risk. Deciphering their functional impact on gene regulation requires cell type-aware modeling approaches to assess the effects of sequence variation on enhancer function and target gene expression. To address this challenge, we generated a comprehensive matched dataset from 190 human donors (115 controls and 75 PD), comprising long-read whole-genome sequencing alongside single nucleus multiome atlases (snATAC-seq and snRNA-seq for 3.1 and 1.1 million nuclei respectively) of the anterior cingulate cortex and substantia nigra. By integrating chromatin accessibility quantitative trait loci (caQTL), DNA methylation QTL (meQTL), and allele-specific chromatin accessibility (ASCA), we identified 53,841 high-confidence cis -acting genetic variants that modulate cell type-specific enhancer accessibility in one or both brain regions. We then demonstrate that sequence-to-function models can accurately predict the impact of these variants directly from the genomic sequence. Novel explainability approaches allowed stratifying these variants according to their regulatory function, with the majority disrupting specific transcription factor binding sites in a cell type specific manner. Integrating these "enhancer variants" (EV) with eQTL mapping and gene locus modeling linked a subset of EVs to their target genes. Finally, we applied these models to prioritize regulatory variants at known PD GWAS loci, bypassing statistical limitations in rare disease-relevant populations like dopaminergic neurons. All together, we establish a unique resource and new sequence modeling strategies to interpret functional non-coding variation in the human brain.
    DOI:  https://doi.org/10.64898/2026.03.15.711881
  64. Am J Hum Genet. 2026 Mar 25. pii: S0002-9297(26)00110-2. [Epub ahead of print]
    BLOC1S1 variants cause lysosomal and autophagic defects resulting in a hypomyelinating leukodystrophy with epileptic encephalopathy.
    Raffaella De Pace, Carlos A Dominguez Gonzalez, Chad D Williamson, Guy Helman, Leslie E Sanderson, Brianna Disanza, Nicole Hsiao-Sánchez, Amy Pizzino, Kayla Muirhead, Joshua L Bonkowsky, Ryan J Taft, Nouriya A Sannaa, Patricia Dias, Ana Sofia Quintas, Mehmet Burak Mutlu, Hasan Bas, Hasan Oztürk, Majid Mojarrad, Masoome Alerasool, Shahriar Sheikhani, Hayder Kadhim Jabbar, Awatif Hameed Issa, Henry Houlden, Emir Zonic, Tahsin Stefan Barakat, Kornelia Tripolski, Antonio Romito, Eden Teferedegn, Arastoo Vossough, Matthew T Whitehead, Elizabeth Bhoj, Rebecca C Ahrens-Nicklas, Cas Simons, Ernst Wolvetang, Tjakko J van Ham, Aida M Bertoli-Avella, Reza Maroofian, Juan S Bonifacino, Adeline Vanderver.
      BLOC1S1 encodes a subunit shared by the BLOC-1 and BLOC-one-related complex (BORC) hetero-octameric complexes that regulate various endolysosomal processes. Here, we report the identification of seven distinct variants in BLOC1S1 in 11 individuals from seven independent families presenting with early psychomotor delay, hypotonia, spasticity, epileptic encephalopathy, optic atrophy, and leuko-axonopathy with hypomyelination. A subset of the affected individuals also have features of hypopigmentation and ocular albinism that are similar, although milder, than those of individuals with BLOC-1-related Hermansky-Pudlak syndrome. Functional analyses show that BLOC1S1 knockout (KO) impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and induced pluripotent stem cell (iPSC)-derived neurons. Transfection experiments reveal that most BLOC1S1 variants exhibit reduced expression, decreased assembly with other BORC/BLOC-1 subunits, and/or impaired restoration of lysosome transport and autophagy in BLOC1S1-KO cells. Additionally, we show that KO of BLOC1S1 reduces pigmentation in a melanocytic cell line and that five of the BLOC1S1 variants partially or fully restore pigmentation. These findings provide genetic, clinical, and functional evidence that loss of function (LoF) of BLOC1S1 leads to more pronounced deficits in BORC than BLOC-1 function. We conclude that the bi-allelic BLOC1S1 variants characterized here primarily result in a neurological disorder with prominent leukodystrophy, similar to the recently reported condition caused by variants in the BORCS8 subunit of BORC. Together, these findings establish BORCopathies as a distinct disease entity.
