bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–04–05
sixty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.
  2. MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.
  3. Neurological manifestations and genotype-phenotype correlations in NDUFAF6-associated mitochondrial disease.
  4. A splicing factor's unexpected detour to the mitochondrial surface.
  5. Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model.
  6. BPM31510 Increases the CoQ Pool in Chemically Induced CoQ-Deficient Cells, CoQ-Deficient Patient Fibroblasts, and in Metabolically Active Murine Tissues.
  7. Mitochondrial genomes on a string of pearls.
  8. Mitochondrial transfer as a therapeutic target for peripheral neuropathy.
  9. Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.
  10. Microscopy in mitochondrial research - a comprehensive review.
  11. An Open-Source Code to Analyze Mitochondrial Intracellular Distribution from Fluorescence Microscopy Images.
  12. Pearling drives mitochondrial DNA nucleoid distribution.
  13. The functional importance of mitochondrial sequences with dual functions: overlapping protein-protein and protein-RNA gene sequences as test cases.
  14. Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
  15. The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.
  16. ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.
  17. Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
  18. MTALTCO1: a 259 amino-acid long mtDNA-encoded alternative protein that challenges conventional understandings of mitochondrial genomics.
  19. Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
  20. Revitalizing mitochondrial quality control: targeting mitochondria-derived vesicles in Parkinson's disease.
  21. Specialized high-capacity mitochondria fuel cell invasion.
  22. The N-terminal segment of the human ANKZF1 negatively regulates its internal mitochondrial targeting signal to prevent localization to mitochondria.
  23. A biallelic MRPL42 variant causes a combined oxidative phosphorylation deficiency syndrome revealed by multi-omics.
  24. Segregation of mtDNA mutations protects mitochondria across kingdoms, with impacts from longevity to agriculture and evolvability.
  25. Metabolic consequences of naturally occurring mitochondrial heteroplasmy in bivalves.
  26. Mitochondrial translational control in cardiovascular diseases: from mechanisms to therapies.
  27. Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.
  28. High-content microscopy quantification of mitochondrial membrane potential.
  29. U2AF regulates the translation and localization of nuclear-encoded mitochondrial mRNAs.
  30. Autophagy dysfunction in iPSCs-derived neurons and midbrain organoids carrying a SNCA triplication.
  31. TUFM: a central regulator in mitochondrial quality control and beyond.
  32. Flip the fuel, and the heat is on! Carnitine synthesis as a physiological mediator of fuel adaptation.
  33. Antitumor natural products targeting mitochondrial NADH: ubiquinone oxidoreductase (complex I): a review.
  34. Pathogenic human mitochondrial tRNA variants impair RNA processing by compromising 5' leader removal.
  35. Bridging population and cell: modelling complex diseases with human induced pluripotent stem cells.
  36. Cytosolic AcCoA: a metabolic signal bridging nutrient sensing and mitophagy.
  37. The role of TOMM20 in Mediating TERT translocation to mitochondria and its impact on mitophagy in membranous nephropathy.
  38. Genome editing in Parkinson's disease: Unlocking therapeutic avenues through CRISPR-Cas systems.
  39. Leber hereditary optic neuropathy triggered by the AstraZeneca coronavirus disease 2019 vaccination.
  40. Arginine ameliorates motor and survival deficits in MFN2-Deficient Drosophila models.
  41. Extracellular vesicle-mediated release of bis(monoacylglycerol)phosphate is regulated by LRRK2 and glucocerebrosidase activity.
  42. Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy.
  43. Combinatorial constraints predict that mitochondrial networks contain a large component.
  44. Mitochondrial NAD kinase Pos5 is required for CoQ biosynthesis in yeasts.
  45. STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels.
  46. The genomic medicine center Karolinska 10-year report on genome sequencing for rare diseases and a strategy for stepwise clinical implementation.
  47. A conserved mammalian mecciRNA, mecciATP6, regulates mitochondrial homeostasis through interaction with HNRNPA3.
  48. Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
  49. Why selection for mitochondrial quality drives the evolution of sexes.
  50. Pck1 Deficiency Drives Mitochondrial Dysfunction and Cellular Senescence in Adipocytes.
  51. NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.
  52. ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.
  53. The 1000 Chinese Pangenome empowers medical and population genetics.
  54. The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.
  55. Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder.
  56. Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.
  57. Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response.
  58. MLL3/4 methyltransferases regulate the differentiation of pluripotent stem cells via cellular respiration.
  59. Dynamic UFMylation governs cellular fitness by coordinating multi-organelle proteostasis.
  60. Mitochondrial protein translation is a heightened dependence and therapeutic vulnerability of chemo-refractory triple negative breast cancer.
  1. Am J Hum Genet. 2026 Mar 30. pii: S0002-9297(26)00113-8. [Epub ahead of print]
    Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.
    Natalie B Tan, Matthias Gautschi, Michael Raum, Daniella H Hock, Robert Kopajtich, Jia Wang, Xiao Qian, Tanavi Sharma, Timothy E Green, Jean-Marc Nuoffer, Katrina M Bell, Katarzyna Pospieszny, Tegan Stait, Chloe Pike, Michelle Cao, Susan M White, David R Thorburn, Theresa Brunet, Matias Wagner, Wolfgang Müller-Felber, Leopold Zeng, Thomas Klopstock, André Schaller, Jing Liu, David A Stroud, Holger Prokisch.
      NDUFA5 encodes a structural subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) located in the peripheral arm of the enzyme complex. Complex I is the largest enzyme of the mitochondrial respiratory chain and is essential for oxidative phosphorylation. There are many well-characterized conditions associated with nuclear-encoded mitochondrial complex I dysfunction, including Leigh syndrome, leukoencephalopathy, lethal infantile mitochondrial disease, hypertrophic cardiomyopathy, and exercise intolerance. The vast majority of these nuclear-encoded mitochondrial complex I deficiencies are autosomal-recessive conditions. To date, variants in NDUFA5 have not been associated with mitochondriopathy in humans. We identified a cohort of four individuals from three unrelated families with bi-allelic variants in NDUFA5. All individuals present with variable multisystem disease in the setting of a mitochondrial complex I deficiency, biochemically proven via an array of respiratory chain enzymology, blue native PAGE, and mass-spectrometry-based proteomics in peripheral blood mononuclear cells, lymphoblastoid cell lines, fibroblasts, and skeletal muscle. Transcriptomics and RT-PCR demonstrated aberrant mRNA expression in all affected individuals. Finally, we generated zebrafish ndufa5 F0 mutants that exhibited defects of morphological development, locomotor deficits, and abnormal brain activity. Our data demonstrate that bi-allelic variants in NDUFA5 cause a mitochondrial complex I deficiency, characterized by a variable multisystem phenotype that encompasses severe congenital heart defects, hematological abnormalities, and neurological involvement consistent with Leigh syndrome.
    Keywords:  CI deficiency; NDUFA5; complex I deficiency; mitochondrial disease; mitochondriopathy
    DOI:  https://doi.org/10.1016/j.ajhg.2026.03.003
  2. Nat Struct Mol Biol. 2026 Apr 01.
    MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.
    Stephen P Burr, Kathryn Auckland, Angelos Glynos, Abhilesh Dhawanjewar, Cameron Ryall, Wei Wei, Antony Hynes-Allen, Malwina Prater, Matylda Sczaniecka-Clift, Julien Prudent, Patrick F Chinnery, Jelle van den Ameele.
