bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–06–15
seventy papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.
  2. Diagnostic Moments in the Rare Disease Life Narratives of Mitochondrial Disease Patients in Germany.
  3. Mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate mt-ND5 stability and metabolism.
  4. A Case of Adult-Onset VLCAD Deficiency.
  5. Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model.
  6. Protocol to extract and measure ubiquinone and rhodoquinone in murine tissues.
  7. Mitochondrial fusion controls the development of specialized mitochondrial structure and metabolism in rod photoreceptor cells.
  8. In-vivo dendrite injury drives local mitochondrial contraction and dendrite branching.
  9. Membranes arrest the coarsening of mitochondrial condensates.
  10. Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
  11. Tissue-specific mitochondrial DNA, MT-TF, pathogenic variants in mitochondrial myopathies.
  12. Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.
  13. Mitochondrial presequences harbor variable strengths to maintain organellar function.
  14. At last: the mitochondrial pyruvate carrier structure revealed!
  15. Mitochondrial molecule has unexpected role in tissue healing.
  16. Molecular Dynamics Simulations of a Putative Novel Mechanism for UCP1-Assisted FA Anion Transport.
  17. A genetically encoded bifunctional enzyme mitigates redox imbalance and lipotoxicity via engineered Gro3P-Glycerol shunt.
  18. Advances in Management of Mitochondrial Myopathies.
  19. An alternative mechanism by which If1 prevents ATP hydrolysis by the ATP synthase subcomplex in S. cerevisiae.
  20. The burden of mitochondrial disease: healthcare and societal costs.
  21. Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
  22. Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.
  23. Mitochondrial fumarate inhibits Parkin-mediated mitophagy.
  24. Impact of PARL-mediated mitochondrial protease activity on calcium regulation.
  25. TANGO2 binds crystallin alpha B and its loss causes desminopathy.
  26. Extracellular vesicle-mediated mitochondria delivery: Premise and promise.
  27. Deleterious mitochondrial heteroplasmies exhibit increased longitudinal change in variant allele fraction.
  28. A molecular basis of Ferredoxin Reductase (FdxR) mutations that result in mitochondriopathies.
  29. Diagnostic yield and limitations of whole-genome sequencing for hereditary cerebellar ataxia.
  30. mitoLEAF: mitochondrial DNA Lineage, Evolution, Annotation Framework.
  31. The trade-off between reproduction and resilience.
  32. Metabolic Pathway Tracing for NAD+ Synthesis and Consumption.
  33. MPSE identifies newborns for whole genome sequencing within 48 h of NICU admission.
  34. N-acetyl-L-cysteine improves mitochondrial and oxidative defects in the acadian variant of fanconi syndrome.
  35. The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.
  36. Defective Mitochondrial Respiration in Hereditary Thoracic Aneurysms.
  37. Construction of mitochondrial-targeted ferritin carrier: subunit-terminal fused mitochondrial presequences facilitate efficient delivery.
  38. A mitochondria-targeted long-wavelength fluorescent probe for imaging sulfur dioxide in ferroptosis.
  39. Nicotinamide Adenine Dinucleotide Supplementation to Alleviate Heart Failure: A Mitochondrial Dysfunction Perspective.
  40. High Succinate peak in Magnetic Resonance Spectroscopy: A Diagnostic Clue for the Leukoencephalopathy Result from Succinate Dehydrogenase Deficiencies.
  41. Mitochondrial Transplantation/Transfer: Promising Therapeutic Strategies for Spinal Cord Injury.
  42. Impacts of pathogenic mutations on the structures of the CHCHD10 monomer: An AlphaFold3 study linked to the generation of conformational ensembles.
  43. Consultation informs strategies for improving the use of functional evidence in variant classification.
  44. Impact of sarcopenia and obesity on skeletal muscle size, gene expression, and mitochondrial function.
  45. Polyphenols and Exercise in Mitochondrial Biogenesis: Focus on Age-Related CNS Disorders.
  46. Differential Ca2+ handling by isolated synaptic and non-synaptic mitochondria: roles of Ca2+ buffering and efflux.
  47. PFKFB2 is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
  48. Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances.
  49. ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium.
  50. eIF5A maintains intestinal epithelial homeostasis by sustaining intestinal stem cells.
  51. A case of mitochondrial diabetes mellitus with successful therapeutic response following the initiation of imeglimin.
  52. Personalized, in vivo gene editing for a newborn.
  53. Potential Therapy for Alzheimer's Disease: Modulating Tunneling Nanotube Dynamics Restores Mitochondrial Transport and Ameliorates Aβ-induced Toxicity.
  54. Mitochondrial Transplantation: A Novel Therapeutic Approach for Treating Diseases.
  55. First in Human Gene Editing for an Inherited Metabolic Disease.
  56. Mitochondrial cardiomyopathy presenting as isolated cardiac involvement with rapid progression due to the MT-TI m.4300A>G mutation.
  57. Targeting mitophagy in the heart: Exploring the therapeutic potential of MicroRNAs.
  58. Charcot-Marie-Tooth disease type 1E: clinical natural history and molecular impact of PMP22 variants.
  59. Generative prediction of causal gene sets responsible for complex traits.
  60. Open-label pilot study using hydroxytyrosol as dietary supplements in patients with mitochondrial diseases.
  61. Using RNA therapeutics to promote healthy aging.
  62. Spatial Atmospheric Pressure MALDI HRMS Analysis of Histological Sections of FFPE Samples Reveals a Unique Subset of the Metabolome.
  63. The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the clinical validity of 111 gene-disease relationships.
  64. The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress.
  65. Artificial intelligence applications in rare and intractable diseases: Advances, challenges, and future directions.
  66. Aging on Chip: Harnessing the Potential of Microfluidic Technologies in Aging and Rejuvenation Research.
  67. Personalized Medicine in Treating Rare Genetic Disorders: A Review.
  68. Metabolic adaptations direct cell fate during tissue regeneration.
  69. Easy-PSAP: an integrated workflow to prioritize pathogenic variants in sequence data from a single individual.
  70. Drp1-Mediated Mitochondrial Fission Is Essential for Chemical-Induced Neuronal Transdifferentiation from Human Primary Fibroblasts.
  1. Am J Hum Genet. 2025 Jun 03. pii: S0002-9297(25)00188-0. [Epub ahead of print]
    Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.
    Hana Antonicka, Woranontee Weraarpachai, Katherine M Szigety, Robert Kopajtich, James B Gibson, Johan L K Van Hove, Marisa W Friederich, Piervito Lopriore, Christiane Neuhofer, Roxanne A Van Hove, Michel A Cole, Richard Reisdorph, James T Peterson, Katherine J Dempsey, Rebecca D Ganetzky, Michelangelo Mancuso, Holger Prokisch, Eric A Shoubridge.
      Using exome sequencing, we identified compound heterozygous variants of unknown significance in FASTKD5, a gene that codes for a mitochondrial protein essential for processing mRNAs at non-canonical cleavage sites in the primary mitochondrial transcript, in three subjects with Leigh syndrome, a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia. Among the three subjects, we identified three missense variants and two frameshift variants leading to a premature stop codon. Analysis of fibroblasts from two subjects showed reduced steady-state levels of FASTKD5 protein by immunoblot, reduced translation of the cytochrome c oxidase subunit 1, impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity. The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype. Expression of a wild-type FASTKD5 cDNA, but not cDNAs expressing the missense mutations, rescued all the molecular defects in the subjects' fibroblasts, demonstrating that the alleles are pathogenic. Two of the three identified missense mutations resulted in near complete loss of function, while one was hypomorphic, resulting from impaired protein stability. These cases of mitochondrial disease associated with bi-allelic variants in FASTKD5 add to a growing list of primary genetic mutations causing Leigh syndrome associated with complex IV deficiency.
    Keywords:  FASTKD5; Leigh syndrome; RNA processing; cytochrome c oxidase deficiency; mitochondrial DNA; mitochondrial disease; mitochondrial gene expression; mitochondrial translation; neurodegenerative disease
    DOI:  https://doi.org/10.1016/j.ajhg.2025.05.007
  2. Med Anthropol. 2025 Jun 08. 1-13
    Diagnostic Moments in the Rare Disease Life Narratives of Mitochondrial Disease Patients in Germany.
    Jacquelyne Luce.
      I draw on interviews I conducted in Germany with four individuals who were eventually diagnosed with mitochondrial disease, a category of rare neurogenetic disorders. Rather than the diagnosis of mitochondrial disease serving as a threshold between a before and after, I show how multiple ″diagnostic moments″ generate and shape mitochondrial disease life narratives as affected individuals embody emergent medical knowledge and navigate scientific unknowns. Attending to the plurality of diagnostic moments in rare disease life narratives illuminates the fragmented temporalities and incoherencies of illness experiences, which are often erased by an emphasis on a singular diagnostic moment.
    Keywords:  Germany; diagnosis; diagnostic moments; mitochondrial disease; narrative; rare disease
    DOI:  https://doi.org/10.1080/01459740.2025.2504366
  3. PNAS Nexus. 2025 Jun;4(6): pgaf178
    Mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate mt-ND5 stability and metabolism.
    Carlotta Giorgi, Femke J Aan, Natalija Glibetic, Daniela Ramaccini, Lorenzo Modesti, Veronica A M Vitto, Vanessa Montoya-Uribe, Austin Corpuz, Sonia Missiroli, Inês Simões, Yaiza Potes, Mariusz R Wieckowski, Joe W Ramos, Paolo Pinton, Michelle L Matter.
      The integrin effector, PTRH2, associates with mitochondria in adherent cells where its function has not been elucidated (Jan Y, et al. 2004. A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors. Cell. 116:751-762; Griffiths GS, et al. 2011. Bit-1 mediates integrin-dependent cell survival through activation of the NF{kappa}B pathway. J Biol Chem. 286:14713-14723). PTRH2 loss-of-function mutations cause multisystem disease in children through an unknown mechanism. We sought to determine the role of mitochondrial PTRH2. We used immunoprecipitation/mass spectrometric proteomics to identify PTRH2 interacting partners: TRABID (a deubiquitinase [DUB]) and respiratory complex I NADH: ubiquinone oxidoreductase core subunit 5 (mt-ND5). We show for the first time that mitochondrial PTRH2 regulates TRABID's ability to deubiquitylate mt-ND5. In cells lacking PTRH2 expression, mt-ND5 stability is significantly increased due to aberrant TRABID-mediated deubiquitylation of mt-ND5. This increase in mt-ND5 stability promotes complex I activity and ATP production, which under stress conditions leads to mitochondrial Ca2+ overload. Reexpression of mitochondrial PTRH2 blocks TRABID-mediated mt-ND5 deubiquitylation, resulting in mt-ND5 polyubiquitylation and proteasomal degradation. Inhibiting complex I or TRABID activity rescued PTRH2 loss-of-function mutant patient cells from mitochondrial Ca2+ overload under stress. Immunostaining analysis of ptrh2+/+ and ptrh2-/- mouse skeletal muscle revealed a negative relationship between PTRH2 and mt-ND5, confirming a regulatory role for PTRH2 in controlling mt-ND5 stability. Taken together, mitochondrial PTRH2 is a regulator of metabolic homeostasis that, when lost, promotes mitochondrial Ca2+ overload when cells are exposed to stress signals. Targeting mt-ND5 stability through PTRH2-mediated regulation of TRABID's DUB function provides a novel mechanistic approach to inhibit mitochondrial Ca2+ overload in diseases that occur due to dysregulated mitochondria.
    Keywords:  PTRH2; TRABID; metabolism; mitochondrial Ca2+ overload; mt-ND5
    DOI:  https://doi.org/10.1093/pnasnexus/pgaf178
  4. J Clin Neuromuscul Dis. 2025 Jun 02. 26(4): 196-199
    A Case of Adult-Onset VLCAD Deficiency.
    Ishwarya Thiruvuru, P Philo Hazeena, Rithvik Ramesh, Sundar Shanmugam, Deepa Avadhani, Lakshmi Narasimhan Ranganathan.
       ABSTRACT: Mitochondrial fatty acid β-oxidation disorders are autosomal recessive disorders that impair mitochondrial β-oxidation and transport of fatty acids. These disorders have diverse clinical presentations. The neonatal-onset form presents with hyperammonemia, transient hypoglycemia, metabolic acidosis, cardiomyopathy, and sudden death. The Late-onset form presents with neuropathy, myopathy, and retinopathy. We report a case of a 25-year-old man who presented with episodic weakness, exercise intolerance, myalgia, and rhabdomyolysis. Whole-exome sequencing identified a pathogenic variant in acyl-Coenzyme A dehydrogenase very long chain gene, confirming a diagnosis of very long-chain acyl-Coenzyme A dehydrogenase deficiency (autosomal recessive).
    Keywords:  VLCAD deficiency; adult-onset myopathy; fatty acid oxidation disorder; metabolic myopathy; recurrent rhabdomyolysis
    DOI:  https://doi.org/10.1097/CND.0000000000000524
  5. Metabolomics. 2025 Jun 11. 21(4): 76
    Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model.
    Karin Terburgh, Nastassja Sweeney, Roan Louw.
       INTRODUCTION: Mitochondrial complex (CI) deficiency frequently manifests as a severe neurometabolic disorder called Leigh syndrome (LS). Research on the Ndufs4 knockout (KO) mouse model has identified neuronal vulnerability to CI deficiency as a major driver of the disease, yet its effects on hepatic function remain unclear. Considering the importance of the liver, and its interconnection with the brain, in regulating whole-body metabolic balance, further investigation into the effects of whole-body Ndufs4 KO on the liver is warranted.
    OBJECTIVES: This study investigated liver bioenergetics and metabolism in Ndufs4 KO and WT mice at the late stage of LS.
    METHODS: Bioenergetic investigations of liver mitochondria (n ≥ 3) included spectrophotometric respiratory chain enzyme (CI-IV) activity assays and high-resolution respirometry. Hypothesis-generating metabolomics of whole-liver extracts (n ≥ 19) utilised 1H-NMR, GC-TOFMS, and LC-MS/MS. Significant alterations were identified via t-tests and effect size calculations.
    RESULTS: Ndufs4 KO livers displayed a significant ~ 86% reduction in CI activity and a ~ 43% decrease in CI contribution to CI + II-driven respiration. CII-driven respiration remained unaffected, providing the predominant electron flux in both genotypes. Metabolic profiling revealed widespread perturbations in Ndufs4 KO hepatic metabolism including glucose-, amino acid-, purine/pyrimidine metabolism and the TCA-cycle.
    CONCLUSION: Despite severe CI deficiency, respiration in the Ndufs4 KO liver remains largely unaffected due to reliance on CII. Nonetheless, advanced LS significantly disrupts liver metabolism, with O-GlcNAcylation and mTOR signalling suggestsed as key areas for future investigation. Altogether, our findings underscore the importance of interorgan metabolic dynamics and the liver-brain axis in neurometabolic disorders like LS.
    Keywords:   Ndufs4 knockout mice; Complex I deficiency; Leigh syndrome; Liver metabolism
    DOI:  https://doi.org/10.1007/s11306-025-02275-7
  6. STAR Protoc. 2025 Jun 12. pii: S2666-1667(25)00286-2. [Epub ahead of print]6(2): 103880
    Protocol to extract and measure ubiquinone and rhodoquinone in murine tissues.