    Keywords:  BLOC-1; BLOC1S1; BORC; autophagy; leukodystrophy; lysosomes; neurodevelopmental disorder
    DOI:  https://doi.org/10.1016/j.ajhg.2026.02.024
  65. Life Sci Alliance. 2026 Jun;pii: e202603631. [Epub ahead of print]9(6):
    TaoChongBao: a large-scale C. elegans missense variant database bridging worm and human genomes.
    Ming Li, Shimin Wang, Yongping Chai, Zhengyang Guo, Zi Wang, Zhe Chen, Kexin Lei, Jingyi Ke, Xingshen Huang, Guanghan Chen, Peng Huang, Kaiming Xu, Zijie Shen, Wei Li, Guangshuo Ou.
      We generated and sequenced 12,069 viable Caenorhabditis elegans strains produced by ethyl methanesulfonate mutagenesis, identifying 20,315,536 variants, including 541,102 unique missense mutations across 20,914 genes. Most strains exhibit resistance to the anti-nematode drug ivermectin, whereas some others display phenotypes like dumpy morphology, uncoordinated movement, multivulva formation, and blistered cuticle. To organize and visualize this resource, we developed TaoChongBao, an open-access database and strain repository that integrates C. elegans mutation data with AlphaMissense-predicted pathogenicity scores and ClinVar clinical annotations. TaoChongBao enables users to explore worm missense variants, identify conserved residues corresponding to human pathogenic sites, and access viable strains for experimental validation. Compared with the previous Million Mutation Project in C. elegans, TaoChongBao expands mutation coverage over 20-fold and emphasizes amino acid-altering variants. This resource provides a scalable platform for functional residuomics, variant interpretation, and comparative analyses between C. elegans and human genomes.
    DOI:  https://doi.org/10.26508/lsa.202603631
  66. Int J Mol Sci. 2026 Mar 12. pii: 2599. [Epub ahead of print]27(6):
    Restoring Mitochondrial Homeostasis: Therapeutic Strategies for Metabolic Dysfunction-Associated Fatty Liver Disease.
    José S Morgado, Ivo F Machado, Anabela P Rolo, Carlos M Palmeira.
      Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most prevalent chronic liver disorder worldwide, driven by metabolic dysfunction, excessive lipid accumulation, and progressive hepatocellular injury. A growing body of evidence identifies mitochondrial impairment as a central contributor to MAFLD pathogenesis and disease progression. Reduced oxidative capacity, elevated reactive oxygen species, and accumulation of dysfunctional mitochondria collectively exacerbate steatosis, inflammation, and metabolic inflexibility. In recent years, therapeutic strategies aimed at restoring mitochondrial homeostasis have gained considerable attention, with particular focus on agents capable of inducing mitochondrial biogenesis through pathways involving PGC-1α, AMPK, SIRT1, and mTOR. This review synthesizes current knowledge on mitochondrial dysfunction in MAFLD and highlights emerging compounds that ameliorate disease phenotypes by enhancing mitochondrial biogenesis. By examining their mechanisms of action and preclinical efficacy, we underscore the therapeutic potential of targeting mitochondrial quality-control pathways, mainly mitochondrial biogenesis, as a promising avenue for mitigating MAFLD progression.
    Keywords:  MAFLD; biogenesis; dynamics; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/ijms27062599
  67. Nat Metab. 2026 Mar 26.
    Often forgotten but essential: long-chain acyl-CoAs in metabolic control.