      Mitochondria contain their own genome, mitochondrial DNA (mtDNA), which is under strict control by the cell nucleus. mtDNA occurs in many copies per cell and mutations often only affect a proportion of them, giving rise to heteroplasmy. mtDNA copy number and heteroplasmy level together shape the tissue-specific impact of mtDNA mutations, eventually giving rise to both rare mitochondrial and common neurodegenerative diseases. Here, we use MitoPerturb-Seq for CRISPR-Cas9-based, high-throughput single-cell interrogation of the nuclear genes and pathways that sense and control mtDNA copy number and heteroplasmy. We screened a panel of mtDNA maintenance genes in mouse cells with a heteroplasmic mtDNA mt-Ta mutation. This revealed both common and perturbation-specific aspects of the integrated stress response to mtDNA depletion caused by Tfam, Opa1 and Polg knockout. These responses are only partially mediated by ATF4 and cause cell-cycle stage-independent slowing of cell proliferation. MitoPerturb-Seq, thus, provides experimental insight into disease-relevant mitochondrial-nuclear interactions and may inform development of therapies targeting cell-type- and tissue-specific vulnerabilities to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41594-026-01779-7
  3. Brain Commun. 2026 ;8(2): fcag095
    Neurological manifestations and genotype-phenotype correlations in NDUFAF6-associated mitochondrial disease.
    Alessandra Torraco, Charlotte L Alston, Giulia Barcia, Daniela Verrigni, Teresa Rizza, Michela Di Nottia, Anastasia Altobelli, Diego Martinelli, Daria Diodato, Stephanie Efthymiou, Melis Kose, Yamna Kriouile, Albert Z Lim, Silvia Morlino, Barbara Siri, Nebal Waill Saadi, Antonio Novelli, Henry Houlden, Carlo Dionisi-Vici, Robert McFarland, Agnès Rötig, Enrico Bertini, Robert W Taylor, Rosalba Carrozzo.
      NDUFAF6 encodes a mitochondrial complex I assembly factor essential for the proper biogenesis and stability of the nicotinamide adenine dinucleotide (NAD) + hydrogen (H) (NADH)-ubiquinone oxidoreductase complex. Pathogenic variants in NDUFAF6 have been increasingly recognized as a cause of mitochondrial disease, particularly Leigh syndrome, a severe neurodegenerative disorder characterized by bilateral symmetrical lesions in the central nervous system. To date, fewer than 50 patients with NDUFAF6-related mitochondrial disease have been reported, displaying a broad phenotypic spectrum ranging from early-onset neurodevelopmental regression to milder, more chronic presentations. The molecular mechanisms underlying these phenotypes are linked to impaired complex I assembly and reduced enzymatic activity, highlighting the critical role of NDUFAF6 in mitochondrial function. Here we present a cohort of 27 patients (14 males and 13 females) from 18 families harbouring biallelic variants in the NDUFAF6 gene. The patient's mean age was 9.15 ± 8.30 years (range: 4 weeks to 25 years); 12 patients (37%) had died by the time the data were collected for this article. The clinical presentation showed wide phenotypic variability, from mild to severe psychomotor regression (74%) most commonly before the age of 5 years, hypotonia (22%), movement disorders (30%), and hypertonia (15%). Bilateral striatal necrosis lesions were the most characteristic features on cranial MRI (67%) although white matter abnormalities were also noted (15%), occasionally accompanied by cystic formations, suggestive of early neurodevelopmental anomalies. Genomic sequencing was applied, leading to the identification of 19 distinct variants in the NDUFAF6 gene, including nine novel variants not previously reported and either absent or extremely rare in public population databases. Functional studies confirmed the pathogenicity of these variants, demonstrating a deleterious effect on NDUFAF6 protein expression and a consequent impairment in complex I assembly and stability. To date, this represents the largest reported cohort of patients with NDUFAF6-associated mitochondrial disease. Our findings provide a comprehensive overview of clinical characteristics-including age of symptom onset, phenotypic variability, and patient outcomes-aiming to improve prognostic information and facilitate genetic counselling in clinical practice.
    Keywords:  Assembly factors; Leigh syndrome; Mitochondrial disease; NADH–ubiquinone oxidoreductase; Respiratory chain complexes
    DOI:  https://doi.org/10.1093/braincomms/fcag095
  4. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00167-X. [Epub ahead of print]86(7): 1195-1196
    A splicing factor's unexpected detour to the mitochondrial surface.
    Ana-Maria Raicu, L Stirling Churchman.
      In this issue of Molecular Cell, Garcia et al.1 reveal an unexpected role for the splicing factor U2AF in repressing translation and influencing the localization of nuclear-encoded mitochondrial mRNAs to the outer mitochondrial membrane.
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.011
  5. bioRxiv. 2026 Mar 25. pii: 2026.03.20.711686. [Epub ahead of print]
    Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model.
    Lucía Fernández-Del-Río, Andrea Eastes, David Rincón Fernández Pacheco, Nikole Scillitani, Jasmine Garza, Matthew Dugan, Matheus Pinto de Oliveira, Pradnya Kadam, Iman Gauhar, Karel Erion, Kathleen Rodgers, Kevin Gaffney, Amy Wang, Marc Liesa, Cristiane Benincá, Orian Shaul Shirihai.
      Primary mitochondrial diseases are clinically and genetically heterogeneous disorders, commonly caused by defects in the oxidative phosphorylation system. This heterogeneity presents major challenges for therapeutic development; however, a shared hallmark across these diseases is the accumulation of dysfunctional mitochondria. Enhancing mitochondrial turnover, by activating the selective degradation of dysfunctional mitochondria via mitophagy, concurrently with the activation of mitochondrial biogenesis, could represent a shared therapeutic strategy for mitochondrial diseases. Here, we describe a novel mitophagy inducer, CAP-1902. CAP-1902 is a new agonist of the MAS G-Protein Coupled Receptor (MasR). In fibroblasts from patients carrying a BCS1L mutation that impairs complex III (CIII) assembly, CAP-1902 increased mitochondrial turnover by promoting both mitophagy and biogenesis. Specifically, MasR activation triggered the AMPK/ULK1/FUNDC1 mitophagy pathway. Knockdown of FUNDC1 blocked mitophagy but not AMPK activation, confirming pathway specificity. Additionally, a decrease in the occurrence of depolarized mitochondria with treatment indicated the selective targeting of accumulated damaged mitochondria in the disease context. MasR activation by CAP-1902 also stimulated the nuclear translocation of PGC-1α, promoting increased expression of transcripts associated with mitochondrial biogenesis, respiratory chain components, and mitochondrial translation. Remarkably, CAP-1902 was ultimately able to restore key defects in CIII-deficient fibroblasts by rescuing bioenergetics and correcting both the aberrant lysosomal distribution and the elevated integrated stress response markers, which is consistent with a shift toward a healthier mitochondrial population. In summary, we describe the first potential GPCR-mediated treatment of mitochondrial diseases and demonstrate that MasR activation by CAP-1902 induces mitochondrial turnover and improves mitochondrial function.
    DOI:  https://doi.org/10.64898/2026.03.20.711686
  6. FASEB J. 2026 Apr 15. 40(7): e71737
    BPM31510 Increases the CoQ Pool in Chemically Induced CoQ-Deficient Cells, CoQ-Deficient Patient Fibroblasts, and in Metabolically Active Murine Tissues.
    Juan J Aristizabal-Henao, Sarah R Wessel, Sylwia A Stopka, Srada Karmacharya, Devon Van Cura, Alba Pesini, Kelsey R Nickerson, Kashni Grover, Oksana Zavidij, Archna Ravi, Andressa L Mota, Kenneth M Rosen, Maria-Dorothea Nastke, Megan K Cox, Niven R Narain, Vijay Modur, Catarina M Quinzii, Stephane Gesta, Michael A Kiebish.