    Madison Jerome, Jessica B Spinelli.
      Ubiquinone (UQ) and rhodoquinone (RQ) are electron carriers for the electron transport chain (ETC). Here, we present a protocol for measuring UQ and RQ in mitochondria purified from murine tissues. We describe steps for isolating mitochondria by centrifugation, isolating UQ and RQ by biphasic extraction, and normalizing samples to the protein content of the mitochondrial pellet. We then detail procedures for analyzing UQ and RQ by integrating peak areas for UQ-9 and RQ-9 (abundant in mice) or UQ-10 and RQ-10 (abundant in human). Thus, through enrichment of mitochondria, we establish a method to measure UQ and RQ in tissues. For complete details on the use and execution of this protocol, please refer to Valeros et al.1.
    Keywords:  cell biology; metabolism; metabolomics
    DOI:  https://doi.org/10.1016/j.xpro.2025.103880
  7. bioRxiv. 2025 May 26. pii: 2025.05.21.655403. [Epub ahead of print]
    Mitochondrial fusion controls the development of specialized mitochondrial structure and metabolism in rod photoreceptor cells.
    Michael Landowski, Ryo Hagimori, Purnima Gogoi, Vijesh J Bhute, Sakae Ikeda, Tetsuya Takimoto, Akihiro Ikeda.
      Mitochondria are dynamic organelles that undergo continuous morphological changes, yet exhibit unique, cell-type-specific structures. In rod photoreceptor cells of the retina, these structures include elongated mitochondria in the inner segments and a distinct, large, circular mitochondrion in each presynaptic terminal. The mechanisms underlying the establishment and maintenance of these specialized mitochondrial morphologies, along with their functional significance, are not well understood. Here, we investigate the roles of mitochondrial fusion proteins mitofusin 1 (MFN1) and mitofusin 2 (MFN2) in shaping these structures and maintaining photoreceptor cell health. Rod photoreceptor cell-specific ablation of MFN1 and MFN2 resulted in mitochondrial fragmentation by one month of age, suggesting that mitochondrial fusion is essential for the development of photoreceptor cell-specific mitochondrial structures. Notably, the layer structures of the retina examined by light microscopy appeared unaffected at this age. Following this time period, significant photoreceptor cell degeneration occurred by three months of age. Furthermore, we showed that impaired mitochondrial fusion perturbed the balance of proteins involved in glycolysis, oxidative phosphorylation (OXPHOS), and β-oxidation, highlighting the critical role of mitochondrial fusion in ensuring the proper levels of proteins necessary for optimal energy metabolism. Additionally, we identified upregulation of cellular stress pathways such as endoplasmic reticulum (ER) stress and unfolded protein response (UPR), which arise in response to energy deprivation, and cytoprotective biosynthetic pathways mediated by CCAAT/enhancer-binding protein gamma (C/EBPγ) and mammalian target of rapamycin complex 1 (mTORC1) signaling. In summary, our findings indicate that mitochondrial fusion through MFN1 and MFN2 is vital for the development of unique mitochondrial structures and proper energy production, underscoring the fundamental importance of mitochondrial dynamics in photoreceptor cell function and survival.
    Significance Statements: Rod photoreceptor cells exhibit unique mitochondrial morphologies and high energy requirements. In this report, we examined how these unique mitochondrial structures are established and their biological significance. We identified that mitochondrial fusion is essential for the development of characteristic mitochondrial morphologies in rod photoreceptor cells. Furthermore, we demonstrated that impaired mitochondrial fusion disrupts the equilibrium of proteins associated with OXPHOS, glycolysis, and β-oxidation, ultimately leading to an imbalance in cellular energy homeostasis. Our findings also revealed activation of cellular stress pathways, including ER stress and the UPR, which are likely triggered by energy depletion. Additionally, we identified activation of cytoprotective biosynthetic pathways that are engaged to preserve cellular homeostasis and function.
    DOI:  https://doi.org/10.1101/2025.05.21.655403
  8. bioRxiv. 2025 Jun 06. pii: 2025.06.05.658131. [Epub ahead of print]
    In-vivo dendrite injury drives local mitochondrial contraction and dendrite branching.
    Patrick T Hwu, Lauren A Kim, Marcelo A Wood, Katherine L Thompson-Peer.
      Mitochondria regulate cellular homeostasis in development and disease, and mitochondrial morphology plays a role in local injury signaling and wound repair. How mitochondria respond during dendrite injury remains an open fundamental question. Here we show that mitochondria contract rapidly and locally after laser dendrotomy. In the proximal intact dendrite, the extent of mitochondrial contraction diminishes with increasing distance from the injury site. We report that mitochondrial contraction is dependent on injury severity and that immediate contraction after injury results in a spatiotemporal increase in dendrite branching. Additionally, we find that mitochondrial contraction is inhibited by KCNJ2 (potassium inwardly rectifying channel subfamily J member 2), providing evidence that mitochondrial contraction is regulated by electrical activity. Mechanistically, we find that injury-induced mitochondrial contraction requires Drp1 (Dynamin related protein 1). In conclusion, these in-vivo findings characterize a dendrite response for mitochondria in neurons and provide insight into the regenerative outcomes of dendrites after injury.
    Graphical abstract: In-vivo dendrite injury drives local mitochondrial contraction and dendrite branching.
    DOI:  https://doi.org/10.1101/2025.06.05.658131
  9. bioRxiv. 2025 Jun 08. pii: 2025.06.06.658068. [Epub ahead of print]
    Membranes arrest the coarsening of mitochondrial condensates.
    Sanjaya V B D Aththawala Gedara, Surya Teja Penna, Marina Feric.
      Mitochondria contain double membranes that enclose their contents. Within their interior, the mitochondrial genome and its RNA products are condensed into ~100 nm sized (ribo)nucleoprotein complexes. How these endogenous condensates maintain their roughly uniform size and spatial distributions within membranous mitochondria remains unclear. Here, we engineered an optogenetic tool (mt-optoIDR) that allowed for controlled formation of synthetic condensates upon light activation in live mitochondria. Using live cell super-resolution microscopy, we visualized the nucleation of small, yet elongated condensates (mt-opto-condensates), which recapitulated the morphologies of endogenous mitochondrial condensates. We decoupled the contribution of the double membranes from the environment within the matrix by overexpressing the dominant negative mutant of a membrane fusion protein (Drp1K38A). The resulting bulbous mitochondria had significantly more dynamic condensates that coarsened into a single, prominent droplet. These observations inform how mitochondrial membranes can limit the growth and dynamics of the condensates they enclose, without the need of additional regulatory mechanisms.
    DOI:  https://doi.org/10.1101/2025.06.06.658068
  10. bioRxiv. 2025 May 29. pii: 2025.05.28.656437. [Epub ahead of print]
    Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
    Yash Flora, Dhriti Shastri, K Adam Bohnert.
      Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans , and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity. Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: mitochondria. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF- 16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11- defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.
    DOI:  https://doi.org/10.1101/2025.05.28.656437
  11. Mol Genet Metab Rep. 2025 Jun;43 101230
    Tissue-specific mitochondrial DNA, MT-TF, pathogenic variants in mitochondrial myopathies.
    Sylvia Rose, Aurélien Trimouille, Didier Lacombe, Edoardo Malfatti, Zahra Assouline, Julie Steffann, Isabelle Desguerre, Arnold Munnich, Agnès Rötig, Giulia Barcia.
      Mitochondrial myopathies are progressive muscle disorders caused by impaired mitochondrial oxidative phosphorylation, leading to reduced adenosine triphosphate production. Skeletal muscles have a high energy demand and are often the first to be affected. In addition to muscular symptoms (muscle weakness, effort intolerance, fatigue), the disease can affect the central and peripheral nervous systems, as well as the heart, liver, kidneys and endocrine system (diabetes). Molecular genetic diagnostic is currently based on leukocyte DNA obtained from blood samples, considered less invasive than muscle biopsy. We report four patients from three families with mitochondrial myopathy associated with ptosis, sensorineural hearing loss, epilepsy, tubulointerstitial nephropathy and cardiomyopathy. Genetic studies identified MT-TF variants (m.586G > A, m.601G > A, m.616 T > C) with highly variable heteroplasmy levels in the same patient from one tissue to another (5 % to 70 % mutant load in circulating blood leukocytes and in muscle respectively). We emphasize the importance of performing mtDNA analysis on muscle DNA, even in patients with negative blood leukocytes mtDNA sequencing, if there is strong clinical suspicion of mitochondrial myopathy.
    Keywords:  Heteroplasmy; MT-TF; Mitochondrial myopathy; Muscle biopsy; mtDNA
    DOI:  https://doi.org/10.1016/j.ymgmr.2025.101230
  12. Life Metab. 2025 Jun;4(3): loaf012
    Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.
    Jack Devine, Anna S Monzel, David Shire, Ayelet M Rosenberg, Alex Junker, Alan A Cohen, Martin Picard.
      Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have consistently high, while others show consistently low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic assays in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mitochondrial DNA (mtDNA) density was correlated between tissues (median r = -0.01 to 0.16), indicating that animals with high mitochondrial content or capacity in one tissue may have low content or capacity in other tissues. Similarly, RNA sequencing (RNAseq)-based indices of mitochondrial expression across 45 tissues from 948 women and men (genotype-tissue expression [GTEx]) showed only small to moderate coherence between some tissues, such as between brain regions (r = 0.26), but not between brain-body tissue pairs (r = 0.01). The mtDNA copy number (mtDNAcn) also lacked coherence across human tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were partially attributable to (i) tissue-specific activation of energy sensing pathways, including the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the integrated stress response (ISR), and other molecular regulators of mitochondrial biology, and (ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with distinct mitochondrial distribution strategies that map onto distinct clinical phenotypes. These data raise the possibility that tissue-specific energy sensing pathways may contribute to idiosyncratic mitochondrial distribution patterns among individuals.
    Keywords:  disease risk; energy sensing; gene regulation; inter-organ crosstalk; mitochondrial biogenesis; mitochondrion
    DOI:  https://doi.org/10.1093/lifemeta/loaf012
  13. bioRxiv. 2025 May 29. pii: 2025.05.26.655807. [Epub ahead of print]
    Mitochondrial presequences harbor variable strengths to maintain organellar function.
    Youmian Yan, Baigalmaa Erdenepurev, Ian Collinson, Natalie M Niemi.
      Hundreds of mitochondrial-destined proteins rely on N-terminal presequences for organellar targeting and import. While generally described as positively charged amphipathic helices, presequences lack a consensus motif and thus likely promote the import of proteins into mitochondria with variable efficiencies. Indeed, the concept of presequence "strength" critically underlies biological models such as stress sensing, yet a quantitative analysis of what dictates "strong" versus "weak" presequences is lacking. Furthermore, the extent to which presequence strength affects mitochondrial function and cellular fitness remains unclear. Here, we capitalize on the high-throughput and kinetic nature of the MitoLuc mitochondrial protein import assay to quantify multiple aspects of presequence strength. We find that select presequences, including those that regulate the mitochondrial unfolded protein response (UPR mt ), are sufficient to impart differential import efficiencies during mitochondrial uncoupling. Surprisingly, we find that presequences beyond those classically associated with stress signaling promote highly variable import efficiency in stressed and basal (i.e., non-stressed) conditions in vitro, suggesting that presequence strength may influence a broader array of processes than currently appreciated. We exploit this variability to demonstrate that only presequences that promote robust import in vitro can fully rescue defects in respiratory growth in Complex IV-deficient yeast, suggesting that presequence strength dictates metabolic potential. Collectively, our findings demonstrate that presequence strength can describe numerous metrics, such as total imported protein, maximal import velocity, or sensitivity to uncoupling, suggesting that the annotation of presequences as "weak" versus "strong" requires more nuanced characterization than is typically performed. Importantly, we find that such variability in presequence strength meaningfully affects cellular fitness in processes beyond stress signaling, suggesting that organisms may broadly exploit presequence strength to fine-tune mitochondrial import and thus organellar homeostasis.
    DOI:  https://doi.org/10.1101/2025.05.26.655807
  14. Trends Pharmacol Sci. 2025 Jun 10. pii: S0165-6147(25)00100-2. [Epub ahead of print]
    At last: the mitochondrial pyruvate carrier structure revealed!
    Brian N Finck, Christy M Hadfield, Kyle S McCommis.
      Mitochondrial pyruvate carrier (MPC) inhibitors have shown promise as therapeutics for treating several chronic diseases. However, the structure of MPC and the molecular mechanisms by which it interacts with inhibitors have remained unclear, impeding rational drug design. Multiple groups have now independently resolved the structure of the MPC heterodimer.
    Keywords:  MPC; cryoEM; mitochondria; pyruvate
    DOI:  https://doi.org/10.1016/j.tips.2025.05.010
  15. Nature. 2025 Jun 11.
    Mitochondrial molecule has unexpected role in tissue healing.
    Ram P Chakrabarty, Navdeep S Chandel.
      
    Keywords:  Biochemistry; Cell biology; Metabolism; Stem cells
    DOI:  https://doi.org/10.1038/d41586-025-01583-1
  16. Acta Physiol (Oxf). 2025 Jul;241(7): e70068
    Molecular Dynamics Simulations of a Putative Novel Mechanism for UCP1-Assisted FA Anion Transport.
    Sanja Vojvodić, Giorgia Roticiani, Mario Vazdar, Elena E Pohl.
       BACKGROUND: Mitochondrial energy can be stored as ATP or released as heat by uncoupling protein 1 (UCP1) during non-shivering thermogenesis in brown adipose tissue. UCP1, located in the inner mitochondrial membrane, reduces the proton gradient in the presence of long-chain fatty acids (FA). FA act as weak, protein-independent uncouplers, with the transport of the FA anion across the membrane being the rate-limiting step. According to the fatty acid cycling hypothesis, UCP1 catalyzes this step through an as-yet-undefined mechanism.
    METHODS: We used computational and experimental techniques, including all-atom molecular dynamics (MD) simulations, membrane conductance measurements, and site-directed mutagenesis.
    RESULTS: We identified two novel pathways for fatty acid anion translocation (sliding) at the UCP1 protein-lipid interface, ending at key arginine residues R84 and R183 in a nucleotide-binding region. This region forms a stable complex with fatty acid anion, which is crucial for anion transport. Mutations of these two arginines reduced membrane conductance, consistent with the MD simulation prediction that the arachidonic acid anion slides between helices H2-H3 and H4-H5, terminating at R84 and R183. Protonation of the arachidonic acid anion predicts its release from the protein-lipid interface, allowing it to move to either cytosolic or matrix leaflets of the membrane.
    CONCLUSION: We provide a novel, detailed mechanism by which UCP1 facilitates fatty acid anion transport, as part of the fatty acid cycling process originally proposed by Skulachev. The residues involved in this transport are conserved in other SLC25 proteins, suggesting the mechanism may extend beyond UCP1 to other members of the superfamily.