    Nils J Færgeman.
      
    DOI:  https://doi.org/10.1038/s42255-026-01509-9
  68. Biol Trace Elem Res. 2026 Mar 26.
    The ATF3-DRP1 Axis Coordinates Mitochondrial Homeostasis and Suppresses Early Apoptosis in Zinc-Deficient Cardiomyocytes.
    Zhaoyuan Wu, Ziwei Guo, Meng Liu, Wei Liu, Rukun Ou, Juan Wang, Chao Wu, Quangen Ma, Jin Ma, Heng Tang, Kaiquan Chen.
      
    Keywords:  Activating transcription factor 3 (ATF3); Cardiomyocyte apoptosis; Dynamin-related protein 1 (DRP1); Mitochondrial fission; NF-κB signaling; Zinc deficiency
    DOI:  https://doi.org/10.1007/s12011-026-05080-y
  69. Neurol Sci. 2026 Mar 28. pii: 383. [Epub ahead of print]47(4):
    Atypical subacute sclerosing panencephalitis mimicking mitochondrial encephalopathy, lactic acidosis and stroke-like episodes.
    Madhu S Gaddigoudar, Ritansh Khera, Ratan Gupta, Arvinder Wander.
      
    DOI:  https://doi.org/10.1007/s10072-026-08972-y
  70. Lancet Neurol. 2026 Apr;pii: S1474-4422(26)00077-3. [Epub ahead of print]25(4): 336
    Lifestyle interventions for Parkinson's disease.
    Elke Kalbe, Eva Schaeffer.
      
    DOI:  https://doi.org/10.1016/S1474-4422(26)00077-3
  71. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261427023
    Challenges and opportunities for the use of telehealth in rare disease diagnosis, treatment, research, and education: key opinion leader interviews by the IRDiRC telehealth task force.
    Melissa A Parisi, Adam L Hartman, Mary Catherine V Letinturier, Elena-Alexandra Tataru, Victoria Antoniadou, Gareth Baynam, Lara Bloom, Marco Crimi, Maria G Della Rocca, Giuseppe Didato, Sofia Douzgou Houge, Anneliene H Jonker, Martina Kawome, Friederike Mueller, James O'Brien, Ratna Dua Puri, Nuala Ryan, Meow-Keong Thong, Birutė Tumienė, Faye H Chen.
      The International Rare Diseases Research Consortium (IRDiRC) Telehealth (TH) Task Force explored the use of TH for improving diagnosis, care, research, and education for rare diseases (RDs) worldwide. The Task Force members interviewed 23 key opinion leaders (KOLs), providing perspectives from experts in the use of TH for the diagnosis, treatment, and prevention of RDs (10 KOLs); for research and evaluation in RDs (7); and for the continuing education of health care providers (HCPs) in RDs (6). The KOLs represented a broad array of diverse perspectives with regard to both geographic regions, including Europe, United States, Sub-Saharan Africa, and Asia, and professional expertise, including rare disease patients and family members, RD association spokespersons, TH association representatives, physicians, researchers, and regulatory authorities. The Task Force solicited KOL opinions to identify factors that influence TH in improving access to diagnosis, care, prevention, and research experiences for RD patients and providers as well as continuing education and peer mentoring for HCPs. This manuscript represents a synthesis of those interviews and some common themes that emerged, along with identification of evidence and knowledge gaps that will benefit from future research efforts to help advance and expand the use of TH for RD care, research, and education. KOLs agreed on the unique elements of RD medical care that could benefit from TH approaches and recognized the increasing role that remote assessments can play in supporting RD research. They identified models for health care provider education afforded by TH that can enhance care for RD patients and broaden the pool of experts in these conditions. While recognizing that barriers to broad implementation exist, they agreed that TH provides a unique tool to provide greater access to care for RD patients worldwide.