      Coenzyme Q10 (CoQ10) is a lipid-soluble redox cofactor essential for mitochondrial electron transport, membrane stabilization, and antioxidant defense in its reduced form. Broad clinical utility has been hampered by poor oral bioavailability and low tissue uptake using nutraceutical formulations. BPM31510 is a novel pharmaceutical nanotechnology formulated with oxidized CoQ10 as a lipid nanoparticle designed to enhance systemic exposure and mitochondrial concentration. Using UHPLC-MS/MS, we quantified oxidized CoQ10, reduced CoQ10, and oxidized CoQ9 in BPM31510- and CoQ10-treated SH-SY5Y neuroblastoma cells following para-aminobenzoic acid (PABA)-induced CoQ deficiency. BPM31510 significantly increased all three analytes and raised ATP content in SH-SY5Y cells more effectively than solubilized CoQ10. In patient-derived fibroblasts with PDSS2, COQ2, or COQ8A mutations, BPM31510 outperformed nutraceutical formulations in enriching CoQ10 levels. In vivo, C57BL/6J mice received BPM31510 (10 or 50 mg/kg, intraperitoneal) or oral CoQ10 twice daily for 14 days. BPM31510 substantially increased oxidized and reduced CoQ10 in plasma, liver, heart, and adipose tissue, enhancing the overall CoQ pool relative to oral CoQ10. MALDI mass spectrometry imaging confirmed oxidized CoQ10 accumulation in myocardial tissue beyond the vasculature, consistent with UHPLC-MS/MS findings. These results demonstrate that BPM31510 targets bioactive CoQ10 to metabolically active tissues, overcoming limitations of oral supplementation, and may provide therapeutic benefit for primary and secondary CoQ10 deficiencies and other mitochondrial or metabolic disorders marked by impaired redox balance and energy homeostasis.
    Keywords:  CoQ10 deficiency; mass spectrometry; mitochondrial disease; quinomics
    DOI:  https://doi.org/10.1096/fj.202503629RR
  7. Science. 2026 Apr 02. 392(6793): 26-28
    Mitochondrial genomes on a string of pearls.
    Jelle van den Ameele, Julien Prudent.
      Transient membrane constrictions, or "pearling," underlie the regular spacing of mitochondrial genomes.
    DOI:  https://doi.org/10.1126/science.aeg3426
  8. Trends Mol Med. 2026 Apr 02. pii: S1471-4914(26)00061-4. [Epub ahead of print]
    Mitochondrial transfer as a therapeutic target for peripheral neuropathy.
    Junlin Wei, Fang Wang.
      Satellite glial cells transfer mitochondria to sensory neurons via myosin 10-dependent tunneling nanotubes. Ji et al. show that this transfer is impaired in diabetic neuropathy, causing energy failure. Restoring it via cell or mitochondrial transplantation alleviates pain and promotes nerve regeneration, revealing a new therapeutic strategy for peripheral neuropathy.
    Keywords:  diabetic peripheral neuropathy; mitochondrial transfer; neuroprotection; satellite glial cells; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.molmed.2026.03.004
  9. FEBS Lett. 2026 Mar 30.
    Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.
    Sahitya Ranjan Biswas, Porter L Tomsick, Alicia M Pickrell, Paul D Morton.
      Primary mitochondrial disorders (PMDs) are inherited metabolic diseases that most often present with neurological symptoms in infancy or adolescence, underscoring the central importance of mitochondrial function to brain health. Historically, the field has emphasized neurodegeneration-consistent with the high energetic demands of postmitotic neurons. However, neurodevelopmental manifestations are now recognized as common early phenotypes, frequently preceding clinical regression in many PMDs. Given the pivotal role of mitochondria in neural stem/progenitor cell maintenance and cell fate decisions, defects in the respiratory chain are poised to disrupt neurogenesis and gliogenesis. Evidence for such developmental vulnerabilities is reviewed here. Likewise, because mitochondrial metabolism and dynamics shift across the oligodendrocyte lineage-from oligodendrocyte precursor cell expansion to differentiation and the energetically intensive phase of myelin synthesis-callosal atrophy in mitochondrial leukoencephalopathies may, at least in part, reflect developmental shortcomings in oligodendrogenesis and myelination. This possibility warrants focused investigation in cellular and in vivo models.
    Keywords:  mitochondria; mitochondria disorders; neural stem cells; oligodendrocytes; white matter
    DOI:  https://doi.org/10.1002/1873-3468.70335
  10. J Cell Sci. 2026 Mar 15. pii: jcs263933. [Epub ahead of print]139(6):
    Microscopy in mitochondrial research - a comprehensive review.
    Prasanna Katti, Prasanna Venkhatesh, C Nivedya, Andrea Marshall, Amber Crabtree, Zahra Elly Soltani, Olga Korolkova, Vineeta Sharma, Suraj Thapliyal, Karthik Naik, Kit Neikirk, Rodolpho Ornitz Oliveira Souza, Sepiso K Masenga, Nelson Wandira, Magdalene Ameka, Okwute M Ochayi, Christian A Combs, Lucy Collinson, Nalan Liv, Antentor Hinton.
      Mitochondria are highly dynamic, double-membrane organelles that play integral roles beyond energy production. Mitochondria adapt their morphology to meet diverse cellular demands, and highly plastic mitochondrial networks interact and communicate with various cellular components to maintain cellular health. Advances in both light and electron microscopy (EM) have greatly enhanced our understanding of mitochondrial structure and function. However, the small diameter of mitochondrial tubules, often near the diffraction limit of light, poses challenges for visualizing submitochondrial structures and protein distributions with conventional microscopy. Recently, super-resolution microscopy has offered unprecedented insights into mitochondrial dynamics, interactions and architecture. In this Review, we discuss how imaging techniques have advanced our understanding of mitochondrial biology. We critically assess the contributions of two-dimensional EM to elucidating the native architecture of cristae and respiratory chain complexes. Additionally, we explore how three-dimensional EM and super-resolution methods have reshaped our comprehension of mitochondrial network dynamics, heterogeneity and interactions with other cellular components. Finally, we discuss the strengths and limitations of various approaches, considering their potential to overcome current challenges and open new avenues in mitochondrial research, and illuminate how advanced microscopy continues to drive discoveries in mitochondrial biology with implications for metabolic diseases and aging.
    Keywords:  CLEM; Confocal; EM; Mitochondria; Super-resolution microscopy; Volume EM
    DOI:  https://doi.org/10.1242/jcs.263933
  11. Biosci Rep. 2026 Mar 30. pii: BSR20260140. [Epub ahead of print]
    An Open-Source Code to Analyze Mitochondrial Intracellular Distribution from Fluorescence Microscopy Images.
    Giovanna C Cavalcante, Alicia J Kowaltowski.
      Mitochondria have a plethora of roles in cells, many of which are related to dynamic changes in their size, shape, and intracellular location. Mitochondrial morphology is commonly assessed by microscopy with targeted fluorescent probes. However, tools to easily estimate mitochondrial localization within a cell are still lacking. A code was designed to estimate per-cell mitochondrial radial localization (perinuclear or peripheral) from fluorescence microscopy files in a variety of formats and using different mitochondrial markers (https://github.com/cavalcantegc/mito_localization.git). Three case studies with different cell types and stainings demonstrate that mitochondrial localization can be easily extracted and plotted with this code.
    Keywords:  Immunofluorescence; MitoTracker; Mitochondria; Mitochondrial localization; Mitochondrial morphology
    DOI:  https://doi.org/10.1042/BSR20260140
  12. Science. 2026 Apr 02. 392(6793): 102-109
    Pearling drives mitochondrial DNA nucleoid distribution.
    Juan C Landoni, Matthew D Lycas, Josefa Macuada, Willi Stepp, Roméo Jaccard, Christopher J Obara, Andrew S Moore, David Hoffman, Jennifer Lippincott-Schwartz, Wallace Marshall, Gabriel Sturm, Suliana Manley.
      The distribution of mitochondrial DNA-containing nucleoids is essential for mitochondrial function and genome inheritance; however, no known mechanisms can explain nucleoid segregation or their regular positioning. In this work, we found that mitochondria frequently undergo a reversible biophysical instability termed "pearling," transforming from a tubular into a regularly spaced beads morphology. Physiological pearling imposed a characteristic length scale and simultaneously mediated nucleoid disaggregation and established internucleoid distancing with high precision. Pearling onset was triggered by calcium influx, whereas the density of lamellar cristae invaginations modulated pearling prevalence and preserved nucleoid spacing following recovery. The dysregulation of mitochondrial calcium influx or inner membrane cristae integrity caused aberrant nucleoid clustering. Our results identify pearling as a mechanism governing nucleoid distribution and inheritance and offer insights into its regulation.
    DOI:  https://doi.org/10.1126/science.adu5646
  13. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250074. [Epub ahead of print]381(1947):
    The functional importance of mitochondrial sequences with dual functions: overlapping protein-protein and protein-RNA gene sequences as test cases.