    Keywords:  anion transporter; cardiolipin; fatty acid cycling; mitochondrial SLC25 family; molecular dynamics simulations; proton transport mechanism
    DOI:  https://doi.org/10.1111/apha.70068
  17. bioRxiv. 2025 Jun 05. pii: 2025.06.02.657195. [Epub ahead of print]
    A genetically encoded bifunctional enzyme mitigates redox imbalance and lipotoxicity via engineered Gro3P-Glycerol shunt.
    Xingxiu Pan, Subrata Munan, Austin L Zuckerman, Andrew Pon, Sara Violante, Justin R Cross, Hardik Shah, Valentin Cracan.
      Dihydroxyacetone phosphate (DHAP), glycerol-3-phosphate (Gro3P) and reduced/oxidized nicotinamide adenine dinucleotide (NADH/NAD + ) are key metabolites of the Gro3P shuttle system that forms a redox circuit, allowing transfer of reducing equivalents between cytosol and mitochondria. Targeted activation of Gro3P biosynthesis was recently identified as a promising strategy to alleviate reductive stress by promoting NAD + recycling, including in cells with an impaired mitochondrial complex I. However, because Gro3P constitutes the backbone of triglycerides under some circumstances, its accumulation can lead to excessive fat deposition. Here, we present the development of a novel genetically encoded tool based on a di-domain glycerol-3-phosphate dehydrogenase from algae Chlamydomonas reinhardtii ( Cr GPDH), which is a bifunctional enzyme that can recycle NAD + while converting DHAP to Gro3P. In addition, this enzyme possesses an N-terminal domain which cleaves Gro3P into glycerol and inorganic phosphate (Pi) (in humans and other organisms, this reaction is catalyzed by a separate glycerol-3-phosphate phosphatase, a reaction also known as "glycerol shunt"). When expressed in mammalian cells, Cr GPDH diminished Gro3P levels and boosted the TCA cycle and fatty acid β-oxidation in mitochondria. Cr GPDH expression alone supported proliferation of HeLa cells under conditions of either inhibited activity of the mitochondrial electron transport chain or hypoxia. Moreover, human kidney cancer cells, which exhibit abnormal lipid accumulation, had decreased triglycerides levels when expressing Cr GPDH. Our findings suggest that the coordinated boosting of both Gro3P biosynthesis and glycerol shunt may be a viable strategy to alleviate consequences of redox imbalance and associated impaired lipogenesis in a wide repertoire of conditions, ranging from primary mitochondrial diseases to obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD).
    DOI:  https://doi.org/10.1101/2025.06.02.657195
  18. Int J Mol Sci. 2025 Jun 05. pii: 5411. [Epub ahead of print]26(11):
    Advances in Management of Mitochondrial Myopathies.
    Athanasios Bangeas, Vasiliki Poulidou, Ioannis Liampas, Chrysa Marogianni, Athina-Maria Aloizou, Zisis Tsouris, Markos Sgantzos, Marianthi Arnaoutoglou, Dimitrios P Bogdanos, Efthimios Dardiotis, Vasileios Siokas.
      Mitochondria, the energy factories of human organisms, can be the cause of a variety of genetic disorders called mitochondrial myopathies. Mitochondrial diseases arise from genetic alterations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) and can manifest with great heterogeneity, leading to multiorgan dysfunction. The purpose of this article is to concisely review the pathophysiology, genetics and main clinical features of mitochondrial myopathies, focusing mainly on the treatment and management of these disorders. Currently, a particular treatment for mitochondrial myopathies does not exist, while the available guidelines concerning management are based on experts' opinions. The therapeutic options currently applied largely aim at symptom relief and amelioration of patients' quality of life. The most commonly used regimens involve the administration of vitamins and cofactors, although hard evidence regarding their true benefit for patients is still lacking. Recent studies have demonstrated promising results for elamipretide; however, phase III clinical trials are still ongoing. Regarding patient management, a multidisciplinary approach with the collaboration of different specialties is required. Further clinical trials for the already applied treatment options, as well as on novel experimental therapies, are of utmost importance in order to improve patients' outcomes.
    Keywords:  management; mitochondrial myopathies; treatment
    DOI:  https://doi.org/10.3390/ijms26115411
  19. EMBO Rep. 2025 Jun 09.
    An alternative mechanism by which If1 prevents ATP hydrolysis by the ATP synthase subcomplex in S. cerevisiae.
    Orane Lerouley, Isabelle Larrieu, Tom Louis Ducrocq, Benoît Pinson, Marie-France Giraud, Arnaud Mourier.
      The mitochondrial F1F0-ATP synthase is crucial for maintaining the ATP/ADP balance which is critical for cell metabolism, ion homeostasis and cell proliferation. This enzyme, conserved across evolution, is found in the mitochondria or chloroplasts of eukaryotic cells and the plasma membrane of bacteria. In vitro studies have shown that the mitochondrial F1F0-ATP synthase is reversible, capable of hydrolyzing instead of synthesizing ATP. In vivo, its reversibility is inhibited by the endogenous peptide If1 (Inhibitory Factor 1), which specifically prevents ATP hydrolysis in a pH-dependent manner. Despite its presumed importance, the loss of If1 in various model organisms does not cause severe phenotypes, suggesting its role may be confined to specific stress or metabolic conditions yet to be discovered. Our analyses indicate that inhibitory peptides are crucial in mitigating mitochondrial depolarizing stress under glyco-oxidative metabolic conditions. Additionally, we found that the absence of If1 destabilizes the nuclear-encoded free F1 subcomplex. This mechanism highlights the role of If1 in preventing harmful ATP wastage, offering new insights into its function under physiological and pathological conditions.
    Keywords:  ATP Synthase; Bioenergetics; F1 Subcomplex; IF1; Mitochondria
    DOI:  https://doi.org/10.1038/s44319-025-00430-8
  20. Value Health. 2025 Jun 07. pii: S1098-3015(25)02377-0. [Epub ahead of print]
    The burden of mitochondrial disease: healthcare and societal costs.
    Deborah Schofield, Katherine Lim, Owen Tan, Rupendra Shrestha, Sameen Haque, Karen Crawley, Sarah West, Adam Percival, Jayamala Parmar, Joshua Kraindler, Carolyn Sue.
       OBJECTIVES: To estimate the burden of mitochondrial disease by measurement of healthcare, societal and lifetime costs of mitochondrial disease.
    METHODS: We recruited patients aged 18 years or over with a clinical confirmation of mitochondrial disease and their carer from a mitochondrial disease referral centre to complete a survey for our study. The survey responses and linked administrative data from the patients and carers were used in a microsimulation model to estimate the healthcare and societal costs of mitochondrial disease.
    RESULTS: 92.5% recruited agreed to participate in our study. We estimated total annual average costs at AU$ 112,721 per household. Of the total annual average costs, a large proportion were societal costs (92%). 4%, 10% and 86% of societal costs were borne by the Commonwealth government, state government and private out-of-pocket, respectively. 8% of the total annual average costs were healthcare, with 61%, 9% and 30% of the annual average health costs borne by the Commonwealth government, state government and private out-of-pocket, respectively. We estimated the total lifetime cost of mitochondrial disease at AU$ 7.6 million per household and the national annual cost is estimated at AU$ 8.6 billion.
    CONCLUSIONS: Mitochondrial disease is an expensive condition with the majority of the costs comprising of societal costs with substantial costs borne privately out-of-pocket. The findings from this study can be used in other studies such as cost-effectiveness analysis to examine the benefits of interventions to treat or prevent mitochondrial disease.
    Keywords:  Economic: Simulation model; cost-of-illness; mitochondrial disease; unit costing
    DOI:  https://doi.org/10.1016/j.jval.2025.05.016
  21. Cell. 2025 Jun 05. pii: S0092-8674(25)00570-7. [Epub ahead of print]
    Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
    Daniel A Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu.
      Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.
    Keywords:  cell fusion; great apes; interspecies composite; interspecies hybrid; metabolism; mitochondria; mitophagy; mtDNA; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.cell.2025.05.020
  22. bioRxiv. 2025 May 28. pii: 2025.05.25.655566. [Epub ahead of print]
    Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.
    Rahul Gupta, Timothy J Durham, Grant Chau, Md Mesbah Uddin, Wenhan Lu, Konrad J Karczewski, Daniel Howrigan, Pradeep Natarajan, Wei Zhou, Benjamin M Neale, Vamsi K Mootha.
      One of the strongest signatures of aging is an accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy. Here we investigate the mechanism underlying this phenomenon by calling mtDNA sequence, abundance, and heteroplasmic variation in human blood using whole genome sequences from ∼750,000 individuals. Our analyses reveal a simple, two-step mechanism: first, individual cells randomly accumulate low levels of "cryptic" mtDNA mutations; then, when a cell clone proliferates, the cryptic mtDNA variants are carried as passenger mutations and become detectable in whole blood. Four lines of evidence support this model: (1) the mutational spectrum of age-accumulating mtDNA variants is consistent with a well-established model of mtDNA replication errors, (2) these mutations are found primarily at low levels of heteroplasmy and do not show evidence of positive selection, (3) high mtDNA mutation burden tends to co-occur in samples harboring somatic driver mutations for clonal hematopoiesis (CH), and (4) nuclear GWAS reveals that germline variants predisposing to CH (such as those near TERT , TCL1A , and SMC4 ) also increase mtDNA mutation burden. We propose that the high copy number and high mutation rate of mtDNA make it a particularly sensitive blood-based marker of CH. Importantly, our work helps to mechanistically unify three prominent signatures of aging: common germline variants in TERT , clonal hematopoiesis, and observed mtDNA mutation accrual.
    DOI:  https://doi.org/10.1101/2025.05.25.655566
  23. Mol Cell. 2025 Jun 03. pii: S1097-2765(25)00460-5. [Epub ahead of print]
    Mitochondrial fumarate inhibits Parkin-mediated mitophagy.
    Su Jin Ham, Sunhoe Bang, Daihn Woo, Jae-Yoon Jo, Takwon Yoo, Eunju Yoon, Yeonju Kyoung, Daehyun Baek, Jong-Seo Kim, Jongkyeong Chung.
      Here, we explore the potential involvement of fumarate, a metabolite generated from the TCA cycle, as a key regulator of PINK1-Parkin-mediated mitophagy. Fumarate engages in a process called succination, forming S-(2-succino) cysteine with protein cysteine residues. Our research demonstrates that this modification specifically targets the sulfhydryl group of cysteine 323 and 451 residues of human Parkin, leading to the inhibition of its mitochondrial localization and E3 ligase activity, thereby impeding PINK1-Parkin-mediated mitophagy. Notably, our investigation reveals that the succinatable cysteines in human Parkin are not conserved in invertebrates, including Drosophila. To assess the functional impact of Parkin succination, we generate Parkin knockin flies with succinatable cysteines. These flies exhibit robust Parkinson's disease (PD)-related phenotypes when exposed to elevated fumarate levels. Collectively, our findings underscore the significance of fumarate as an endogenous regulator of PINK1-Parkin-mediated mitophagy, offering insights into the intricate interplay between mitochondrial metabolic activities and PD pathology.
    Keywords:  ANT1; PINK1; Parkinson's disease; VDAC1/2; fumarate; parkin; succination
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.021
  24. Biochim Biophys Acta Mol Cell Res. 2025 Jun 06. pii: S0167-4889(25)00103-X. [Epub ahead of print] 119998
    Impact of PARL-mediated mitochondrial protease activity on calcium regulation.
    Donato D'Angelo, Aya Al Saidi, Giorgia Ghirardo, Denis Vecellio Reane, Nicola Gasparini, Rosario Rizzuto, Anna Raffaello.
      The presenilin-associated rhomboid-like protein (PARL) is a mitochondrial inner membrane serine protease that is a key regulator of several cellular processes, including apoptosis, metabolism, inflammation and stress responses. While recent studies suggest that PARL may play a role in mitochondrial calcium homeostasis, the underlying mechanisms remain poorly understood. In this study, we investigated the effects of PARL modulation on mitochondrial and cytosolic calcium dynamics, as well as mitochondrial membrane potential. Our results show that altering PARL protein levels, through both overexpression and silencing, significantly affects mitochondrial calcium uptake, without influencing cytosolic calcium transients or mitochondrial membrane potential. Despite the observed changes in mitochondrial calcium dynamics, PARL does not interact with the mitochondrial calcium uniporter complex (mtCU) regulators MICU1 and MICU2, which are critical for regulating mitochondrial calcium influx. However, we observed alterations in the protein levels of MICU1 and MICU2, either in their monomeric or dimeric forms, suggesting that PARL may influence these mtCU components indirectly. Interestingly, the pore-forming subunit MCU, and the structural subunit EMRE, essential for the assembly of the mtCU, were unaffected by PARL modulation. These findings suggest that the role of PARL in modulating mitochondrial calcium homeostasis may involve indirect mechanisms, potentially involving other regulatory pathways. Overall, our study provides novel insights into the functional role of PARL in mitochondrial calcium regulation, offering potential avenues for further investigation into its broader cellular functions.
    Keywords:  Calcium signaling; Mitochondria; Mitochondrial calcium uniporter; Mitochondrial intermembrane proteolysis; PARL; Rhomboid protease
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119998
  25. Nat Commun. 2025 Jun 06. 16(1): 5261
    TANGO2 binds crystallin alpha B and its loss causes desminopathy.
    Maike Stentenbach, Laetitia A Hughes, Samuel V Fagan, Blake Payne, Danielle L Rudler, Stefan J Siira, Tim McCubbin, Anaëlle Chopin, Kara L Perks, Judith A Ermer, James Hendry, Teagan S Er, Shanti Balasubramaniam, Joel A Eliades, Livia C Hool, Nicolle H Packer, Edward S X Moh, Benjamin S Padman, Oliver Rackham, Aleksandra Filipovska.
      Mutations in the TANGO2 gene cause an autosomal recessive disorder characterised by developmental delay, stress-induced episodic rhabdomyolysis, and cardiac arrhythmias along with severe metabolic crises. Although TANGO2 mutations result in a well characterised disease pathology, the function of TANGO2 is still unknown. To investigate the function of TANGO2, we knocked out the TANGO2 gene in human cells and mice. We identify that loss of TANGO2 impairs intermediate filament structure, resulting in fragmented mitochondrial networks and formation of cup-like mitochondria. In male mice, loss of TANGO2 caused heart defects, reduced muscle function and glucose intolerance by remodelling of intermediate filaments, which altered the mitochondrial and cytoplasmic proteomes, N-glycosylation and nucleocytoplasmic O-GlcNAcylation. We identify that TANGO2 binds the small heat shock protein crystallin alpha B (CRYAB) to prevent the aggregation of the intermediate filament desmin and in the absence of TANGO2, mice develop desminopathy, which is consistent with features found in patients carrying mutations in either desmin or CRYAB.
    DOI:  https://doi.org/10.1038/s41467-025-60563-1
  26. J Cereb Blood Flow Metab. 2025 Jun 11. 271678X251349304
    Extracellular vesicle-mediated mitochondria delivery: Premise and promise.
    Devika S Manickam, Paromita Paul Pinky, Purva Khare.