    Keywords:  IRDiRC; decentralized clinical trial; eHealth; key opinion leader; peer mentoring; rare disease; rare disease care; rare disease education; rare disease research; teleconsultation; telehealth; telemedicine
    DOI:  https://doi.org/10.1177/26330040261427023
  72. Cell Rep. 2026 Mar 26. pii: S2211-1247(26)00270-6. [Epub ahead of print]45(4): 117192
    Gcn2 deficiency triggers anemia and hypoxic intolerance in zebrafish.
    Chengdong Liu, Chenxi Wang, Jican Zhao, Weiyi Xia, Wanjuan Yu, Huihui Zhou, Xiya Wu, Mingjun Tang, Huan Zeng, Yanfei Tang, Ranran Zhao, Ling Lu, Xuan Wang, Kangsen Mai, Gen He.
      The integrated stress response (ISR) is a conserved signaling hub that orchestrates cellular adaptation to diverse stressors to maintain intracellular homeostasis. However, the specific role of the ISR in regulating hypoxic adaptation and redox homeostasis remains poorly defined. Here, we identify general control nonderepressible 2 (GCN2) as an essential factor for maintaining redox balance and suppressing ferroptosis. Gcn2-deficient zebrafish exhibit hypersensitivity to hypoxia, characterized by excessive heme degradation and mitochondrial damage. Loss of Gcn2 leads to upregulation of hmox1a, reduced erythrocyte numbers, and elevated levels of free ionic iron, collectively contributing to the development of anemia. Mechanistically, loss of Gcn2 downregulates slc3a2b, resulting in disturbed cysteine metabolism. This defect impairs glutathione biosynthesis, triggering ferroptosis characterized by elevated oxidative stress and iron-dependent lipid peroxidation. GCN2 deficiency also induces ferroptosis in HeLa cells. Our findings elucidate a critical role for GCN2 in protecting against ferroptosis and promoting hypoxic tolerance.
    Keywords:  CP: cell biology; CP: metabolism; GCN2; SLC3A2; ferroptosis; hypoxia; integrated stress response; redox homeostasis; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2026.117192
  73. Exp Brain Res. 2026 Mar 22. pii: 76. [Epub ahead of print]244(4):
    Knockdown of RNF128 attenuated Parkinson's-induced mitochondrial dysfunction in neurons by stabilizing the SIRT1 protein.
    Jianeng Dong, Lifen Zhang, Yanqin Gao, Yuting Chen, Chunhua Tian, Chunxiang Wang, Huai Huang, Zhenghu Xu.
      
    Keywords:  Mitochondrial function; Neurons; Parkinson’s disease; RNF128; SIRT1
    DOI:  https://doi.org/10.1007/s00221-026-07272-3
  74. Stem Cell Res. 2026 Mar 16. pii: S1873-5061(26)00062-0. [Epub ahead of print]93 103966
    Generation of Friedreich's ataxia induced pluripotent stem cells carrying the FXN c.165 + 5G>C splicing mutation.
    Pouiré Yameogo, Brandon J Gerhart, Monica F Sentmanat, Amber Neilson, Xiaoxia Cui, Mayank Verma, David R Lynch, Jill S Napierala, Marek Napierala.
      Friedreich's ataxia (FRDA) is a multisystem, autosomal recessive disease caused by biallelic expansion of GAA repeats in intron 1 of the frataxin gene (FXN). While ∼96% of FRDA patients carry expanded GAA repeats on both FXN alleles, ∼4% are compound heterozygous with expanded GAA repeats on one allele and another mutation on the second allele. We generated induced pluripotent stem cells from blood lymphocytes from a FRDA patient carrying the FXN c.165 + 5G > C point mutation, which interferes with canonical splicing of intron 1 of the FXN gene. These cells allow for development of therapeutic approaches that target splicing defect in FRDA.
    DOI:  https://doi.org/10.1016/j.scr.2026.103966
  75. Lancet Neurol. 2026 Apr;pii: S1474-4422(26)00094-3. [Epub ahead of print]25(4): 343
    Miratul Muqit: leading an alliance to decode Parkinson's disease.