    Noam Shtolz, Li Horovitz, Yuval Caruchero, Dan Mishmar.
      Human mitochondrial DNA (mtDNA) contains 13 protein-coding subunits of the oxidative phosphorylation pathway, 22 tRNA and two rRNA genes. However, accumulating evidence suggests that mtDNA encodes additional overlapping genetic elements, including mitochondrial-derived peptides (MDPs) and alternative reading frames. Here, we assessed signatures of selection across 66 328 human mtDNAs and studied the potential impact of disease-causing mutation within these mtDNA overlapping sequences. By employing frame-specific dN/dS analysis for the overlapping reading frames, and codon position-specific diversity calculations we found that SHLP6 and SHLP3 (within 16S rRNA) display significant signatures of purifying selection. Mutational asymmetry analysis revealed purifying selection in both frames and strands of GAU/COX1, while other alternative reading frames show asymmetric patterns, supporting negative selection primarily on the encompassing canonical gene. Analysis of mito-ribosome profiling (HEK293 cells) revealed translation initiation signatures only for SHLP6 and ALTND4, providing functional support for their translation in HEK293 cells. Analysis of disease-causing mutations revealed that several such mutations have predicted deleterious effects on both canonical and alternative sequences, though canonical genes tend to be more frequently affected. Taken together, we provide evolutionary and functional evidence supporting biological relevance of certain MDPs and underline the need to re-evaluate the functionality of mutations in such sequences. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  mitochondria; mtDNA; mutations; overlapping sequences; selection
    DOI:  https://doi.org/10.1098/rstb.2025.0074
  14. Autophagy. 2026 Mar 31. 1-3
    Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
    Polyxeni Papadea, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) is transmitted asexually without recombination and accumulates mutations at a high rate, which eventually should cause a mutational meltdown. Two processes operating in the maternal germline, the genetic bottleneck and purifying selection, are counteracting this decline but the exact molecular mechanisms and their possible link remain incompletely understood. To address this, we investigated the role of autophagy and mtDNA copy number in shaping purifying selection during maternal mtDNA transmission. Using a carefully designed breeding strategy in mice expressing a proofreading-deficient mitochondrial DNA polymerase, we generated animals carrying random mtDNA mutations and simultaneously introduced moderately decreased or increased mtDNA copy number, or impaired autophagy. Mutation patterns in control animals closely resembled those observed in humans, showing strong purifying selection against non-synonymous mutations, particularly in oxidative phosphorylation (OXPHOS) genes. Our recent work provides new insight by identifying autophagy as a key mediator of germline purifying selection of mtDNA. Moreover, we demonstrate that mtDNA copy number directly influences the efficiency of purifying selection, revealing that these two processes are functionally interconnected.
    Keywords:  Bottleneck; maternal transmission; mitochondria; mitophagy; mtDNA mutations
    DOI:  https://doi.org/10.1080/15548627.2026.2650772
  15. J Biol Chem. 2026 Mar 31. pii: S0021-9258(26)00283-8. [Epub ahead of print] 111413
    The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.
    Jayashree S Ladke, Azmi Khan, Anshit Singh, Henning J Jessen, Ullas Kolthur-Seetharam, Manish Jaiswal, Rashna Bhandari.
      Inorganic polyphosphate (polyP) is a linear polymer of phosphate residues linked by phosphoanhydride bonds. PolyP remains poorly understood in mammals due to its low abundance and lack of information on its metabolism. We developed a DAPI fluorescence-based assay to quantify the low levels of polyP present in mammalian cell lines and tissues, detecting an enrichment of polyP in the mitochondria compared with the nucleus and post-mitochondrial fraction. Mitochondrial polyP synthesis was found to depend on active FoF1 ATP synthase and an intact proton gradient across the inner mitochondrial membrane. Additionally, orthophosphate (Pi) is essential for mitochondrial polyP production, and ATP enhances Pi-driven polyP synthesis in isolated mitochondria. We discovered that the inositol pyrophosphate 5-InsP7, synthesized by IP6K1, regulates mitochondrial polyP levels. Mice and cells deficient in IP6K1 showed a significant reduction in mitochondrial polyP synthesis compared with wild type controls. Cells lacking IP6K1 also showed impaired mitochondrial respiration. The expression of active IP6K1, but not its catalytically inactive form, restored mitochondrial polyP synthesis in IP6K1 deficient cells, but mitochondrial respiration was rescued by expression of either active or inactive IP6K1. These data show that IP6K1 regulates mitochondrial function and polyP production both through the synthesis of 5-InsP7 and via a catalytic activity-independent mechanism. Our findings uncover a link between 5-InsP7, an energy sensor, and polyP, an energy store, in the regulation of mammalian mitochondrial homeostasis.
    Keywords:  ATP synthase; cell metabolism; inorganic polyphosphate; inositol phosphate; inositol pyrophosphates; mitochondria; mitochondrial membrane potential; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.jbc.2026.111413
  16. Aging (Albany NY). 2026 Mar 27. 18(1): 213-233
    ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.
    Victoria C Sanfrancesco, David A Hood.
      In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging. To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body KO and WT male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial ROS production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance. Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.
    Keywords:  ATF5; aging; mitochondria; skeletal muscle; stress response
    DOI:  https://doi.org/10.18632/aging.206365
  17. Aging Cell. 2026 Apr;25(4): e70452
    Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
    Amélia Lalou, Ioanna Daskalaki, Ilias Gkikas, Sandra Rodríguez-López, Jean-David Morel, Giorgia Benegiamo, Adrien Faure, Arwen W Gao, Joaquim Barmaz, Qi Wang, Terytty Yang Li, Feng Gao, Danaé Broustail, Kristina Schoonjans, Giovanni D'Angelo, Johan Auwerx.
      Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly activated the mitochondrial unfolded protein response (UPRmt) mediator ATFS-1, upregulated MSR pathways, and modulated mitochondrial function across species, similarly to doxycycline. Interestingly, both compounds also engaged the insulin/IGF-1 signaling (IIS) pathway in C. elegans, revealing an integrated stress response involving coordinated action of ATFS-1 and the FOXO transcription factor DAF-16, distinct from canonical IIS activation. Experiments in human HEK293T cells confirmed the translational potential, with both compounds inducing mitochondrial stress and modulating mitochondrial function in mammalian systems. This study highlights the potential of harnessing the MSR to promote longevity and mitigate age-related functional decline. The identification of terbinafine and miglustat as mitochondrial stressors paves the way for novel anti-aging therapies.
    Keywords:   Caenorhabditis elegans ; aging; doxycycline; drug repositioning; longevity; miglustat; mitochondria; terbinafine
    DOI:  https://doi.org/10.1111/acel.70452
  18. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250078. [Epub ahead of print]381(1947):
    MTALTCO1: a 259 amino-acid long mtDNA-encoded alternative protein that challenges conventional understandings of mitochondrial genomics.
    Francis Robitaille, Amy Campbell, Aziz Ben Hadj, Sarah Cornet, Ludovic Nadeau-Lachance, Thierry Niaison, Thierry Choquette, Liam Nyffeler, Xavier Roucou, Annie Angers, Sophie Breton.