      Mitochondrial transfer is highly significant under physiological as well as pathological states given the emerging recognition of mitochondria as cellular "processors" akin to microchip processors that control the operation of a mobile device. Mitochondria play indispensable roles in healthy functioning of the brain, the organ with the highest energy demand in the human body and therefore, loss of mitochondrial function plays a causal role in multiple brain diseases. In this review, we will discuss various aspects of extracellular vesicle (EV)-mediated mitochondrial transfer and their effects in increasing recipient cell/tissue bioenergetics with a focus on these processes in brain cells. A subset of EVs with particle diameters >200 nm, referred to as medium-to-large EVs (m/lEVs), are known to entrap mitochondria during EV biogenesis. The entrapped mitochondria are likely a combination of either polarized, depolarized mitochondria or a mixture of both. We will also discuss engineering approaches to control the quality and quantity of mitochondria entrapped in the m/lEVs. Controlling mitochondrial quality can allow for optimizing/maximizing the therapeutic potential of m/lEV mitochondria-a novel drug with immense potential to treat a wide range of disorders associated with mitochondrial dysfunction.
    Keywords:  Extracellular vesicles (EVs); medium-to-large EVs; microvesicles; mitochondria; small EVs
    DOI:  https://doi.org/10.1177/0271678X251349304
  27. iScience. 2025 Jun 20. 28(6): 112590
    Deleterious mitochondrial heteroplasmies exhibit increased longitudinal change in variant allele fraction.
    Lieke M Kuiper, Wen Shi, Joost A M Verlouw, Yun Soo Hong, Pascal Arp, Daniela Puiu, Linda Broer, Jiaqi Xie, Charles Newcomb, Stephen S Rich, Kent D Taylor, Jerome I Rotter, Joel S Bader, Eliseo Guallar, Joyce B J van Meurs, Dan E Arking.
      A common feature of human aging is the acquisition of somatic mutations, and mitochondria are particularly prone to mutation, leading to a state of mitochondrial DNA heteroplasmy. Cross-sectional studies have demonstrated that detection of heteroplasmy increases with participant age, a phenomenon that has been attributed to genetic drift. In this large-scale longitudinal study, we measured heteroplasmy in two prospective cohorts (combined n = 1404) at two time points (mean time between visits, 8.6 years), demonstrating that deleterious heteroplasmies were more likely to increase in variant allele fraction (VAF). We further demonstrated that increase in VAF was associated with increased risk of overall mortality. These results challenge the claim that somatic mtDNA mutations arise mainly due to genetic drift, instead suggesting a role for positive selection for a subset of predicted deleterious mutations at the cellular level, despite a negative impact of these mutations on overall mortality.
    Keywords:  Cell biology; Genetics
    DOI:  https://doi.org/10.1016/j.isci.2025.112590
  28. J Inorg Biochem. 2025 Jun 04. pii: S0162-0134(25)00149-7. [Epub ahead of print]271 112969
    A molecular basis of Ferredoxin Reductase (FdxR) mutations that result in mitochondriopathies.
    Amit Kumar, Janie E McGlohon, D Fernando Estrada.
      Inherited mutations in the Ferredoxin Reductase (FdxR) gene can result in a spectrum of disorders that include auditory and optic neural atrophies as well as adrenal insufficiency. FdxR (also referred to as Adrenodoxin Reductase) is a flavoprotein located in the inner mitochondrial membrane. It is responsible for mediating electron transfer from NADPH to either Fdx1 (Adrenodoxin), which is the sole reductant for all seven mitochondrial cytochromes P450, or to the related ferredoxin Fdx2, which is a component in the FeS cluster biogenesis pathway. In most cases, the mechanistic causes that underpin FdxR-related neuropathies and steroid imbalances remain unknown. In this study, we investigate three clinically relevant variants of FdxR (R211Q, R275C, and R355Q) that exhibit classic FdxR-related disease phenotypes and are widely distributed in the protein. We use a combination of biophysical and biochemical techniques to evaluate both the FdxR:Fdx1 complex and the FdxR:Fdx2 complex since these redox complexes represent an important branch point in FdxR function. Two key findings from this study are that i) all three mutants alter the recognition of Fdx1 and Fdx2, despite R275C and R355Q being located distally from the expected site of interaction, and ii) R275C and R355Q disrupt the functional complex with Fdx1, but not with Fdx2. These findings are supplemented with 2D NMR data of each mutant FdxR complex. In summary, this work implicates protein instability and degradation as the proximal cause of FdxR-related disease, with a secondary cause being the disruption of cytochrome P450-mediated metabolism in mitochondria.
    Keywords:  Electron transfer; Ferredoxin reductase; Ferredoxin1; Ferredoxin2; Flavin adenine dinucleotide (FAD); Mitochondriopathies; Nuclear magnetic resonance (NMR); Protein stability; Protein-protein interaction
    DOI:  https://doi.org/10.1016/j.jinorgbio.2025.112969
  29. Brain Commun. 2025 ;7(3): fcaf188
    Diagnostic yield and limitations of whole-genome sequencing for hereditary cerebellar ataxia.
    Wai Yan Yau, Roisin Sullivan, Emer O'Connor, David Pellerin, Michael H Parkinson, Paola Giunti, Marie-Josée Dicaire, Matt C Danzi, Stephan Züchner, Bernard Brais, Nicholas W Wood, Henry Houlden, Jana Vandrovcova.
      Less than half of the individuals with hereditary cerebellar ataxia receives a genetic diagnosis. Repeat expansions account for disproportionate number of hereditary cerebellar ataxia and have genetically heterogeneous causes. These genetic loci include ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, ATXN8OS, ATXN10, PPP2R2B, TBP, ATN1, FMR1, BEAN1, NOP56, GLS, THAP11, GAA-FGF14, ZFHX3, FXN and RFC1. This study aims to assess the yield of short-read whole genome sequencing in the molecular diagnosis of hereditary cerebellar ataxia. We recruited 380 patients (351 probands) from a national ataxia centre in United Kingdom. They underwent short-read whole genome sequencing as a part of the 100 000 Genomes Project. Bioinformatic pipeline of whole genome sequencing include variant prioritization in selected virtual gene panels, customized analysis with a focus on repeat expansions, structural variants and recently reported hereditary cerebellar ataxia genes. All potential genetic variants were reviewed in a multidisciplinary team, and further confirmation tests were performed as appropriate. Whole genome sequencing identified causative variants in 115 (33%) out of 351 probands. We established 46 distinct presumptive molecular diagnoses with the most frequent being SPG7 (n = 22), RFC1 (n = 20) and CACNA1A (n = 10). However, it failed to detect any probands with novel ataxia gene GAA-FGF14, which was subsequently identified on polymerase chain reaction screening in 10 unsolved probands. In conclusion, whole genome sequencing is a useful diagnostic test in hereditary cerebellar ataxia patients and can be used to detect repeat expansions, structural and mitochondrial variants. However, identification of complex structural variants and sizing of large repeat expansions remains a challenge and require alternative molecular testing techniques.
    Keywords:  ataxia; movement disorders; neurogenetics; whole-genome sequencing
    DOI:  https://doi.org/10.1093/braincomms/fcaf188
  30. NAR Genom Bioinform. 2025 Jun;7(2): lqaf079
    mitoLEAF: mitochondrial DNA Lineage, Evolution, Annotation Framework.
    Nicole Huber, Noah Hurmer, Arne Dür, Walther Parson.
      The study of mitochondrial DNA (mtDNA) provides invaluable insights into genetic variation, human evolution, and disease mechanisms. However, maintaining a consistent and reliable classification system requires continuous updates. Since Phylotree updates ended in 2016, the accumulation of new haplogroup findings in individual studies has highlighted the critical need for a centralized resource to ensure consistent classifications. To address this gap, we present mitoLEAF, a collaborative, freely accessible, and academically driven repository for mitochondrial phylogenetic analyses. Unlike commercial alternatives that restrict access to their customers through subscription or purchase, mitoLEAF is openly accessible and replicable, ensuring transparency and scientific reproducibility. Hosted as a GitHub repository and supported by an interactive website, mitoLEAF provides an evolving, quality-controlled phylogenetic resource derived from GenBank, EMPOP, and peer-reviewed literature. In this first release, it expands the haplogroup landscape from 5435 to 6409 haplogroups, integrating recent findings and improving phylogenetic accuracy. By excluding known pathogenic variants, mitoLEAF aims to mitigate ethical concerns associated with reporting medically relevant variants. By prioritizing open science over commercial interests, mitoLEAF serves as a vital, community-driven platform for mitochondrial research, fostering collaboration and continuous development.
    DOI:  https://doi.org/10.1093/nargab/lqaf079
  31. Trends Endocrinol Metab. 2025 Jun 10. pii: S1043-2760(25)00102-X. [Epub ahead of print]
    The trade-off between reproduction and resilience.
    Liankui Zhou, Ying Liu.
      The mitochondrial unfolded protein response (UPRmt) is a transcriptional program that alleviates mitochondrial dysfunction by facilitating the recovery of the mitochondrial network. In Caenorhabditis elegans, reproductive maturity leads to suppression of the UPRmt, suggesting a trade-off between maintenance of stress resilience and fertility. Here, we examine emerging evidence suggesting that the reproduction-associated suppression of UPRmt is a representative example of the physiological costs of reproduction. We focus on the germline-to-soma intertissue signaling mechanisms recently identified in C. elegans, which modulate systemic physiological responses during reproduction. These findings not only illuminate the trade-offs between stress resistance and reproductive capacity but also underscore the broader implications of intertissue communication in coordinating resource allocation.
    Keywords:  Caenorhabditis elegans; intertissue signaling networks; mitochondrial unfolded protein response; proteostasis regulation; reproduction-associated trade-offs
    DOI:  https://doi.org/10.1016/j.tem.2025.05.003
  32. Methods Mol Biol. 2025 ;2925 203-222
    Metabolic Pathway Tracing for NAD+ Synthesis and Consumption.
    Tumpa Dutta, Stephen J Gardell.
      NAD+ is an abundant cellular metabolite which plays vital roles in central metabolism while serving as a cofactor for oxidoreductases and cosubstrate for sirtuins and poly(ADP-ribose)polymerases (PARPs). Decreased tissue NAD+ levels have been linked to aging-associated metabolic decline and a host of chronic diseases. Cellular steady-state NAD+ levels are governed by contemporaneous synthetic and consumptive processes. Hence, lower NAD+ levels in aged tissues can arise from decreased synthesis or increased consumption. A static snapshot of the tissue levels of NAD+ is inadequate for assessing the highly dynamic pathway network which mediates NAD+ synthesis and consumption. Metabolic pathway tracing with stable isotope-labeled NAD+ precursors (e.g., nicotinamide (NAM), nicotinic acid (NA), tryptophan) and high-resolution mass spectrometry (HRMS) can unveil the individual contributions of synthesis and consumption to the steady-state NAD+ concentration. The metabolic fate of the NAD+ precursor can also be traced to metabolic products of NAD+ including NADH, NADP, and NADPH as well as intermediates in the various NAD+ biosynthetic pathways. Metabolic tracing of NAD+ synthesis and degradation as well as conversion of NAD+ to its downstream products is a highly versatile technique. It can be used to interrogate isolated cells, tissues slices, or specimens collected from preclinical or clinical in vivo studies (e.g., blood, urine, tissues). Bold claims about the pivotal role of NAD+ in human health and disease are typically fraught with uncertainty due to an incomplete understanding of NAD+ metabolism. Insight gleaned from metabolic pathway tracing can shed important new light on NAD+ metabolism and help to critically evaluate the intriguing link between cellular NAD+ levels and healthy aging.
    Keywords:  Mass isotopomer distribution profiling; Mass spectrometry; NAD+ consumption; NAD+ flux; NAD+ metabolism; NAD+ synthesis; Stable isotope tracing
    DOI:  https://doi.org/10.1007/978-1-0716-4534-5_14
  33. NPJ Genom Med. 2025 Jun 12. 10(1): 47
    MPSE identifies newborns for whole genome sequencing within 48 h of NICU admission.
    Bennet Peterson, Edwin F Juarez, Barry Moore, Edgar Javier Hernandez, Erwin Frise, Jianrong Li, Yves Lussier, Martin Tristani-Firouzi, Martin G Reese, Sabrina Malone Jenkins, Stephen F Kingsmore, Matthew N Bainbridge, Mark Yandell.
      Identifying critically ill newborns who will benefit from whole genome sequencing (WGS) is difficult and time-consuming due to complex eligibility criteria and evolving clinical features. The Mendelian Phenotype Search Engine (MPSE) automates the prioritization of neonatal intensive care unit (NICU) patients for WGS. Using clinical data from 2885 NICU patients, we evaluated the utility of different machine learning (ML) classifiers, clinical natural language processing (CNLP) tools, and types of Electronic Health Record (EHR) data to identify sick newborns with genetic diseases. Our results show that MPSE can identify children most likely to benefit from WGS within the first 48 h after NICU admission, a critical window for maximally impactful care. Moreover, MPSE provided stable, robust means to identify these children using many combinations of classifiers, CNLP tools, and input data types-meaning MPSE can be used by diverse health systems despite differences in EHR contents and IT support.
    DOI:  https://doi.org/10.1038/s41525-025-00506-3
  34. Exp Biol Med (Maywood). 2025 ;250 10448
    N-acetyl-L-cysteine improves mitochondrial and oxidative defects in the acadian variant of fanconi syndrome.
    Inas Al-Younis, Rebeca Martín-Jiménez, Mehtab Khan, Yann Baussan, Caroline Jose, Yves Thibeault, Etienne Hebert-Chatelain.
      The Acadian variant of Fanconi Syndrome (AVFS) is a rare genetic disorder characterized by renal deficiencies. AVFS is caused by a mutation to NDUFAF6 encoding a complex I assembly factor, and leading to metabolic alterations. We confirmed that fibroblasts derived from AVFS patients have lower complex I activity, mitochondrial membrane potential and cellular respiration. These mitochondrial defects were accompanied by higher levels of 8-hydroxy-2'deoxyguanosine, malondialdehyde and carbonyl, which are markers of oxidative damage to DNA, lipids and proteins, respectively. Thus, we hypothesized that the antioxidant N-Acetyl-L-cysteine (NAC) would reduce oxidative stress and mitochondrial defects in AVFS fibroblasts. Treatment with NAC during 5 days partially restored complex I activity, mitochondrial membrane potential and cellular respiration in AVFS fibroblasts. NAC also prevented oxidative damage in AVFS fibroblasts. This work shows for the first time that the physiopathology of AVFS includes high oxidative stress. It also reveals that NAC and other antioxidant-based strategies might represent an effective pharmacological treatment for AVFS.
    Keywords:  antioxidant; kidney disease; mitochondrial disease; oxidative stress; rare disease
    DOI:  https://doi.org/10.3389/ebm.2025.10448
  35. bioRxiv. 2025 Jun 06. pii: 2025.06.03.656903. [Epub ahead of print]
    The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.
    Sarah J Shemtov, Eric McGann, Lucy Carrillo, Sangmin Lee, Herbert Anson, Claire S Chung, Maria-Eleni Anagnostou, Guan-Ju D Lai, Bert M Verheijen, Junxiang Wan, Ivetta Vorobyova, Monica Sanchez-Contreras, Cheryl A Conover, Max A Thorwald, Pinchas Cohen, Scott R Kennedy, Jean-François Gout, Suraiya Haroon, Marc Vermulst.
      Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian lifespan and protects against a range of age-related diseases. Surprisingly though, we found that reduced IGF-1 signaling fails to extend the lifespan of mitochondrial mutator mice. Accordingly, most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the pro-longevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome and that mitochondrial mutations may impose a hard limit on mammalian lifespan. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.
    DOI:  https://doi.org/10.1101/2025.06.03.656903
  36. Cells. 2025 May 23. pii: 768. [Epub ahead of print]14(11):
    Defective Mitochondrial Respiration in Hereditary Thoracic Aneurysms.
    Daniel Marcos-Ríos, Antonio Rochano-Ortiz, Nerea Méndez-Barbero, Jorge Oller.
      Thoracic aortic aneurysms are life-threatening vascular conditions linked to inherited disorders such as Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, and familial thoracic aortic aneurysms and dissections. While traditionally associated with the extracellular matrix and contractile defects in vascular smooth muscle cells, emerging evidence suggests the key role of mitochondrial dysfunction. Here, we show that the overexpression of ACTA2R179H and TGFBR2G357W in murine aortic VSMCs reduces Mitochondrial Transcription Factor A (Tfam) expression, decreases mitochondrial DNA (mtDNA) content, and impairs oxidative phosphorylation, shifting metabolism toward glycolysis. Notably, nicotinamide riboside, a NAD+ precursor, restores mitochondrial respiration, increases Tfam and mtDNA levels, and promotes a contractile phenotype by enhancing actin polymerization and reducing matrix metalloproteinase activity. These findings identify mitochondrial dysfunction as a shared feature in hereditary thoracic aortic aneurysm, not only in Marfan syndrome, but also in other genetic forms, and highlight mitochondrial boosters as a potential therapeutic strategy.
    Keywords:  Loeys-Dietz syndrome; Marfan syndrome; aneurysm; familial thoracic aortic aneurysm; mitochondria; nicotinamide riboside; vascular smith muscle cells
    DOI:  https://doi.org/10.3390/cells14110768
  37. J Adv Res. 2025 Jun 09. pii: S2090-1232(25)00418-7. [Epub ahead of print]
    Construction of mitochondrial-targeted ferritin carrier: subunit-terminal fused mitochondrial presequences facilitate efficient delivery.
    Jia Zeng, Yitong Li, Xinning Fang, Han Yu, Mengyuan Xu, Xiangyu Zhao, Zhenghong Wu, Xiaole Qi.
       INTRODUCTION: Protein sorting within mitochondria is intricately linked to the amino acid sequence facilitating the transmembrane transport of proteins into this organelle. Leveraging the Mitochondrial Targeting Signal (MTS)-mediated protein sorting mechanism presents a promising strategy for directing therapeutic agents into the mitochondria.
    OBJECTIVES: By fusing MTS to the subunit terminus of recombinant heavy chain ferritin (HFn), we aim to establish a highly effective mitochondrial targeting vector. This fusion is designed to enhance the ability to specifically direct and accumulate within mitochondria, and to precisely deliver Lonidamine (LND), a selective metabolic inhibitor, into these organelles, ultimately realizing potent anti-tumor activity.
    METHODS: Utilizing gene engineering strategies, a plasmid encoding MTS-modified HFn (MTS-HFn) was transferred into E.coli to induce protein expression. At the cellular level, the mitochondrial targeting capacity of MTS-HFn was investigated. Subsequently, LND was encapsulated within MTS-HFn, and its tumoral accumulation and anti-tumor efficacy were studied in tumor-bearing models.
    RESULTS: MTS-HFn demonstrated exceptional mitochondrial targeting, achieving a 2.7-fold higher accumulation in mitochondria compared to wild-type HFn. The targeting mechanism exploration unveiled that the positive charge of MTS drives aggregation of HFn around mitochondria, and mediates its entry into the mitochondrial matrix via the TOM/TIM complex. In vivo antitumor activity studies revealed that MTS-HFn preserved its inherent tumor targeting ability and significantly enhanced the tumor suppressive effect of LND, yielding an inhibition rate of 51.06%.
    CONCLUSION: This vector inspired by natural mitochondrial protein sorting represents an optimal hierarchical delivery system for targeting both tumor and mitochondrial, offering a dependable alternative for precise treatment strategies in mitochondrial diseases.
    Keywords:  Hierarchical delivery; Human ferritin nanocage; Mitochondria targeting; Mitochondrial targeting signal
    DOI:  https://doi.org/10.1016/j.jare.2025.06.015
  38. Anal Methods. 2025 Jun 09.
    A mitochondria-targeted long-wavelength fluorescent probe for imaging sulfur dioxide in ferroptosis.
    Yulong Wu, Tianyu Zhang, Guangyi Jiang, Qingxia Duan, Chen Zuo, Wei Shu.
      Ferroptosis, an iron-dependent, lipid peroxidation-mediated type of programmed cell death, is crucial in the pathogenesis of numerous diseases. Mitochondria, central to cellular energy production, are significantly involved in ferroptosis. Sulfur dioxide (SO2) is generated within both the mitochondria and cytoplasm, and its abnormal levels are linked to mitochondrial dysfunction and various diseases. To detect mitochondrial HSO3- in ferroptosis, we developed CMP, a long-wavelength fluorescent probe with high specificity and a rapid response. CMP utilizes a benzopyrylium cation for HSO3- recognition and mitochondrial targeting. It reacts with HSO3-via Michael addition, quenching fluorescence at 622 nm, and achieves ultrasensitive detection. CMP enables real-time HSO3- monitoring in HeLa cells and zebrafish, and successfully detected increased mitochondrial HSO3- levels during Erastin-induced ferroptosis and CCCP-induced apoptosis. CMP offers a valuable tool for studying ferroptosis-related diseases.
    DOI:  https://doi.org/10.1039/d5ay00578g
  39. Nutrients. 2025 May 29. pii: 1855. [Epub ahead of print]17(11):
    Nicotinamide Adenine Dinucleotide Supplementation to Alleviate Heart Failure: A Mitochondrial Dysfunction Perspective.
    Fan Yu, Huiying Zhao, Lu Luo, Wei Wu.
      Heart failure represents the terminal stage in the development of many cardiovascular diseases, and its pathological mechanisms are closely related to disturbances in energy metabolism and mitochondrial dysfunction in cardiomyocytes. In recent years, nicotinamide adenine dinucleotide (NAD+), a core coenzyme involved in cellular energy metabolism and redox homeostasis, has been shown to potentially ameliorate heart failure through the regulation of mitochondrial function. This review systematically investigates four core mechanisms of mitochondrial dysfunction in heart failure: imbalance of mitochondrial dynamics, excessive accumulation of reactive oxygen species (ROS) leading to oxidative stress injury, dysfunction of mitochondrial autophagy, and disturbance of Ca2+ homeostasis. These abnormalities collectively exacerbate the progression of heart failure by disrupting ATP production and inducing apoptosis and myocardial fibrosis. NAD+ has been shown to regulate mitochondrial biosynthesis and antioxidant defences through the activation of the deacetylase family (e.g., silent information regulator 2 homolog 1 (SIRT1) and SIRT3) and to increase mitochondrial autophagy to remove damaged mitochondria, thus restoring energy metabolism and redox balance in cardiomyocytes. In addition, the inhibition of NAD+-degrading enzymes (e.g., poly ADP-ribose polymerase (PARP), cluster of differentiation 38 (CD38), and selective androgen receptor modulators (SARMs)) increases the tissue intracellular NAD+ content, and supplementation with NAD+ precursors (e.g., β-nicotinamide mononucleotide (NMN), nicotinamide riboside, etc.) also significantly elevates myocardial NAD+ levels to ameliorate heart failure. This study provides a theoretical basis for understanding the central role of NAD+ in mitochondrial homeostasis and for the development of targeted therapies for heart failure.
    Keywords:  ATP; heart failure; mitochondrial dysfunction; nicotinamide adenine dinucleotide; redox
    DOI:  https://doi.org/10.3390/nu17111855
  40. Iran J Child Neurol. 2025 ;19(1): 97-105
    High Succinate peak in Magnetic Resonance Spectroscopy: A Diagnostic Clue for the Leukoencephalopathy Result from Succinate Dehydrogenase Deficiencies.
    Habibe Koc Ucar, Leman Tekin Orgun, Ebru Arhan, Ayse Serdaroglu, Kursad Aydin.
      The Succinate Dehydrogenase (SDH) enzyme is known as Complex-II in the electron transport chain. This study reports the clinical and molecular investigations of three pediatric patients (two of whom are siblings), with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to SDH gene mutations. The patients presented with severe hypotonia, developmental delay, spasticity, macrocephaly, and megalencephaly. Magnetic Resonance Imaging (MRI) revealed signal changes in the frontal, temporal, parietal, occipital cerebral, and cerebellar white matter, corpus striatum, thalamus, substantia nigra, inferior olivary nucleus, pyramidal tracts at the level of the pons and posterior limb of the internal capsule. Other typical findings involved a high succinate peak at 2.42 ppm and lactate peak at 1.3 ppm in Magnetic Resonance Spectroscopy (MRS). The siblings presented due to compound heterozygous c.143A>T (p. Asp48Val) and c.308T>C (p. Met103Thr) SDHB mutations, while the other patient presented due to compound heterozygous c.1754G>A (p. Arg585Gln) and c.1786G>C (p. Asp596His) SDHA mutation. The demonstration of succinate peak, particularly MRS, is highly diagnostic regarding SDH deficiency. MRS should be a standard part of routine radiological exams when there is a suspicion of a neurometabolic disease, especially mitochondrial disorders. Additionally, employing Next-Generation Sequencing (NGS) is advisable for patients as it allows for accurate diagnosis without requiring invasive procedures like muscle biopsies.
    Keywords:  Complex-II-deficiencies; Leukoencephalopathy; Magnetic resonance spectroscopy; Succinate dehydrogenase
    DOI:  https://doi.org/10.22037/ijcn.v19i1.35156
  41. J Orthop Translat. 2025 May;52 441-450
    Mitochondrial Transplantation/Transfer: Promising Therapeutic Strategies for Spinal Cord Injury.
    Xiaochun Xiong, Chao Zhou, Yijun Yu, Qiong Xie, Linying Xia, Qingping Li, Hongming Lin, Songou Zhang, Wenqing Liang.
      Spinal cord injury (SCI) remains an unresolved and complex medical challenge. In SCI, mitochondrial dysfunction leads to calcium overload and an increase in reactive oxygen species (ROS). Intercellular mitochondrial transfer has the potential to rescue surviving neurons, while exogenous mitochondrial transplantation can be performed through direct injection or cell-assisted methods. This review explored the current state of research on mitochondrial transplantation and transfer as potential treatments for SCI. It also analyzed the therapeutic implications, influencing factors, and advanced delivery methods for both endogenous mitochondrial transfer and exogenous mitochondrial transplantation. Furthermore, future research directions, including optimizing mitochondrial delivery methods, determining optimal dosages for different delivery approaches, were discussed based on larger animal models and clinical trials. The goal of this review was to introduce novel concepts and prospects for SCI therapy and to contribute to the advancement of medical research in this field.
    The Translational Potential of This Article: At present, SCI lacks effective therapies, with mitochondrial dysfunction playing a central role in neuronal damage. Mitochondrial transplantation holds promise for restoring bioenergetic function. However, key challenges remain, including optimizing delivery methods, determining appropriate dosages, scalability, donor mitochondrial sourcing, regulatory hurdles and ensuring successful integration. Addressing these issues requires non-invasive platforms, validation in large-animal models, and clinical trials. This approach may bridge mitochondrial biology with translational engineering, thereby advancing the development of regenerative therapies for SCI.
    Keywords:  Autologous; Exogenous; Mitochondrial transplantation; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.jot.2025.04.017
  42. Int J Biol Macromol. 2025 Jun 07. pii: S0141-8130(25)05523-0. [Epub ahead of print]318(Pt 2): 144970
    Impacts of pathogenic mutations on the structures of the CHCHD10 monomer: An AlphaFold3 study linked to the generation of conformational ensembles.
    Fatma Irem Akkum, Cahit Emre Ozbas, Melisa Damar, Vladimir N Uversky, Rumeysa Fayetorbay, David E Kang, Junga Alexa Woo, Orkid Coskuner-Weber.
      CHCHD10, a member of the coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein family, plays a critical role in mitochondrial function. The link between pathological mutations and CHCHD10 is important and increasingly recognized, especially due to mitochondrial dysfunction and its association with neurodegenerative diseases. Several mutations in CHCHD10 have been directly linked to human diseases, such as Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), mitochondrial myopathies, and Spinal Muscular Atrophy-Jokela type (SMAJ). In this study, we investigate the structural properties of wild-type and mutant CHCHD10 proteins using AlphaFold3 linked to the generation of conformational ensembles. Structural changes may modulate interactions, flexibility, and aggregation tendencies, potentially influencing neurodegenerative disease pathogenesis linked to mitochondrial dysfunction. Notably, disease-associated mutations like R15S, P23L, and S59L alter secondary structure formations such as 310-helices and β-sheets. Despite, we find that the compactness of CHCHD10 is not significantly altered by genetic mutations since radius of gyration values range between 32.69 Å and 35.94 Å. All in all, we find that the compactness is not but the secondary and tertiary structure properties are affected by pathological mutations. We propose that evolution may have optimized CHCHD10 to maintain a suitable radius of gyration that provides sufficient flexibility through its intrinsically disordered region while ensuring efficient interaction with diverse molecules. Thus, alterations in secondary and tertiary structures through mutations might be a mechanism for fine-tuning the protein's functionality while preserving its optimal state. These characteristics might be related to the pathologies of neurodegenerative diseases linked to mitochondrial dysfunction.
    Keywords:  AlphaFold3; CHCHD10; Conformational ensembles; Pathogenic mutations; Structure-function relationship
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144970
  43. Am J Hum Genet. 2025 Jun 05. pii: S0002-9297(25)00183-1. [Epub ahead of print]112(6): 1489-1495
    Consultation informs strategies for improving the use of functional evidence in variant classification.
    Rehan M Villani, Bronwyn Terrill, Emma Tudini, Maddison E McKenzie, Corrina C Cliffe, Christopher N Hahn, Ben Lundie, Tessa Mattiske, Ebony Matotek, Abbye E McEwen, Sarah L Nickerson, James Breen, Douglas M Fowler, John Christodoulou, Lea Starita, Alan F Rubin, Amanda B Spurdle.
      When investigating whether a variant identified by diagnostic genetic testing is causal for disease, applied genetics professionals evaluate all available evidence to assign a clinical classification. Functional assays of higher and higher throughput are increasingly being generated and, when appropriate, can provide strong functional evidence for or against pathogenicity in variant classification. Despite functional assay data representing unprecedented value for genomic diagnostics, challenges remain around the application of functional evidence in variant curation. To investigate a growing gap articulated in recent international studies, we surveyed genetic diagnostic professionals in Australasia to assess their application of functional evidence in clinical practice. The survey results echo the universal difficulty in evaluating functional evidence but expand on this by indicating that even self-proclaimed expert respondents are not confident to apply functional evidence, mainly due to uncertainty around practice recommendations. Respondents also identified the need for support resources and educational opportunities, and in particular requested expert recommendations and updated practice guidelines to improve translation of experimental data to curation evidence. We then collated a list of 226 functional assays and the evidence strength recommended by 19 ClinGen Variant Curation Expert Panels. Specific assays for more than 45,000 variants were evaluated, but evidence recommendations were generally limited to lower throughput and strength. As an initial step, we provide our collated list of assay evidence as a source of international expert opinion on the evaluation of functional- evidence and conclude that these results highlight an opportunity to develop additional support resources to fully utilize functional evidence in clinical practice.