    Faith McLellan.
      
    DOI:  https://doi.org/10.1016/S1474-4422(26)00094-3
  76. Sovrem Tekhnologii Med. 2026 ;18(1): 5-20
    TEM-based Study of the Phenotype of Astrocytes Differentiated from Induced Pluripotent Stem Cells from a Healthy Donor and a Patient with Parkinson's Disease.
    K A Kutukova, M V Ivanov, E V Novosadova, A V Brydun, E L Arsenyeva, L V Novosadova, I V Kokorev, I A Grivennikov, V S Sukhorukov, S N Illarioshkin.
      The aim of this study was to study the role of transmission electron microscopy (TEM) in assessment of the phenotype of astrocytes obtained with the directed differentiation technique from induced pluripotent stem cells (iPSCs) from a healthy donor and from a patient with a hereditary form of Parkinson's disease (PD).
    Materials and Methods: Monolayer astrocyte cultures differentiated from iPSCs from a healthy donor and a PD patient having the G2019S mutation in the LRRK2 gene were used in the study. The obtained glial cultures were characterized using real-time PCR and immunocytochemical staining for glia-specific genes and proteins. TEM was used to examine astrocyte ultrastructure.
    Results: PCR analysis and immunocytochemical staining demonstrated that cell lines received from a healthy donor and a PD patient expressed the required pattern of glia-specific genes and synthesized astrocyte-specific proteins. However, some glia-specific genes were expressed at reduced levels by mutant cells. One of the most typical ultrastructural features of astrocytes received from iPSCs from a PD patient was destructive changes in mitochondria, including mitochondrial clearing, swelling, and cristae destruction. In many cells, mitochondria were completely absent after a long culturing. Another characteristic feature of cells with a mutation in the LRRK2 gene was the accumulation of vacuoles with contents of varied electron density. Distinct changes in the ultrastructure of nuclei, protein-synthesizing organelles, and cytoskeletal elements were also seen in cultured astrocytes with a PD-associated LRRK2 mutation. Here, the morphometric study did not reveal any differences in the average cell area, nuclear area, cytoplasm area, or nuclear-cytoplasmic ratio between astrocytes of the control line and the PD mutation line.
    Conclusion: Reprogramming and obtaining of astrocytes from iPSCs received from a donor with a PD-associated mutation in the LRRK2 gene allow to assess the nature and dynamics of pathological morphochemical and ultrastructural changes caused by the mutation during gliogenesis. The use of combined techniques (PCR, immunocytochemistry, TEM) to compare cell cultures differentiated from iPSCs allow to assess, on the one hand, general culture parameters, such as the dynamics of culture differentiation based on changes in the expression level of specific genes and immunocytochemical markers, and on the other hand, morphofunctional changes at the level of individual cells. TEM demonstrates significant potential for studying cell cultures differentiated from iPSCs. This technique is instrumental for phenotyping the resulting cells based on their ultrastructure, assessing the degree of their morphological maturity, and identifying minor ultrastructural changes in cells, both pathological and differentiation-associated. The results of this TEM-based study indicate a pronounced decrease in mitochondrial viability and other ultrastructural abnormalities, thus confirming the idea of a significant role of astroglia in the development of the neurodegenerative process in the LRRK2-associated PD; hence, astroglia can be a basis for development of new approaches as well as for searching pharmacological targets in the pathogenetic therapy of the disease.
    Keywords:  LRRK2; Parkinson’s disease; astrocytes; differentiation; electron microscopy; induced pluripotent stem cells
    DOI:  https://doi.org/10.17691/stm2026.18.1.01
  77. Nat Metab. 2026 Mar 26.
    Atlas of one-carbon metabolism in conventional and germ-free mice reveals folate as a key determinant of biochemical pathways.