      Mitochondrial alternative open reading frames (ORFs) substantially broaden the functional scope traditionally attributed to mitochondrial DNA, encoding peptides and proteins that participate in diverse cellular processes. These newly identified ORFs are embedded within annotated sequences, both coding and non-coding, and reveal layers of overlapping genetic information. We report the discovery of MTALTCO1, a 259 amino-acid protein, the longest mitochondrial alternative protein identified to date, encoded by an ORF located within the human cytochrome oxidase 1 gene, in the +3 reading frame. We confirm the expression and mitochondrial origin of MTALTCO1 through multiple independent lines of evidence, including a custom-designed antibody, mass spectrometry-derived peptides, sequence analysis and inhibitors of mitochondrial expression. Despite encoding AGR codons as arginine, contrary to the prevailing view that these function invariably as stop codons in the vertebrate mitochondrial genetic code, MTALTCO1 shows strong evidence of mitochondrial translation, challenging established models of mitochondrial codon usage and gene expression. Co-immunoprecipitations and pulldown assays delineate MTALTCO1's interaction landscape across major cellular pathways. Finally, we present the first in-depth analysis of conservation for a mitochondrial alternative ORF overlapping a reference protein-coding gene and discuss the results in light of MTALTCO1's suggested role in protein scaffolding. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  alternative proteins; conservation; intrinsically disordered proteins; mitochondria; mitochondrial-derived peptides; mitrochondrial translation; overlapping open reading frame; overprinting; protein function; scaffold proteins
    DOI:  https://doi.org/10.1098/rstb.2025.0078
  19. Cell Metab. 2026 Mar 27. pii: S1550-4131(26)00104-X. [Epub ahead of print]
    Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
    Filip J Larsen.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.010
  20. Biochem Pharmacol. 2026 Mar 29. pii: S0006-2952(26)00268-6. [Epub ahead of print] 117935
    Revitalizing mitochondrial quality control: targeting mitochondria-derived vesicles in Parkinson's disease.
    Jimna Mohamed Ameer, Sneha Mary Alexander, K Navya, Rajesh A Shenoi, Goutam Chandra.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the midbrain substantia nigra, resulting in debilitating motor and non-motor symptoms. No disease modifying therapy is currently available for PD patients. Mounting evidence implicates impaired mitochondrial quality control (MQC) as a central driver of PD pathogenesis. MQC maintains mitochondrial integrity and function through coordinated mechanisms such as mitochondrial biogenesis, dynamics, mitophagy, the ubiquitin-proteasome system, and the formation of mitochondria-derived vesicles (MDVs). MDVs are small vesicular structures that selectively sequester and transport damaged mitochondrial components to lysosomes for degradation, representing a rapid and localized quality control pathway distinct from mitophagy. Beyond their degradative role, MDVs also participate in inter-organelle signalling and intercellular communication, suggesting a broader influence on neuronal homeostasis. Disruption of MDV biogenesis, trafficking, or clearance has been emerging as a key contributor of mitochondrial dysfunction and neurodegeneration in PD. This review synthesizes current understanding of MDV biology, its integration within the MQC network, role in PD pathogenesis and explores how targeting MDV pathways may offer novel diagnostic and therapeutic strategies to modify disease progression in PD.
    Keywords:  Endolysosome; Mitochondrial dynamics; Mitophagy; SNARE proteins; Transport vesicles; Ubiquitin-protein ligases
    DOI:  https://doi.org/10.1016/j.bcp.2026.117935
  21. Curr Biol. 2026 Apr 01. pii: S0960-9822(26)00310-6. [Epub ahead of print]
    Specialized high-capacity mitochondria fuel cell invasion.
    Isabel W Kenny-Ganzert, Lena P Basta, Lianzijun Wang, Qiuyi Chi, Laura C Kelley, Caitlin Y Su, Jake Leyhr, Katherine S Morton, Joel N Meyer, David R Sherwood.
      Cell invasion through basement membrane (BM) is energetically intensive. How cells produce high ATP levels to power invasion is understudied. By endogenously tagging 20 mitochondrial proteins, we identified a specialized mitochondrial subpopulation within the C. elegans anchor cell (AC) that localizes to the BM breaching site and generates elevated ATP levels to fuel invasion. These electron transport chain (ETC)-enriched high-capacity mitochondria are compositionally unique, harboring increased protein import machinery and dense cristae enriched with ETC components. High-capacity mitochondria emerge at the time of AC specification and depend on the AC pro-invasive transcriptional program. Finally, we show that netrin signaling through an Src kinase directs microtubule polarization, facilitating metaxin adaptor complex-dependent ETC-enriched mitochondrial trafficking to the AC invasive front. Our studies reveal that an invasive cell produces high ATP levels by generating and localizing high-capacity mitochondria. This might be a common strategy used by other cells to meet the energetically demanding processes.
    Keywords:  ATP; basement membrane; cell invasion; cell specification; electron transport chain; live imaging; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.cub.2026.03.023
  22. FEBS J. 2026 Apr 01.
    The N-terminal segment of the human ANKZF1 negatively regulates its internal mitochondrial targeting signal to prevent localization to mitochondria.
    Mudassar Ali, Bhoopesh Maheswaran, Devid Sahu, Nidhi Malhotra, Koyeli Mapa.
      ANKZF1, the mammalian ortholog of yeast Vms1, is a multidomain cytosolic protein. Occasionally, the protein is also found in mitochondria, although the reason for its mitochondrial localization and the mechanism of its mitochondrial targeting remain unclear. Despite the absence of any predicted mitochondrial targeting sequence or domain (MTS/MTD) in the protein, ANKZF1 possesses multiple internal matrix-targeting sequence-like sequences (iMTS-Ls). In this study, we demonstrate that the N-terminal 73 residues of ANKZF1 negatively regulate its mitochondrial targeting, and this portion of the protein is sufficient to hinder mitochondrial targeting of Δ73-ANKZF1 upon co-expression. Using a series of truncation mutants of ANKZF1, we further demonstrate that the iMTS-Ls comprised of residues 231-240 of ANKZF1 are essential for its mitochondrial localization. Furthermore, the sequence of this region is well conserved across different organisms, indicating the structural and functional importance and role in maintaining the mitochondrial targeting of the protein. Importantly, residues 231-324 of ANKZF1 form two consecutive predicted iMTS-Ls, which together constitute an independent mitochondrial signal sequence that can target green fluorescent protein (GFP) to the mitochondria when fused to the N terminus. Furthermore, by molecular dynamics simulation, we show that the deletion of the N-terminal 74 amino acids of ANKZF1 leads to a massive structural rearrangement within the protein, causing the opening of its C-terminal part and solvent exposure of the 231-240 residues. We postulate that these structural rearrangements and exposure of the internal MTS in the absence of the N-terminal segment of ANKZF1 lead to its mitochondrial translocation.
    Keywords:  ANKZF1; MD simulation; mitochondria; mitochondrial targeting signal; proteotoxic stress
    DOI:  https://doi.org/10.1111/febs.70526
  23. NPJ Genom Med. 2026 Apr 03.
    A biallelic MRPL42 variant causes a combined oxidative phosphorylation deficiency syndrome revealed by multi-omics.
    Felix Boschann, Johannes Kopp, Susanne Römer, Oliver Küchler, Hristiana Lyubenova, Nicolai von Kügelgen, Erik Hertstein, Lea Hagelstein, Christian Becker, Kerstin Becker, Sebastian Brachs, Knut Mai, David Meierhofer, Dominik Seelow, Stefan Mundlos, Denise Horn, Markus Schuelke, Björn Fischer-Zirnsak.
      Pathogenic variants affecting components of the mitochondrial translation machinery lead to various impairments of mitochondrial function and thereby cause a spectrum of multisystem diseases. In an infant with a fatal, metabolic multisystem condition we performed a comprehensive multi-omics approach and detected the intronic biallelic variant NM_014050.4:c.219+6 T > A in MRPL42 (mitochondrial ribosomal protein L42) encoding a component of the large mitochondrial ribosomal subunit. RNA-seq revealed a strong reduction and aberrant splicing of the majority of MRPL42 transcripts leading to a frameshift and thereby to a premature termination codon: p.(Asn46Leufs*18). However, additional use of the canonical splice site led to a low residual expression of the wildtype transcript and MRPL42 protein abundance was consequently strongly reduced. Complex I and IV activity of the oxidative phosphorylation (OXPHOS) system were reduced and a decrease of complex I, III, IV, and mitoribosomal-related proteins was identified by proteomics. Complementation with wildtype MRPL42 corrected most of these phenotypes confirming that they were a direct consequence of the limited availability of MRPL42. Our multi-omics data confirm biallelic MRPL42 loss-of-function as the underlying cause of the fatal mitochondrial disease in our patient. Therefore, we propose MRPL42 deficiency as the cause of a mitochondrial ribosome-related combined OXPHOS-deficiency syndrome.