    Keywords:  ACMG/AMP guidelines; assay; clinical genomics; diagnostic genetics; education; functional evidence; pathogenicity assessment; variant classification
    DOI:  https://doi.org/10.1016/j.ajhg.2025.05.003
  44. Geroscience. 2025 Jun 12.
    Impact of sarcopenia and obesity on skeletal muscle size, gene expression, and mitochondrial function.
    Hector G Paez, Christopher R Pitzer, Jessica L Halle, Peter J Ferrandi, James A Carson, Junaith S Mohamed, Stephen E Alway.
      Skeletal muscle is a primary tissue of dysfunction during both aging and obesity. Recently, the coincidence of obesity and aging has gained attention due to the intersection of the obesity epidemic with an aging demographic. Both aging and obesity are associated with marked defects in skeletal muscle metabolic health. Despite these findings, we have a poor understanding of how obesity and aging may interact to impact skeletal muscle mass and metabolic health. Therefore, we investigated the impact of high-fat diet (HFD)-induced obesity on skeletal muscle mass, mitochondrial function, transcriptomics, and whole-body metabolism in young and aged mice. We observed main effects of diet and age on several measures of whole-body metabolic function (VO2, VCO2, and RER). Complex I-driven mitochondrial proton leak was significantly elevated by HFD-induced obesity across both age groups; however, a main effect of aging for reduced complex I leak was detected in the soleus muscle. Interestingly, aged animals fed a HFD did not exhibit lower muscle mass than chow-fed young animals, but did present with stark increases in muscle triglyceride content and a unique transcriptional response to HFD. HFD-induced obesity impacted the muscle transcriptome differently in the muscles of young and aged mice, indicating that obesity can change altered gene expression with age. Our findings suggest that the presence of obesity can both compound and counteract age-associated changes to muscle mass, gene expression, and mitochondrial function.
    Keywords:  Aging; Metabolism; Mitochondria; Obesity; Sarcopenic obesity; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11357-025-01726-2
  45. Mol Neurobiol. 2025 Jun 13.
    Polyphenols and Exercise in Mitochondrial Biogenesis: Focus on Age-Related CNS Disorders.
    Junbiao Tu.
      Age-related central nervous system (CNS) disorders, including neurodegenerative diseases, represent a growing global health burden. Mitochondrial dysfunction is a recognized hallmark in the pathogenesis of these conditions, emphasizing the critical importance of maintaining neuronal energy homeostasis and cellular integrity. Mitochondrial biogenesis, the dynamic process of generating new, functional mitochondria, is paramount for neuronal health and resilience against age-related decline. This review investigates the therapeutic potential of physical activity and polyphenols in modulating mitochondrial biogenesis and offering neuroprotection within the context of age-related CNS disorders. We explore how regular exercise profoundly impacts the brain by enhancing synaptic plasticity, promoting neurogenesis via neurotrophic factors like BDNF, and stimulating mitochondrial biogenesis through pathways such as PGC-1alpha activation. These adaptations collectively improve cognitive function and bolster neuronal resistance to damage. Concurrently, polyphenols, known for their antioxidant and anti-inflammatory properties, demonstrate significant neuroprotective effects. They are capable of crossing the blood-brain barrier and influencing key neuronal signaling pathways, directly stimulating mitochondrial biogenesis, and mitigating oxidative stress, thereby supporting neuronal survival. By synthesizing current evidence, this review highlights the complementary and potentially synergistic roles of exercise and polyphenols in preserving mitochondrial health and function in the CNS. The combined impact of these interventions offers a promising non-pharmacological strategy to combat age-related neurodegeneration. Future research should focus on optimizing exercise protocols and polyphenol interventions in human trials to maximize their neurotherapeutic benefits for CNS disorders.
    Keywords:  Age-related central nervous system disorders; Exercise; Mitochondrial biogenesis; Polyphenol
    DOI:  https://doi.org/10.1007/s12035-025-05121-y
  46. Front Synaptic Neurosci. 2025 ;17 1562065
    Differential Ca2+ handling by isolated synaptic and non-synaptic mitochondria: roles of Ca2+ buffering and efflux.
    Jyotsna Mishra, Kyle Bevers, Keguo Li, Armaan Zare, James S Heisner, Ailing Tong, Wai-Meng Kwok, David F Stowe, Amadou K S Camara.
      Mitochondria regulate intracellular calcium ion (Ca2+) signaling by a fine-tuned process of mitochondrial matrix (m) Ca2+ influx, mCa2+ buffering (sequestration) and mCa2+ release (Ca2+ efflux). This process is critically important in the neurosynaptic terminal, where there is a simultaneous high demand for ATP utilization, cytosolic (c) Ca2+ regulation, and maintenance of ionic gradients across the cell membrane. Brain synaptic and non-synaptic mitochondria display marked differences in Ca2+ retention capacity. We hypothesized that mitochondrial Ca2+ handling in these two mitochondrial populations is determined by the net effects of Ca2+ uptake, buffering or efflux with increasing CaCl2 boluses. We found first that synaptic mitochondria have a more coupled respiration than non-synaptic mitochondria; this may correlate with the higher local energy demand in synapses to support neurotransmission. When both mitochondrial fractions were exposed to increasing mCa2+ loads we observed decreased mCa2+ sequestration in synaptic mitochondria as assessed by a significant increase in the steady-state free extra matrix Ca2+ (ss[Ca2+]e) compared to non-synaptic mitochondria. Since, non-synaptic mitochondria displayed a significantly reduced ss[Ca2+]e, this suggested a larger mCa2+ buffering capacity to maintain [Ca2+]m with increasing mCa2+ loads. There were no differences in the magnitude of the transient depolarizations and repolarizations of the membrane potential (ΔΨm) and both fractions exhibited similar gradual depolarization of the baseline ΔΨm during additional CaCl2 boluses. Adding the mitochondrial Na+/Ca2+ exchanger (mNCE) inhibitor CGP37157 to the mitochondrial suspensions unmasked the mCa2+ sequestration and concomitantly lowered ss[Ca2+]e in synaptic vs. non-synaptic mitochondria. Adding complex V inhibitor oligomycin plus ADP (OMN + ADP) bolstered the matrix Ca2+ buffering capacity in synaptic mitochondria, as did Cyclosporin A (CsA), in non-synaptic. Our results display distinct differences in regulation of the free [Ca2+]m to prevent collapse of ΔΨm during mCa2+ overload in the two populations of mitochondria. Synaptic mitochondria appear to rely mainly on mCa2+ efflux via mNCE, while non-synaptic mitochondria rely mainly on Pi-dependent mCa2+ sequestration. The functional implications of differential mCa2+ handling at neuronal synapses may be adaptations to cope with the higher metabolic activity and larger mCa2+ transients at synaptosomes, reflecting a distinct role they play in brain function.
    Keywords:  Ca2+ buffering; Ca2+ efflux; bioenergetics; non-synaptic mitochondria; synaptic mitochondria
    DOI:  https://doi.org/10.3389/fnsyn.2025.1562065
  47. bioRxiv. 2025 May 27. pii: 2025.05.26.656235. [Epub ahead of print]
    PFKFB2 is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
    Kylene M Harold, Satoshi Matsuzaki, Atul Pranay, Jie Zhu, Anna Faakye, Kenneth M Humphries.
       Background: The heart's constant energy demands make metabolic flexibility critical to its function as nutrient availability varies. The enzyme phosphofructokinase-2/fructose 2,6-bisphosphatase (PFKFB2) contributes to this flexibility by acting as a positive or negative regulator of cardiac glycolysis. We have previously shown that PFKFB2 is degraded in the diabetic heart and that a cardiac-specific PFKFB2 knockout (cKO) impacts ancillary glucose pathways and mitochondrial substrate preference. Therefore, defining PFKFB2's role in mitochondrial metabolic flexibility is paramount to understanding both metabolic homeostasis and metabolic syndromes. Further, it is unknown how PFKFB2 loss impacts the heart's response to acute stress. Here we examined how cardiac mitochondrial flexibility and the post-translational modification O-GlcNAcylation are affected in cKO mice in response to fasting or pharmacologic stimulation.
    Methods: cKO and litter-matched controls (CON) were sacrificed in the fed or fasted (12 hours) states, with or without a 20 minute stimulant stress of caffeine and epinephrine.Mitochondrial respiration, metabolomics, and changes to systemic glucose homeostasis were evaluated.
    Results: cKO mice had moderate impairment in mitochondrial metabolic flexibility, affecting downstream glucose oxidation, respiration, and CPT1 activity. O-GlcNAcylation, a product of ancillary glucose metabolism, was upregulated in cKO hearts in the fed state, but this was ameliorated in the fasted state. Furthermore, metabolic remodeling in response to PFKFB2 loss was sufficient to impact circulating glucose in fasted and stressed states.
    Conclusions: PFKFB2 is essential for fed-to-fasted changes in cardiac metabolism and plays an important regulatory role in protein O-GlcNAcylation. Its loss also affects systemic glucose homeostasis under stressed conditions.
    Graphic Abstract:
    Research Perspective: This study raises and answers three key questions: how PFKFB2 contributes to cardiac mitochondrial metabolic flexibility, how post-prandial status regulates O-GlcNAcylation in a PFKFB2-dependent manner, and how altered cardiac glucose use impacts systemic glucose homeostasis under stress.These findings highlight a novel role for nutrient state in regulating cardiac metabolism, and especially O-GlcNAcylation, with PFKFB2 loss.Future studies should investigate whether reducing O-GlcNAcylation through fasting is sufficient to ameliorate pathological changes observed in the absence of PFKFB2.
    DOI:  https://doi.org/10.1101/2025.05.26.656235
  48. Signal Transduct Target Ther. 2025 Jun 11. 10(1): 190
    Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances.
    Xieyang Xu, Yan Pang, Xianqun Fan.
      Mitochondria are the energy production centers in cells and have unique genetic information. Due to the irreplaceable function of mitochondria, mitochondrial dysfunction often leads to pathological changes. Mitochondrial dysfunction induces an imbalance between oxidation and antioxidation, mitochondrial DNA (mtDNA) damage, mitochondrial dynamics dysregulation, and changes in mitophagy. It results in oxidative stress due to excessive reactive oxygen species (ROS) generation, which contributes to cell damage and death. Mitochondrial dysfunction can also trigger inflammation through the activation of damage-associated molecular patterns (DAMPs), inflammasomes and inflammatory cells. Besides, mitochondrial alterations in the functional regulation, energy metabolism and genetic stability accompany the aging process, and there has been a lot of evidence suggesting that oxidative stress and inflammation, both of which are associated with mitochondrial dysfunction, are predisposing factors of aging. Therefore, this review hypothesizes that mitochondria serve as central hubs regulating oxidative stress, inflammation, and aging, and their dysfunction contributes to various diseases, including cancers, cardiovascular diseases, neurodegenerative disorders, metabolic diseases, sepsis, ocular pathologies, liver diseases, and autoimmune conditions. Moreover, we outline therapies aimed at various mitochondrial dysfunctions, highlighting their performance in animal models and human trials. Additionally, we focus on the limitations of mitochondrial therapy in clinical applications, and discuss potential future research directions for mitochondrial therapy.
    DOI:  https://doi.org/10.1038/s41392-025-02253-4
  49. JACC Basic Transl Sci. 2025 Jun 10. pii: S2452-302X(25)00221-9. [Epub ahead of print]10(7): 101301
    ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium.
    Mariam Meddeb, Navid Koleini, Mohammad Keykhaei, Ting Liu, Marcus Rhodehamel, Lorena Mandarano, Farnaz Farshidfar, Liang Zhao, Seoyoung Kwon, Gizem Keceli, Ismayil Ahmet, Nazareno Paolocci, Virginia Hahn, Kavita Sharma, Erika L Pearce, David A Kass.
      ATP-citrate lyase (ACLY) regulates lipogenesis and cell proliferation, and forms a cytosolic TCA-bypass circuit impacting NADH. We show that acute and chronic ACLY inhibition in cardiomyocytes depresses the NAD+/NADH ratio by increasing mitochondrial NADH. Acute suppression causes dose-dependent cytotoxicity, but at low doses augments aerobic respiration without impeding myocyte function. ACLY is reduced in human failing myocardium, and mice with myocardial or myocyte ACLY knockdown display mildly depressed function, particularly after pressure-overload, and exertional limitations. NAD+ enhancement ameliorates dysfunction/toxicity from ACLY inhibition. These results reveal that ACLY intrinsically regulates cardiac NAD+/NADH balance and respiration, which can affect rest and reserve heart function.
    Keywords:  TCA cycle; heart disease; metabolism; myocardium; redox; reductive stress
    DOI:  https://doi.org/10.1016/j.jacbts.2025.04.015
  50. Cell Regen. 2025 Jun 09. 14(1): 23
    eIF5A maintains intestinal epithelial homeostasis by sustaining intestinal stem cells.
    Leilei Li, Yanhui Xiao, Liansheng Liu, Qianying Zhang, Yong Zhang, Dahai Zhu, Ye-Guang Chen.
      Intestinal homeostasis is sustained by self-renewal of intestinal stem cells (ISCs), which continuously divide and produce proliferative transit-amplifying (TA) and then progenitor cells. Eukaryotic translation initiation factor 5A (eIF5A), a conserved translation factor, involves in a variety of cellular processes, yet its role in intestinal homeostasis remains unclear. Here, we demonstrate that eIF5A is indispensable for maintaining intestinal epithelial homeostasis. Conditional knockout of Eif5a in the adult mouse intestinal epithelium leads to stem cell loss, suppressed cell proliferation, and increased apoptosis within the crypts, concurrent with shortened gut length, reduced mouse body weight and rapid animal mortality. Consistently, Eif5a deletion in intestinal organoids also exhibits resembling cellular phenotypes. Mass spectrometry analysis reveals a significant downregulation of mitochondrial proteins, particularly those involved in mitochondrial translation, upon eIF5A depletion. Analysis of a published single-cell RNA sequencing dataset shows that mitochondrial translation-related genes, including Dars2, are highly expressed in ISC, TA and progenitor cells. Furthermore, eIF5A-deficient organoids exhibit impaired mitochondrial function, characterized by reduced ATP levels and increased reactive oxygen species (ROS). These findings highlight a critical role for eIF5A in sustaining intestinal epithelial homeostasis by regulating mitochondrial translation, providing a new insight into the molecular mechanism underlying intestinal stem cell renewal and tissue maintenance.
    Keywords:  Intestinal homeostasis; Intestinal stem cells; Mitochondrial translation; eIF5A
    DOI:  https://doi.org/10.1186/s13619-025-00243-z
  51. Intractable Rare Dis Res. 2025 May 31. 14(2): 148-150
    A case of mitochondrial diabetes mellitus with successful therapeutic response following the initiation of imeglimin.