    Jonathan Williams, Woo Sung Kim, Rebecca Danner, Juyeong Cho, Bianca F Silva, David A Harris, Federico E Rey, Snehal N Chaudhari.
      Folates participate in the one-carbon metabolism (OCM) cycle, supporting many biochemical pathways. Existing methods to profile folate are limited in the diversity of vitamers they measure and the samples they profile. Here we present a metabolomics workflow for stable extraction, separation and measurement of folates, along with precursors and products of OCM-associated pathways. We profile these metabolites in 37 mouse tissues to chart an interactive 'OCM atlas' ( https://chaudharilab.com/folate-atlas/ ), revealing vast heterogeneity across organs and an uncharacterized folate derivative. We discover that, in adult mice, the gut microbiota is a consumer of folate and folate polyglutamylation in the host is not regulated by folate availability. Germ-free mice show tissue-specific shifts in methyl donor abundances relative to conventionally raised mice, indicative of altered DNA methylation. Correlation analyses uncover the central roles of folates in potentially modulating other biochemical pathways in tissues, thus linking microbial folate consumption directly to its global impacts on host metabolism.
    DOI:  https://doi.org/10.1038/s42255-026-01489-w
  78. Antioxid Redox Signal. 2026 Apr;44(10-12): 464-487
    Mitochondrial Dysfunction in Renal Aging: A Vicious Cycle Driving Kidney Disease Progression.
    Wenpei Yu, Qing Ouyang, Weicen Liu, Lu Jia, Bin Wang.
       SIGNIFICANCE: The aging of the global population is linked to an increase in age-related diseases. The kidneys undergo both structural and functional declines with age, and aging is a significant risk factor for kidney diseases. Mitochondrial dysfunction is recognized as a crucial factor affecting kidney aging. Although the importance of disrupted mitochondrial homeostasis in renal aging has gained increasing attention, the associations and causal mechanisms have not been systematically summarized.
    RECENT ADVANCES: Mitochondria are highly dynamic organelles that operate in various functions, including cell metabolism, redox regulation, cell division, and cell death, and are closely associated with both cell senescence and kidney diseases. Furthermore, aging is also associated with mitochondrial redox dysfunction, abnormal calcium homeostasis, impaired quality control (QC), and increased mitochondrial DNA (mtDNA) leakages. Mitochondrial dysfunction and cellular senescence may sustain a vicious cycle in renal injury. Several types of drugs show promising potential in alleviating renal injury by modulating mitochondria-related aging phenotypes.
    CRITICAL ISSUES: Dysregulated redox status, mitochondrial metabolic reprogramming, mtDNA abnormalities, impaired mitochondrial QC, and mitochondrial calcium overload are the factors that establish a self-perpetuating vicious cycle that promotes renal aging. In addition, the roles of mitochondria-associated senescence in both acute kidney injury and chronic kidney disease are examined and summarized, with potential differences and promising interventions targeting mitochondrial dysfunction and cell senescence also highlighted.
    FUTURE DIRECTIONS: Clinically available interventions specifically aimed at addressing mitochondrial aging remain underdeveloped and require further clinical trials. Future research should also focus on creating drugs that can precisely target mitochondrial senescence to prevent the progression of age-related kidney diseases. Antioxid. Redox Signal. 44, 464-487.
    Keywords:  acute kidney injury; cell senescence; chronic kidney disease; mitochondrial dysfunction; renal aging
    DOI:  https://doi.org/10.1177/15230864251410936
  79. Toxics. 2026 Feb 28. pii: 208. [Epub ahead of print]14(3):
    Mitochondrial Ultrastructure, Fission Proteins, Activity, and Motor Dysfunctions in the Innovative Parkinson's Disease Model Induced by Manganese Inhalation.