    DOI:  https://doi.org/10.1038/s41525-026-00564-1
  24. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250075. [Epub ahead of print]381(1947):
    Segregation of mtDNA mutations protects mitochondria across kingdoms, with impacts from longevity to agriculture and evolvability.
    Iain G Johnston.
      Mitochondrial DNA (mtDNA) encodes essential bioenergetic and metabolic machinery across eukaryotes, but it is susceptible to mutational damage. The high copy number, physical location and inheritance patterns of mtDNA mean that specialist approaches to mitigate such damage are needed. A common theme across many species is segregation or 'sorting out' of different mtDNA types-generating variance in mutant frequencies within and between generations, so that multiscale selection can act to remove deleterious mutations. Eukaryotes with different physiologies and ecologies use different strategies for this segregation. This article attempts to review and-with the aid of some bioinformatics and new modelling results-synthesize the ways that this segregation is achieved across different eukaryotic organisms. In parallel, the importance of segregation in human disease, longevity, agriculture and for biology on a rapidly changing planet is discussed. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  bottleneck; cross-eukaryote; evolution; mitochondria; mtDNA
    DOI:  https://doi.org/10.1098/rstb.2025.0075
  25. Proc Biol Sci. 2026 Apr 01. pii: 20252965. [Epub ahead of print]293(2068):
    Metabolic consequences of naturally occurring mitochondrial heteroplasmy in bivalves.
    Ariane Pouliot-Drouin, Stefano Bettinazzi, Oscar Paque, Sophie Breton.
      Oxidative phosphorylation, the cornerstone of mitochondrial energy production, is a tightly regulated process that relies on the strict interaction between mitochondrial and nuclear genomes. This intricate relationship requires the two genomes to coevolve to maintain mitochondrial function. However, when multiple mitochondrial variants coexist within an individual, a phenomenon known as heteroplasmy, this delicate balance can be disrupted, leading to bioenergetic inefficiencies and diseases. Interestingly, heteroplasmy naturally occurs in over a hundred species of bivalve molluscs, where paternal mitochondrial DNA is, in theory, exclusively inherited by male offspring and segregates in male gametes. Here, we leveraged this unique natural system to investigate the sex-specific distribution and translation pattern of somatic heteroplasmy, along with its impact on cellular bioenergetics in the bivalve species Mytilus edulis and Ruditapes philippinarum. By examining the relationship between heteroplasmy levels, haplotype expression and key enzymes involved in energy production, we uncovered unexpected findings. Contrary to predictions, somatic heteroplasmy was prevalent in both sexes and across both species. While heteroplasmy did not significantly affect overall bioenergetics, females of M. edulis showed notable exceptions in their gills. Possible compensatory mechanisms and species- or sex-specific adaptation to heteroplasmy are discussed.
    Keywords:  bioenergetics; doubly uniparental inheritance; heteroplasmy; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.1098/rspb.2025.2965
  26. Redox Biol. 2026 Mar 26. pii: S2213-2317(26)00141-2. [Epub ahead of print]92 104143
    Mitochondrial translational control in cardiovascular diseases: from mechanisms to therapies.
    Yunong Deng, Ningning Guo, Die Li, Zhihua Wang.
      Mitochondria orchestrate cardiac metabolic homeostasis, and their dysfunction constitutes a fundamental mechanism driving cardiovascular diseases (CVDs). During eukaryotic evolution, most of the mitochondrial genes required for oxidative phosphorylation (OXPHOS) function have been transferred to the nuclear genome, except for 13 genes coding for core subunits of the OXPHOS machinery. The translational regulation of these 13 genes inside mitochondria is precisely and dynamically regulated according to the external environment under diverse metabolic conditions. However, our understanding of these biological processes in CVDs remains limited. This review summarizes recent advances in the regulatory processes of mitochondrial translation, highlighting mitoribosome biogenesis, dynamic tRNA epitranscriptomic modifications, and coupling between translation and inner-membrane assembly. We additionally integrate emerging upstream regulatory mechanisms, including redox and metabolite-sensitive signaling, mitoepigenetic remodeling, and mitochondria-localized microRNA (mitomiR)-mediated control of mitochondrial RNA fate, which collectively tune translational output under stress. Moreover, this review delineates how these processes are dysregulated in major cardiovascular pathologies, including ischemia-reperfusion (I/R) injury, cardiac hypertrophy, heart failure (HF), and inherited cardiomyopathies. Emerging therapeutic strategies designed to restore translational fidelity and throughput, ranging from pharmacological interventions and metabolic tuning to precise mitochondrial gene editing, are also discussed. By repositioning mitochondrial translation from a passive marker of injury to a druggable control node, this review offers a new paradigm for targeting mitochondrial translation to preserve myocardial resilience and treat CVDs.
    Keywords:  Cardiovascular diseases; Mitochondrial translation; Mitoribosome; OXPHOS; tRNA modification
    DOI:  https://doi.org/10.1016/j.redox.2026.104143
  27. iScience. 2026 Apr 17. 29(4): 115184
    Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.
    Edziu Franczak, McLane M Montgomery, Zoe S Terwilliger, Raphael T Aruleba, Polina Krassovskaia, Ilya N Boykov, James T Hagen, Emely A Pacheco, Brett R Chrest, Tonya N Zeczycki, Kayla J Vandiver, P Darrell Neufer, Joseph M McClung, Kelsey H Fisher-Wellman.
      Oxidative phosphorylation (OxPhos) relies on coordinated synthesis of nuclear- and mitochondrial-encoded protein subunits comprising mitochondrial respiratory complexes. Despite a causal link between accumulated mtDNA mutations and age-related diseases, the impact of mtDNA mutation burden on cellular bioenergetics across major organ systems remains only partially resolved. Herein, we leveraged a comprehensive mitochondrial phenotyping platform to assess the phenotypic consequences of heightened mtDNA mutation burden across 8 murine tissues using the polymerase γ (PolG) mutator mouse, incapable of mtDNA proofreading. Despite reductions in OxPhos protein expression, maximal mitochondrial respiratory capacity remained largely intact in PolG Mut mice. Further analysis revealed partial functional deficits in NADH-linked respiration exhibited in brown adipose, colon, kidney, lung, and bone marrow-derived mononuclear cells. In contrast, respiration routed from CII-CIII-CIV was largely preserved across all tissues. Together, these findings suggest that NADH oxidation at respiratory complex I (CI) is the primary functional consequence of heightened mtDNA mutational load.
    Keywords:  Biochemistry; Genomics; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115184
  28. Methods Cell Biol. 2026 ;pii: S0091-679X(25)00100-1. [Epub ahead of print]204 141-153
    High-content microscopy quantification of mitochondrial membrane potential.
    Camilla Bean, Federica Dal Bello, Caterina Vianello, Luca Persano, Elena Rampazzo, Tomáš Knedlík, Emad Norouzi Esfahani, Saradha Ramesh, Alessio Gianelle, Marta Giacomello.
      In nearly all pathophysiological processes, mitochondrial membrane potential serves as a crucial indicator of mitochondrial function and activity. However, there remains a need for high-content imaging techniques that incorporate multiparametric measurements for comprehensive mitochondrial assessment. This paper introduces a novel unbiased approach for quantifying mitochondrial membrane potential in vitro, applicable to both two-dimensional and three-dimensional experimental systems. Furthermore, the incorporation of automated image analysis with machine learning algorithms enabled precise identification and segregation of distinct cell types within complex co-culture systems, allowing for targeted evaluation of individual subpopulations. Here, we provide a protocol for large-scale profiling of mitochondrial activity across various experimental contexts.
    Keywords:  Automated image analysis; Co-culture; High-content microscopy; Machine learning; Mitochondrial membrane potential; NSCs; Single muscle fibers; Spheroids; TMRM
    DOI:  https://doi.org/10.1016/bs.mcb.2025.03.019
  29. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00162-0. [Epub ahead of print]86(7): 1293-1310.e14
    U2AF regulates the translation and localization of nuclear-encoded mitochondrial mRNAs.