    Atsushi Ishimura, Satomi Suzuki.
      Mitochondria are present in cells throughout the body and play a crucial role in energy production. They contain their own DNA, and mutations in this DNA can lead to a reduction in pancreatic beta cells and decreased insulin secretion, contributing to the development of diabetes. Insulin therapy has been considered a rational treatment, as the primary issue is impaired insulin secretion, but it primarily serves as a coping mechanism. Recently, however, imeglimin ‒ a drug believed to influence various mitochondria-mediated processes ‒ has been introduced and is expected to offer therapeutic benefits for mitochondrial diabetes. Here, we report a case of successful glycemic control following the addition of imeglimin in a patient with mitochondrial diabetes mellitus. After starting imeglimin, the patient's blood glucose levels stabilized, and he continues treatment. While the molecular target of imeglimin remains unknown, it is possible that the drug may offer significant benefits for patients with mitochondrial diabetes mellitus.
    Keywords:  imeglimin; intractable disease; mitochondrial diabetes mellitus
    DOI:  https://doi.org/10.5582/irdr.2025.01019
  52. Nat Med. 2025 Jun 06.
    Personalized, in vivo gene editing for a newborn.
    Karen O'Leary.
      
    Keywords:  Gene therapy; Genetics; Paediatrics
    DOI:  https://doi.org/10.1038/d41591-025-00037-5
  53. Biochem Biophys Res Commun. 2025 Jun 04. pii: S0006-291X(25)00871-X. [Epub ahead of print]775 152157
    Potential Therapy for Alzheimer's Disease: Modulating Tunneling Nanotube Dynamics Restores Mitochondrial Transport and Ameliorates Aβ-induced Toxicity.
    Jing Chen, Qianya Zhang.
      The development of therapies for Alzheimer's disease (AD) has long been constrained by the limitations of single-target strategies. Based on the core pathological features of AD-the cascade amplification effects of β-amyloid (Aβ) transcellular transport and mitochondrial dysfunction-combined with recent breakthrough discoveries: ① In vivo observation of tunneling nanotubes (TNTs) formation in the cerebral cortex of mouse models, ② Aβ-induced TNTs formation, ③ TNTs-mediated intercellular propagation of Aβ pathology, ④ TNTs-driven compensatory transfer of functional mitochondria between cells, this review proposes an innovative dual-directional regulatory strategy that precisely targets the molecular mechanisms of TNTs to simultaneously suppress Aβ pathological propagation and enhance mitochondrial rescue in diseased cells. By systematically elucidating: ① The molecular mechanisms underlying TNTs-mediated specific transport of Aβ and functional mitochondria, ② The molecular basis for directional regulation of TNTs transport, this strategy aims to develop potential therapeutic agents for AD, offering a novel intervention paradigm to overcome the current therapeutic impasse in AD treatment.
    Keywords:  Alzheimer's disease; Mitochondria; Tunneling nanotubes; β-Amyloid
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152157
  54. MedComm (2020). 2025 Jun;6(6): e70253
    Mitochondrial Transplantation: A Novel Therapeutic Approach for Treating Diseases.
    Xinglu Miao, Pei Jiang, Zhaoping Wang, Weihua Kong, Lei Feng.
      Advances in mitochondrial biology have led to the development of mitochondrial transplantation as a novel and promising therapeutic strategy. This review provides a comprehensive analysis of the multifaceted roles of mitochondria in health and disease, highlighting their central functions in energy production, antioxidant defense, calcium signaling, apoptosis regulation, and mitochondrial homeostasis maintenance. We explore the mechanisms by which transplanted mitochondria exert their therapeutic effects, including restoring ATP production, attenuating oxidative stress, modulating inflammatory responses, reducing cellular apoptosis, promoting cell repair and regeneration, facilitating neural circuit reconstruction, and exhibiting antitumor properties. Key preclinical studies demonstrating the efficacy of mitochondrial transplantation across in vitro and in vivo disease models are discussed, along with the status of clinical trials. The review also critically compares mitochondrial transplantation with other mitochondria-targeted therapies, evaluating their relative advantages and limitations. Finally, we discuss the current challenges of translating this innovative therapy into clinical practice, such as mitochondrial isolation and purification, storage, targeted delivery, potential immune responses, and long-term safety and efficacy concerns. This review aims to stimulate further research and development in this promising field, paving the way for novel therapeutic interventions for various diseases.
    Keywords:  disease therapy; mitochondria; mitochondrial transplantation; therapeutic strategy
    DOI:  https://doi.org/10.1002/mco2.70253
  55. J Inherit Metab Dis. 2025 Jul;48(4): e70056
    First in Human Gene Editing for an Inherited Metabolic Disease.
    Shamima Rahman, Julien Baruteau.
      
    DOI:  https://doi.org/10.1002/jimd.70056
  56. Eur Heart J Case Rep. 2025 Jun;9(6): ytaf198
    Mitochondrial cardiomyopathy presenting as isolated cardiac involvement with rapid progression due to the MT-TI m.4300A>G mutation.
    Lingcheng Zhu, Jinghui Li, Minjie Lu.
      
    DOI:  https://doi.org/10.1093/ehjcr/ytaf198
  57. Mech Ageing Dev. 2025 Jun 06. pii: S0047-6374(25)00058-2. [Epub ahead of print]226 112082
    Targeting mitophagy in the heart: Exploring the therapeutic potential of MicroRNAs.
    Amin Javadifar, Masoud Tahani, Sorousha Khayat, Shiva Rakhshani Nasab, Sercan Karav, Prashant Kesharwani, Amirhossein Sahebkar.
      Mitophagy, a selective form of autophagy, plays an indispensable role in preserving mitochondrial integrity by eliminating dysfunctional mitochondria, thereby sustaining cellular homeostasis. This process is particularly critical in cardiomyocytes, which rely heavily on high-quality mitochondria to meet their substantial energy demands. Impaired mitophagy has been implicated in the pathogenesis of various cardiovascular diseases, including ischemic heart disease, heart failure, and cardiomyopathy. Emerging evidence highlights the pivotal regulatory role of microRNAs (miRNAs)-small non-coding RNA molecules-in modulating mitophagy by targeting key genes such as PINK1, Parkin, and FUNDC1, which are integral to mitochondrial quality control. This review comprehensively examines the dual capacity of miRNAs to either enhance or suppress mitophagy and evaluates the implications of these regulatory actions for cardiovascular health. For instance, miRNAs such as miR-24-3p and miR-125a-5p modulate mitophagy pathways, influencing cardiac function in distinct ways. Additionally, miRNAs like miR-34a and miR-330-3p may exert broader effects on mitochondrial homeostasis in cardiac tissue. This paper further explores the therapeutic potential of targeting miRNAs to restore mitophagy equilibrium and mitigate mitochondrial dysfunction, offering novel avenues for cardiovascular disease management. By synthesizing recent findings, this review underscores the promise of miRNA-based interventions and identifies critical directions for future research.
    Keywords:  Cardiac health; Cardiovascular diseases; MicroRNAs; Mitochondrial quality control; Mitophagy; Therapeutic targets
    DOI:  https://doi.org/10.1016/j.mad.2025.112082
  58. Brain. 2025 Jun 09. pii: awaf219. [Epub ahead of print]
    Charcot-Marie-Tooth disease type 1E: clinical natural history and molecular impact of PMP22 variants.
    Inherited Neuropathy Consortium
      Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare, autosomal dominant peripheral neuropathy caused by missense variants, deletions, and truncations within the peripheral myelin protein-22 (PMP22) gene. CMT1E phenotypes vary depending on the specific variant, ranging from mild to severe, and there is little natural history and phenotypic progression data on individuals with CMT1E. Patients with CMT1E were evaluated during initial and follow-up visits at sites within the Inherited Neuropathy Consortium. Clinical characteristics were obtained from history, neurological exams, and nerve conduction studies. Clinical outcome measures were used to quantify baseline and longitudinal changes, including the Rasch-modified CMT Examination Score version 2 (CMTESv2-R) and the CMT Pediatric Scale (CMTPedS). The trafficking of PMP22 variants in transfected cells was correlated to disease severity. Twenty-four presumed disease-causing PMP22 variants were identified in 50 individuals from 35 families, including 19 missense variants, three in-frame deletions, and two truncations. Twenty-nine patients presented with delayed walking during childhood. At their baseline evaluation, the mean CMTESv2-R in 46 patients was 16 ± 7.72 (out of 32), and the mean CMTPedS from 17 patients was 28 ± 6.35 (out of 44). Six individuals presented with hearing loss, eleven with scoliosis, three with hip dysplasia, and one with both scoliosis and hip dysplasia. Twenty variants were localized within in transmembrane domains; 31 of 35 individuals with these variants had moderate to severe phenotypes. Three variants were found in the extracellular domain and were associated with milder phenotypes. Reduced expression of PMP22 at the cell surface, and the location of missense variants within in the transmembrane domain correlated with disease severity. Pathogenic PMP22 variants located within the transmembrane regions usually cause a moderate to severe clinical phenotype, beginning in early childhood, and have impaired trafficking to the plasma membrane.
    Keywords:   PMP22 ; Charcot-Marie-Tooth type 1E (CMT1E); natural history
    DOI:  https://doi.org/10.1093/brain/awaf219
  59. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2415071122
    Generative prediction of causal gene sets responsible for complex traits.
    Benjamin Kuznets-Speck, Buduka K Ogonor, Thomas P Wytock, Adilson E Motter.
      The relationship between genotype and phenotype remains an outstanding question for organism-level traits because these traits are generally complex. The challenge arises from complex traits being determined by a combination of multiple genes (or loci), which leads to an explosion of possible genotype-phenotype mappings. The primary techniques to resolve these mappings are genome/transcriptome-wide association studies, which are limited by their lack of causal inference and statistical power. Here, we develop an approach that combines transcriptional data endowed with causal information and a generative machine learning model designed to strengthen statistical power. Our implementation of the approach-dubbed transcriptome-wide conditional variational autoencoder (TWAVE)-includes a variational autoencoder trained on human transcriptional data, which is incorporated into an optimization framework. Given a trait phenotype, TWAVE generates expression profiles, which we dimensionally reduce by identifying independently varying generalized pathways (eigengenes). We then conduct constrained optimization to find causal gene sets that are the gene perturbations whose measured transcriptomic responses best explain trait phenotype differences. By considering several complex traits, we show that the approach identifies causal genes that cannot be detected by the primary existing techniques. Moreover, the approach identifies complex diseases caused by distinct sets of genes, meaning that the disease is polygenic and exhibits distinct subtypes driven by different genotype-phenotype mappings. We suggest that the approach will enable the design of tailored experiments to identify multigenic targets to address complex diseases.
    Keywords:  biological networks; complex systems; gene regulatory networks; generative deep learning; nonlinear dynamics
    DOI:  https://doi.org/10.1073/pnas.2415071122
  60. Orphanet J Rare Dis. 2025 Jun 06. 20(1): 283
    Open-label pilot study using hydroxytyrosol as dietary supplements in patients with mitochondrial diseases.
    Tsz Sum Wong, Emily Man, Ian Chi Kei Wong, Shirley Xue Li, Hui Zhi, Ka Man Carmen Yeung, Ka Yee Yip, Anna Ka Yee Kwong, Kiran Moti Belaramani, Suet Na Wong, Anne Mei Kwun Kwok, Miu Mak, Toby Chun Hei Chan, Pui Yee Lau, Yee Ling Elaine Kan, Kwok Chun Wong, Freddie Poon, Vansie Kwok, Chun Yin Dick Li, Paul Lau, Sze Man Lam, Vanessa Chu, Chi Fung Godfrey Chan, Cheuk Wing Fung.
       BACKGROUND: Mitochondrial Diseases (MDs) refers to a heterogeneous group of inherited metabolic disorders resulting in defective cellular energy production due to abnormal oxidative phosphorylation (OXPHOS) caused by pathogenic mitochondrial DNA or nuclear DNA variants. As mitochondria are pivotal for cell bioenergetics, MDs could potentially affect multisystem, leaving a devastating and life-threatening impact. The treatment of MDs present significant challenges due to the complexity of the disease and the wide heterogeneity of its molecular defects. Thus, the need for innovative and more comprehensive therapeutic approaches is evident.
    METHODS: This longitudinal, open-label study was a pilot trial involving 9 paediatric MD patients, aiming to gain a better understanding on the impact of hydroxytyrosol (HT) on the clinical outcomes of MD patients and to assess the feasibility and logistics of using HT as a dietary supplement for MD patients. Subjects received HT daily as dietary supplements for 12 months. Following this period, patients were then randomly assigned to either discontinue HT or continue receiving HT as their dietary supplements for an additional 6 months. Outcome measures that were assessed included the International Paediatric Mitochondrial Disease Scores, biochemical parameters, and quality of life assessments.
    RESULTS: Among the outcome measures assessed, HT supplementation demonstrated the most considerable impact on improving the health-related quality of life according to the PedsQL scoring system and potential effects on a subgroup of MD patients with Mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS).
    DISCUSSION: This study demonstrated that HT supplementation resulted in improvement in health-related quality of life in MD patients, while the subgroup of MELAS patients showed additional potential beneficial effect from HT use. As a pilot trial, this study importantly highlighted HT's tolerability in MD patients, which would facilitate trials of larger scale to be performed in the future.
    CONCLUSION: This study highlights the use of HT as a health supplement and its potential therapeutic effects in paediatric patients diagnosed with MDs, especially in MELAS patients. The results lay the foundation for future large-scale clinical trials. Consequently, further clinical intervention studies and investigations into HT's potential therapeutic mechanisms at the molecular and intercellular levels are strongly encouraged.
    Keywords:  Hydroxytyrosol; MELAS; Mitochondrial diseases; Pilot study
    DOI:  https://doi.org/10.1186/s13023-025-03795-0
  61. Nat Aging. 2025 Jun 11.
    Using RNA therapeutics to promote healthy aging.
    Shuying Chen, Qian Chen, Xinru You, Zhuoming Zhou, Na Kong, Fabrisia Ambrosio, Yihai Cao, Reza Abdi, Wei Tao.
      Aging is characterized by a gradual decline of cellular and physiological functions over time and an increased risk of different diseases. RNA therapeutics constitute an emerging approach to target the molecular mechanisms of aging and age-related diseases via rational design and have several advantages over traditional drug therapies, including high specificity, low toxicity and the potential for rapid development and production. Here, we discuss the latest developments in RNA therapeutics designed to promote healthy aging, including RNA activation, messenger RNA therapy, RNA interference, antisense oligonucleotides, aptamers and CRISPR-Cas-mediated RNA editing. We also review the latest preclinical and clinical studies of RNA technology for treating age-related diseases, including neurodegenerative, cardiovascular and musculoskeletal diseases. Finally, we discuss the challenges of RNA technology aimed at supporting healthy aging. We anticipate that the fusion of RNA therapeutics and aging biology will have an important effect on the development of new medicines and maximization of their efficacy.
    DOI:  https://doi.org/10.1038/s43587-025-00895-1
  62. Methods Mol Biol. 2025 ;2925 145-160
    Spatial Atmospheric Pressure MALDI HRMS Analysis of Histological Sections of FFPE Samples Reveals a Unique Subset of the Metabolome.