    Cesar Alfonso Garcia-Caballero, Jose Luis Ordoñez-Librado, Avril De Alba-Ríos, Enrique Montiel-Flores, Omar Emiliano Aparicio-Trejo, Fernando García-Arroyo, Belén Cuevas-Lopez, José Pedraza-Chaverri, Vianey Rodríguez-Lara, Rocío Tron-Alvarez, Ana Luisa Gutierréz-Valdez, Javier Sánchez-Betancourt, Leonardo Reynoso-Erazo, Maria Rosa Avila-Costa.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, yet its pathogenic mechanisms remain incompletely understood, highlighting the need for reliable experimental models. We previously developed a murine model based on inhalation of a manganese mixture (MnCl2 and Mn(OAc)3), which reproduces dopaminergic neuron loss in the substantia nigra pars compacta (SNc) and motor impairment. However, its capacity to mimic mitochondrial dysfunction, a key mechanism in PD, had not been explored. This study evaluated mitochondrial ultrastructure, fission and fusion proteins, and the activity of electron transport chain complexes I and IV, alongside fine motor performance. Forty male CD1 mice were divided into control (deionized water) and manganese-exposed groups (0.04 M MnCl2 + 0.02 M Mn(OAc)3), inhaled for 1 h twice weekly over five months. Manganese inhalation induced significant fine motor deficits, increased mitochondrial number with reduced area and circularity, and disorganized cristae. Drp1 and Fis1 levels were elevated, accompanied by decreased activity of complexes I and IV, predominantly in the SNc. These findings demonstrate that this progressive, bilateral model reproduces mitochondrial and motor alterations resembling those observed in PD, supporting its utility for testing mitochondria-targeted therapeutic strategies.
    Keywords:  Drp1; Fis1; Parkinson’s disease; animal model; manganese; mitochondria; mitochondrial activity; ultrastructure
    DOI:  https://doi.org/10.3390/toxics14030208
  80. Biomaterials. 2026 Mar 24. pii: S0142-9612(26)00176-6. [Epub ahead of print]332 124152
    A supramolecular fluorescent probe targeting mitochondrial iron for assisting early Parkinson's disease diagnosis.
    Bo Xiao, Shiqin Zhou, Ran Cen, Qinghong Bai, Weishang Yuan, Xin Xiao, Jian Feng, Jianzhuang Jiang.
      Early detection of Parkinson's disease (PD) before irreversible dopaminergic neuron loss remains a critical unmet need. Herein a novel supramolecular probe, DTPP@Q[7], was constructed via a host-guest assembly in which the fluorescent molecule DTPP is combined with the macrocycle cucurbit[7]uril (Q[7]) for real-time monitoring mitochondrial iron overload, an early pathological driver of PD. Encapsulation of DTPP fluorophore by Q[7] exposes the TPP targeting group, enabling precise mitochondrial localization (Pearson coefficient 0.95 with Mito-Tracker) while imparting higher photostability. The probe exhibits high selectivity and sensitivity for Fe3+, with a detection limit of 0.36 μM. Fluorescence quenching induced by mitochondrial Fe3+ correlates with ferroptosis markers (ROS, GPX4, LPO, and MDA) in PD cells and tracks mitochondrial dysfunction, pathological α-synuclein aggregation, and altered dopamine synthesis, demonstrating dynamic reporting of neurodegenerative progression. In an MPTP mouse model, intranasal DTPP@Q[7] enables noninvasive monitoring of cerebral iron imbalance: probe fluorescence decreases dose-dependently and correlates with substantia nigra iron accumulation (R2 > 0.99). In the high-dose MPTP group fluorescence fell by 76%, α-synuclein is upregulated ∼2.5-fold, and tyrosine hydroxylase expression drops nearly 40%. By capturing molecular pathology prior to neuronal morphological damage, DTPP@Q[7] offers a promising molecular strategy for early PD diagnosis.
    Keywords:  Early diagnosis; Iron metabolism; Mitochondrial targeting; Parkinson's disease; Supramolecular probe
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124152
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