    Gloria R Garcia, Murali Palangat, Josquin Moraly, Benjamin T Donovan, Bixuan Wang, Ira Phadke, David Sturgill, Jiji Chen, Guofeng Zhang, Ronald J Holewinski, Brittney Short, Gustavo A Rivero, David M Swoboda, Naomi Taylor, Kathy McGraw, Daniel R Larson.
      The mechanisms underlying molecular targeting to mitochondria remain enigmatic, yet this process is crucial for normal cellular function. The RNA-binding proteins U2AF1 and U2AF2 form a heterodimer (U2AF) that shuttles between the nucleus and cytoplasm, regulating splicing in the nucleus and translation in the cytoplasm. Our study in human bronchial epithelial cells (HBECs) identifies an unexpected role for U2AF in mitochondrial function. We demonstrate that U2AF interacts with nuclear-encoded mitochondrial (NE-mt) mRNAs and proteins, inhibits translation, localizes to the mitochondria, and regulates mRNA localization to mitochondria. Moreover, an oncogenic point mutation in U2AF1(S34F) disrupts this regulation, leading to altered mitochondrial structure, increased translation, large changes in the mitochondria proteome, and oxidative phosphorylation (OXPHOS)-dependent metabolic rewiring, recapitulating changes observed in bone marrow progenitors from patients with myelodysplastic syndromes. These findings reveal a non-canonical role for U2AF, where it modulates multiple aspects of mitochondrial function by regulating the translation and mitochondrial localization of nuclear-encoded mRNAs.
    Keywords:  U2AF1; cancer; mRNA localization; metabolism; mitochondria; myeloid leukemia; translation
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.006
  30. NPJ Parkinsons Dis. 2026 Mar 31.
    Autophagy dysfunction in iPSCs-derived neurons and midbrain organoids carrying a SNCA triplication.
    Catarina Serra-Almeida, Javier Jarazo, Gemma Gomez-Giro, Isabel Rosety, Alise Zagare, Daniele Ferrante, Cláudia Saraiva, Daniela Frangenberg, Jennifer Modamio-Chamarro, Elisa Zuccoli, Ana Clara Cristóvão, Liliana Bernardino, Jens Christian Schwamborn.
      Parkinson's disease (PD), characterized by α-Synuclein aggregation and dopaminergic neuronal loss, has no current cure. Autophagy is critical for α-Synuclein clearance, yet its real-time dynamics remain challenging to assess in human-relevant systems. Here, we used live-cell imaging to assess autophagy within human neuronal cultures and midbrain organoids (hMOs) derived from induced pluripotent stem cells (iPSCs) of PD patients carrying a triplication of the α-Synuclein gene (3xSNCA). Using the LC3-Rosella dual-fluorescent reporter, we quantified autolysosomes dynamics in real time. In 3xSNCA neuronal cultures, we detected early autophagy defects. In 3xSNCA hMOs, reduced autolysosome area, increased total and phosphorylated α-Synuclein (pS129), and decreased electrophysiological activity were observed at 50 days of differentiation (DoD). By 70 DoD, autophagy impairment became more pronounced, overlapping with dopaminergic neuron dysfunction. These findings support the use of human iPSCs-derived models to study autophagy dysfunction in PD and demonstrate a temporal correlation between impaired autophagy, α-Synuclein pathology and neuronal degeneration.
    DOI:  https://doi.org/10.1038/s41531-026-01330-x
  31. Cell Death Discov. 2026 Mar 28.
    TUFM: a central regulator in mitochondrial quality control and beyond.
    Xuanyi Li, Liangjie Dong, Tian Xiao, Jiayi Chen, Hang Ye, Siyi Zhu, Fulin Chen, Yuan Yu.
      Tu translation elongation factor, mitochondrial (TUFM) is a highly conserved, nuclear-encoded GTPase that is indispensable for mitochondrial protein synthesis. Beyond this canonical function, TUFM has emerged as a central regulator of mitochondrial quality control (MQC), orchestrating mitochondrial biogenesis, dynamics, and mitophagy through a location-dictates-function paradigm. Its subcellular localization and activity are precisely regulated by post-translational modifications, including phosphorylation, lactylation, ubiquitination, and acetylation, which collectively dictate its functional outputs in cellular homeostasis and stress responses. TUFM also serves as a critical interface in host-pathogen interactions, where viruses often hijack its pro-mitophagic function to evade mitochondrial antiviral signaling. Functioning as a cellular fate switch, the TUFM-MQC axis determines context-dependent pathological outcomes: its hyperactivation promotes cell growth and fuels oncogenesis, whereas its deficiency exacerbates cell death and contributes to neurodegeneration, inflammatory damage, and metabolic dysfunction. This review synthesizes current mechanistic insights into TUFM as a central MQC coordinator and delineates how its functional imbalance redirects cellular trajectories toward survival or death. Deciphering the regulatory logic and spatiotemporal dynamics of this pivotal hub offers promising avenues for developing targeted strategies to restore cellular homeostasis across a spectrum of diseases.
    DOI:  https://doi.org/10.1038/s41420-026-03075-1
  32. Trends Endocrinol Metab. 2026 Apr 02. pii: S1043-2760(26)00068-8. [Epub ahead of print]
    Flip the fuel, and the heat is on! Carnitine synthesis as a physiological mediator of fuel adaptation.
    Nicolai R Hathiramani, Alexandra E Jerrett, Jessica B Spinelli.
      To what extent does de novo carnitine synthesis in tissues dictate their fuel preference? Recently, Auger et al. identified Solute Carrier 25A45 (SLC25A45) as a mitochondrial trimethyllysine importer for carnitine biosynthesis. SLC25A45 enables certain tissues to constitutively utilize fatty acids as fuel and, upon bioenergetic crisis, mediates a fuel switch that restores homeostasis.
    Keywords:  GLP-1RA; TML transporter; carnitine biosynthesis; cold adaptation; fuel switching; mitochondria
    DOI:  https://doi.org/10.1016/j.tem.2026.03.007
  33. Front Pharmacol. 2026 ;17 1799383
    Antitumor natural products targeting mitochondrial NADH: ubiquinone oxidoreductase (complex I): a review.
    Jiaqi Gou, Lingdang Chen, Yuting Xu, Binbin Liao, Yuanmin Shen, Juntao Tai, Jianying Zhang, Aixue Zuo.
      Mitochondrial complex I (NADH:ubiquinone oxidoreductase) is a critical hub for bioenergetics and redox signaling. Beyond its canonical role in oxidative phosphorylation and ATP synthesis, complex I regulates the intracellular NADH/NAD+ balance and reactive oxygen species (ROS) production, both of which are vital for tumor survival. Consequently, targeting complex I has emerged as a promising therapeutic strategy. Increasing evidence shows that diverse natural products-ranging from alkaloids to annonaceous acetogenins-exert potent antitumor effects by inhibiting complex I. These compounds disrupt mitochondrial function, inducing metabolic stress and cancer cell death. However, a systematic overview linking their chemical structures to specific binding modes and antitumor mechanisms is currently lacking. In this review, we summarize recent advances in natural products targeting mitochondrial complex I. We categorize these agents based on their structural characteristics and discuss their distinct mechanisms, such as acting as "deep tunnel blockers" versus "shallow pocket binders." This work aims to provide a theoretical foundation for the rational development of novel complex I-targeted antitumor drugs.
    Keywords:  NADH; antitumor mechanisms; mitochondria; mitochondrial complex I; natural products; ubiquinone oxidoreductase
    DOI:  https://doi.org/10.3389/fphar.2026.1799383
  34. bioRxiv. 2026 Mar 27. pii: 2026.03.25.714317. [Epub ahead of print]
    Pathogenic human mitochondrial tRNA variants impair RNA processing by compromising 5' leader removal.
    Jubilee H Muñozvilla, Avery Ontiveros, Tatiana V Mishanina.