    Gilles Frache, David C Muddiman, Simona Ospitalieri, Caleigh R O'Connor, Dietmar R Thal, Peter D E M Verhaert.
      We describe a method that allows high-resolution mass spectrometry (HRMS) imaging of metabolites in tissue sections from formaldehyde-fixed, paraffin-embedded (FFPE) biobanks. This top-down variant of MS imaging expands the molecular scope of mass spectrometry histochemistry (MSHC) from peptidomics to metabolomics. The method makes the vast archives of FFPE biobanks accessible for MSHC-based biomarker discovery research of not only small endogenous peptides but also (a subset of) metabolites. FFPE biobank tissues include well-documented clinical samples representing diseases with a high medical need and often presently not clinically diagnosable and/or curable.Our protocol starts with FFPE tissue sections prepared from samples procured from biobanks. We describe how to remove paraffin and coat the section with MALDI matrix while maximally reducing analyte delocalization or washout. We detail appropriate programming of the MSHC data acquisition and illustrate a way to process MSHC data (including conversion to the generic imzML format) and browse MSHC datasets. Finally, we show options to present the data in the form of annotated MSHC images.
    Keywords:  Atmospheric pressure MALDI; Formaldehyde-fixed paraffin-embedded tissues; Mass spectrometry histochemistry; Orbitrap HRMS; Top-down mass spectrometry imaging
    DOI:  https://doi.org/10.1007/978-1-0716-4534-5_10
  63. Genet Med Open. 2025 ;3 103429
    The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the clinical validity of 111 gene-disease relationships.
    Eleanor C Broeren, Vanessa N Gitau, Alicia B Byrne, Pamela Ajuyah, Marie B Balzotti, Jonathan S Berg, Krista Bluske, B Monica Bowen, Matthew P Brown, Amanda Buchanan, Brendan T Burns, Nicole J Burns, Anjana Chandrasekhar, Aditi Chawla, Jessica X Chong, Maya Chopra, Amanda R Clause, Marina T DiStefano, Stephanie DiTroia, Marwa A Elnagheeb, Amanda N Girod, Himanshu Goel, Katie L Golden-Grant, Thuong Ha, Ada Hamosh, Jennifer M Huang, Madeline Y Hughes, Saumya S Jamuar, Sylvia Kam, Akanchha Kesari, Ai Ling Koh, Rhonda N T Lassiter, Sarah E Leigh, Gabrielle Lemire, Jiin Ying Lim, Alka Malhotra, Hannah R McCurry, Becky Milewski, Shahida Moosa, Stephen A Murray, Emma H Owens, Elizabeth E Palmer, Brooke C Palus, Mayher J Patel, Revathi Rajkumar, Julie C Ratliff, F Lucy Raymond, Bruno Della Ripa Rodrigues Assis, Samin A Sajan, Zinayida Schlachetzki, Sarah A Schmidt, Zornitza Stark, Samuel P Strom, Julie P Taylor, Courtney Thaxton, Devon L Thrush, Sabrina Toro, Kezang C Tshering, Nicole A Vasilevsky, Bess Wayburn, Ryan F Webb, Anne O'Donnell-Luria, Alison J Coffey.
       Purpose: The Clinical Genome Resource (ClinGen) Gene Curation Expert Panels have historically focused on specific organ systems or phenotypes; thus, the ClinGen Syndromic Disorders Gene Curation Expert Panel (SD-GCEP) was formed to address an unmet need.
    Methods: The SD-GCEP applied ClinGen's framework to evaluate the clinical validity of genes associated with rare syndromic disorders. A total of 111 gene-disease relationships (GDRs) associated with 100 genes spanning the clinical spectrum of syndromic disorders were curated.
    Results: From April 2020 through March 2024, 38 precurations were performed on genes with multiple disease relationships and were reviewed to determine if the disorders were part of a spectrum or distinct entities. A total of 14 genes were lumped into a single disease entity, and 24 were split into separate entities, of which 11 were curated by the SD-GCEP. A full review of 111 GDRs for 100 genes followed, with 78 classified as Definitive, 9 as Strong, 15 as Moderate, and 9 as Limited, highlighting cases in which further data are needed. All diseases involved 2 or more organ systems, whereas the majority (88/111 GDRs, 79.2%) had 5 or more organ systems affected.
    Conclusion: The SD-GCEP addresses a critical gap in gene curation efforts, enabling inclusion of genes for syndromic disorders in clinical testing and contributing to keeping pace with the rapid discovery of new genetic syndromes.
    Keywords:  ClinGen; Gene curation; Gene-disease relationship; Rare disease; Syndromic disorders
    DOI:  https://doi.org/10.1016/j.gimo.2025.103429
  64. Mol Cell. 2025 Jun 05. pii: S1097-2765(25)00461-7. [Epub ahead of print]
    The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress.
    Yumeng Zu, Chou Wu, Feifei Li, Hong Yao, Yuyue Xia, Ruoxi Zhang, Lulu Li, Shuangquan Chen, Qi Shi, Shuang Xi, Huanhuan Pang, Minghui Liu, Leibo Wang, Sandi Terpack, Weihua Wang, She Chen, Hong Zhang, Yibing Wang, Maojun Yang, Shanjin Huang, Fuling Zhou, Yu Tang, Zeping Hu, Shilong Fan, Yefeng Tang, Young-Sam Lee, Gelin Wang.
      Nicotinamide adenine dinucleotide (NAD+) is a crucial compound in energy metabolism and cell signaling. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme responsible for NAD+ biosynthesis from nicotinamide (NAM). Here, we report that NAMPT activity is inhibited by adenosine monophosphate (AMP) in response to energy stress. Our global metabolite-protein interaction mapping reveals that NAMPT differentially interacts with AMP from fasted mouse livers. Crystal structures of NAMPT-AMP show that AMP binds similarly to the NAMPT reaction product, nicotinamide mononucleotide (NMN). The inhibition of NAMPT by AMP can be relieved by NAMPT activators or adenosine triphosphate (ATP), likely in a competitive manner. Based on these findings, we further investigated upstream factors contributing to AMP accumulation and found that activation of purine synthesis unexpectedly promotes the rise of AMP during fasting. Notably, an increased AMP/ATP ratio correlates with NAD+ decline in ischemic stroke models, in which NAMPT activators can otherwise confer protection.
    Keywords:  AMP; ATP; NAD(+) biosynthesis; NAMPT; energy stress; fasting; ischemia; purine synthesis
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.022
  65. Intractable Rare Dis Res. 2025 May 31. 14(2): 88-92
    Artificial intelligence applications in rare and intractable diseases: Advances, challenges, and future directions.
    Kenji Karako.
      Rare and intractable diseases affect an estimated 3.5% to 5.9% of the global population but remain largely underserved in terms of diagnosis and treatment, with effective therapies available for only about 5% of conditions. This paper presents an overview of recent advances in artificial intelligence (AI) applications targeting these challenges. In diagnostic support, AI has been utilized to analyze genomic data and facial images, enhancing the accuracy and efficiency of identifying rare genetic syndromes. In therapeutic development, AI-driven analysis of biomedical knowledge graphs has enabled the prediction of potential treatment candidates for diseases lacking existing therapies. Additionally, generative models have accelerated drug discovery by identifying novel targets and designing candidate compounds, some of which have progressed to clinical evaluation. AI has also facilitated clinical trial support by automating patient eligibility screening using electronic health records, improving recruitment efficiency for trials that often struggle with small, geographically dispersed patient populations. Despite these advancements, challenges remain in ensuring data quality, interpretability of AI outputs, and the standardization of infrastructure across institutions. Moving forward, international data-sharing platforms integrating diverse modalities - clinical, genomic and image - are expected to play a pivotal role in enabling reliable, scalable, and ethically responsible AI applications. These developments hold the potential to transform the landscape of rare disease diagnosis, treatment, and research.
    Keywords:  artificial intelligence; intractable diseases; rare diseases
    DOI:  https://doi.org/10.5582/irdr.2025.01030
  66. Adv Healthc Mater. 2025 Jun 12. e2500217
    Aging on Chip: Harnessing the Potential of Microfluidic Technologies in Aging and Rejuvenation Research.
    Limor Zwi-Dantsis, Vignesh Jayarajan, George M Church, Roger D Kamm, João Pedro de Magalhães, Emad Moeendarbary.
      Aging is a complex process and the main risk factor for many common human diseases. Traditional aging research using short-lived animal models and two-dimensional cell cultures has led to key discoveries, but their relevance to human aging remains debatable. Microfluidics, a rapidly growing field that manipulates small volumes of fluids within microscale channels, offers new opportunities for aging research. By enabling the development of advanced three-dimensional cellular models that closely mimic human tissues, microfluidics allows more accurate investigation of aging processes while reducing costs, resource use, and culture time. This review explores how microfluidic systems, particularly organ-on-chip models, can improve our understanding of aging and age-related diseases, bridge the gap between animal models and human biology, and support the discovery of rejuvenation therapies. We highlight their role in monitoring aging biomarkers, analyzing functional cellular changes, and identifying longevity-promoting compounds. The ability of microfluidics to detect, analyze, and remove senescent cells is also discussed, along with emerging applications such as partial reprogramming for cellular rejuvenation. Furthermore, we summarize how these devices support single-cell analysis and recreate specific tissue microenvironments that influence aging. Insights from microfluidic approaches hold promise for developing therapeutic strategies to extend healthspan and promote longevity.
    Keywords:  aging research; microfluidics; organ‐on‐a‐chip; rejuvenation
    DOI:  https://doi.org/10.1002/adhm.202500217
  67. J Pharm Bioallied Sci. 2025 May;17(Suppl 1): S59-S62
    Personalized Medicine in Treating Rare Genetic Disorders: A Review.
    Ansari Zebanaz, Affan M Kareem, Ashwini A Aher, Sunil N Thitame.
      Personalized medicine creates revolutionary treatments for rare genetic disorders through medicine that adjusts to individual genetic information. The development of next-generation sequencing and whole-genome sequencing through genomic research has made precise medical diagnoses along with personalized treatments possible. The current therapies using CRISPR-Cas9 and gene therapy methods tend to fix harmful mutations effectively. Biomarker discovery, along with precise diagnostic techniques enables doctors to develop precise treatment methods through targeted therapeutic approaches. The ongoing revolution in rare disease management through personalized medicine faces hurdles of affordability and barrier to access and ethical questions but continues to create better individualized therapeutic solutions.
    Keywords:  CRISPR-Cas9; genetic profiling; multi-omics; personalized medicine; rare genetic disorders
    DOI:  https://doi.org/10.4103/jpbs.jpbs_583_25
  68. Nature. 2025 Jun 11.
    Metabolic adaptations direct cell fate during tissue regeneration.
    Almudena Chaves-Perez, Scott E Millman, Sudha Janaki-Raman, Yu-Jui Ho, Clemens Hinterleitner, Valentin J A Barthet, John P Morris, Francisco M Barriga, Jose Reyes, Aye Kyaw, H Amalia Pasolli, Dana Pe'er, Craig B Thompson, Lydia W S Finley, Justin R Cross, Scott W Lowe.
      Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes1-3. Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex4-6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.
    DOI:  https://doi.org/10.1038/s41586-025-09097-6
  69. Hum Hered. 2025 Jun 10. 1-11
    Easy-PSAP: an integrated workflow to prioritize pathogenic variants in sequence data from a single individual.
    Marie-Sophie C Ogloblinsky, Marc B Gros-La-Faige, Daniel P Lewinsohn, Mathilde Nguyen, Lourdes Velo-Suarez, Anthony Herzig, Thomas E Ludwig, Helen Castillo-Madeen, Donald F Conrad, Emmanuelle Génin, Gaëlle Marenne.
      Introduction Next-Generation Sequencing data analysis has become an integral part of clinical genetic diagnosis, raising the question of variant prioritization. The Population Sampling Probability (PSAP) method has been developed to tackle the issue of variant prioritization in the exome of a single patient, by leveraging allele frequencies from population databases and a variant pathogenicity score. Methods Here, we present Easy-PSAP, a completely new implementation of the PSAP method comprising two user-friendly and highly adaptable pipelines. Easy-PSAP allows the gene-based recalibration of any in silico pathogenicity prediction score compared to scores of variants seen in the general population, including popular scores like CADD or AlphaMissense. Easy-PSAP can evaluate genetic variants at the scale of a whole exome or a whole genome using information from the latest population and annotation databases. Results Through simulations on synthetic disease exomes, we show that Easy-PSAP is able to rank more than 50% of causal pathogenic variants in the top 10 variants for an autosomal dominant model of transmission and in the top 1 for an autosomal recessive model of transmission. Discussion These findings, along with the accessibility of the pipeline to both researchers and clinicians, make Easy-PSAP a state-of-the-art tool for variant prioritization in Next Generation Sequencing (NGS) data that can continue to evolve as new frameworks and databases become available. Easy-PSAP is implemented in R and bash within an open-source Snakemake framework. It is available on GitHub alongside conda environments containing the required dependencies (https://github.com/msogloblinsky/Easy-PSAP).
    DOI:  https://doi.org/10.1159/000543671
  70. J Mol Neurosci. 2025 Jun 13. 75(2): 75
    Drp1-Mediated Mitochondrial Fission Is Essential for Chemical-Induced Neuronal Transdifferentiation from Human Primary Fibroblasts.
    Jijuan Yang, Chun Li, Chunhua Wang, Xuemei Wang, Jiaqi Liu, Nan Yu, Wenqing Du, Shuhong Chi.
      Neuronal replacement therapy recently holds promise for neurodegenerative disease treatment. Somatic cell-derived neurons are the main cell source for this therapy; however, the induction mechanisms remain to be fully elucidated. Emerging evidence indicates that mitochondrial architecture undergoes substantial remodeling throughout cellular reprogramming processes. To explore the implications of mitochondrial dynamics in chemical-induced neuronal transdifferentiation, human foreskin fibroblasts (HFFs) were directly reprogrammed into functional neurons with our previously developed small molecule compound. The results showed that the mitochondrial morphology of HFFs shifted from tubular and reticular to fragmented shapes at an early stage of induced neurulation. Concurrently, gene and protein expression levels of the mitochondrial fission protein Drp1 was significantly increased in HFFs after induction. Both Drp1-specific siRNA and Drp1-GTPase inhibitor mdivi-1 treatment significantly attenuated the neuronal transdifferentiation of HFFs to neurons respectively, which can be attributed to the modulation of mitochondrial dynamics toward a fusion-dominant state through Drp1 suppression. Collectively, our experimental findings establish Drp1-dependent mitochondrial fission as a critical early requirement in the chemical reprogramming cascade that facilitates HFF transdifferentiation into neuronal lineages. Targeting Drp1 may enhance the efficiency of neuronal transdifferentiation, thereby providing sufficient therapeutically relevant neurons for neurodegenerative disease treatment.
    Keywords:  Dynamin-related protein1; Mdivi-1; Mitochondrial dynamics; Neuron transdifferentiation; Somatic reprogramming
    DOI:  https://doi.org/10.1007/s12031-025-02367-y
This page is being maintained by Thomas Krichel. It was last updated on 2025‒06‒15 at 11:27.