      Human mitochondrial genome (mtDNA) encodes multiple proteins in the oxidative phosphorylation complexes as well as the ribosomal and transfer RNAs (tRNAs) needed for in situ translation. These genes are transcribed from only three promoters, producing polycistronic transcripts that are co-transcriptionally cleaved by mitochondrial RNase enzymes to release majority of individual gene products. tRNAs separate many of these genes and are thought to serve as "punctuation" marks that enable RNase recognition, binding, and hydrolysis of the 5' "leader" and 3' "trailer" sequences flanking the tRNA. Mutations in the tRNA genes dominate the mtDNA-linked mitochondrial pathologies; yet a systematic study of the impact of tRNA sequence variation on the RNase-catalyzed processing is lacking. Here, we employed human mitochondrial tRNA Tyr as a model system to dissect the effect of tRNA variants on the in vitro 5' leader and 3' trailer hydrolysis. We found that nucleotide variations located near the catalytic interfaces - particularly within or near the tRNA acceptor stem - showed the strongest defects in 5' processing and prevented release of the downstream tRNA in a tRNA cluster where multiple tRNAs are transcribed in tandem. This work provides mechanistic insight into how mutations disrupt coordinated mitochondrial tRNA processing and establish a framework for predicting variant effects based on their structural position relative to the processing enzymes.
    DOI:  https://doi.org/10.64898/2026.03.25.714317
  35. Eur J Hum Genet. 2026 Mar 31.
    Bridging population and cell: modelling complex diseases with human induced pluripotent stem cells.
    Eva S van Zanten, Elizabeth A Loehrer, Joyce B J van Meurs, Roberto Narcisi, Joost H Gribnau, Raymond A Poot, Hieab H H Adams.
      Induced pluripotent stem cells (iPSCs) have emerged as a powerful tool in biomedical research, enabling the study of cellular function and early disease mechanisms within patient-specific genetic contexts. Traditionally, iPSCs have been used to model monogenic diseases, where highly penetrant variants produce robust cellular phenotypes detectable in few cell lines. Recent advances in scalability and standardisation now enable systematic comparisons across many donors. This development is particularly relevant for complex diseases, which are driven by numerous genetic variants with small individual effects and therefore require population-scale designs to resolve genotype-phenotype relationships. However, several limitations of iPSC technology continue to challenge the reliability and reproducibility of such studies, constraining their translational relevance. Here, we review the challenges and opportunities of using iPSCs to model complex diseases, structured around three key themes: detecting subtle effects, modelling environmental context, and expanding genetic diversity.
    Keywords:  Complex diseases; Disease modelling; Functional genomics; Genetic variation; Induced pluripotent stem cells
    DOI:  https://doi.org/10.1038/s41431-026-02071-4
  36. Trends Biochem Sci. 2026 Mar 28. pii: S0968-0004(26)00007-1. [Epub ahead of print]
    Cytosolic AcCoA: a metabolic signal bridging nutrient sensing and mitophagy.
    Jiayi Chen, Xin Pan.
      How cells sense energy status to precisely regulate organelle fate is a central question in life sciences. Recent work by Zhang et al. reframes cytosolic acetyl-coenzyme A (AcCoA) from a metabolic substrate into a signaling metabolite that directly regulates mitophagy, thereby establishing a molecular link between nutrient sensing and mitochondrial homeostasis.
    Keywords:  NLRX1; cytosolic AcCoA; mitophagy
    DOI:  https://doi.org/10.1016/j.tibs.2026.01.007
  37. BMC Nephrol. 2026 Apr 01.
    The role of TOMM20 in Mediating TERT translocation to mitochondria and its impact on mitophagy in membranous nephropathy.
    Limiao Yang, Hongle Yang, Mingming Zhang, Feifei Zhang, Xiaomei Liu, Zhiping Zhang, Jing Wang, Xiaolu Chen, Yuexuan Wang, Rui Zhang, Weihao Li.
      
    Keywords:  Membranous nephropathy; Mitochondrial translocation; Mitophagy; Telomerase reverse transcriptase; The outer mitochondrial membrane 20
    DOI:  https://doi.org/10.1186/s12882-026-04910-4
  38. Neurochem Int. 2026 Mar 27. pii: S0197-0186(26)00040-9. [Epub ahead of print]196 106149
    Genome editing in Parkinson's disease: Unlocking therapeutic avenues through CRISPR-Cas systems.
    Ravi Pratap Singh, Prasenjit Maity, Charu Jaiswal.
      Parkinson's disease (PD) is an illness that causes both motor and non-motor symptoms in the patient which occurs as a result of a progressive loss of dopamine-producing neurons in the substantia nigra. Even though the success of symptomatic treatments is promising, at the same time there is currently no effective therapy that can halt or reverse disease progression. Key genes such as SNCA, LRRK2, and PINK1 are considered as the main hopefuls aspect for the treatment of Parkinson's because mutations of these genes are the reason for the appearance of the familial and sporadic kinds of the disease, respectively. The CRISPR-Cas system, a breakthrough genome-editing technology which enables precise and targeted genetic modifications, renders the possibilities of both PD research and therapy. Examining the mechanics of prime editing, base editing, and CRISPR-Cas9 highlights how effective and precise these methods are for modifying genes. An overview of recent developments in the use of CRISPR to create PD models is also included in the current review, with a focus on the roles these models play in clarifying disease pathways and locating new treatment targets. These models include isogenic cell lines, transgenic animals, and induced pluripotent stem cells (iPSCs). This review highlights the potential of CRISPR-based strategies to correct PD-associated mutations, modulate pathogenic gene expression, and develop neuroprotective interventions targeting key processes such as mitochondrial dysfunction. Furthermore, it critically evaluates the role of CRISPR-based technologies as transformative tools in PD research and therapy while highlighting key challenges for their clinical translation.
    Keywords:  CRISPR; Cas-9; Gene therapy; Genes; Neurodegeneration, and disease modelling; Parkinson; iPSCs
    DOI:  https://doi.org/10.1016/j.neuint.2026.106149
  39. Oman J Ophthalmol. 2026 Jan-Apr;19(1):19(1): 137-139
    Leber hereditary optic neuropathy triggered by the AstraZeneca coronavirus disease 2019 vaccination.
    Anan A Aljawi, Nooran Osama Badeeb.
      Leber hereditary optic neuropathy (LHON) is a rare mitochondrial disorder primarily affecting young males, characterized by progressive vision loss due to retinal ganglion cell degeneration. LHON is typically associated with specific mitochondrial mutations with potential triggers such as environmental factors and, more recently, postvaccination complications. We present a case of a 35-year-old male who experienced LHON onset 3 weeks following administration of the AstraZeneca Coronavirus disease 2019 vaccine. Despite lacking traditional risk factors, genetic testing confirmed the presence of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain four (MT-ND4) m.11778G >A mutation. The patient's presentation contributed to a delay in diagnosing LHON as demyelinating disease optic neuritis, and after excluding all the possible causes, the diagnosis of postvaccination LHON was considered. Continued vigilance and awareness among healthcare providers are essential for prompt identification and management of LHON in postvaccination contexts.
    Keywords:  Coronavirus disease 2019; hereditary optic neuropathy; vaccine; vision loss
    DOI:  https://doi.org/10.4103/ojo.ojo_431_24
  40. Neurotherapeutics. 2026 Apr 02. pii: S1878-7479(26)00070-X. [Epub ahead of print]23(3): e00900
    Arginine ameliorates motor and survival deficits in MFN2-Deficient Drosophila models.
    Masahiro Ando, Yuji Okamoto, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Chikashi Yano, Risa Nagatomo, Takahiro Hobara, Fumikazu Kojima, Yu Hiramatsu, Satoshi Nozuma, Yusuke Sakiyama, Hiroshi Takashima.
      Charcot-Marie-Tooth disease type 2 A (CMT2A) is an inherited axonal neuropathy linked to mutations in MFN2, a key regulator of mitochondrial dynamics. Currently, no effective drug therapies exist. l-arginine has shown promise in treating mitochondrial disorders, though its effect on MFN2-associated neuropathy remains uncertain. To investigate this, we used Drosophila models with the neuron-specific knockdown of Marf, the fly ortholog of MFN2, employing a temporally controlled GAL4/UAS system. Flies were administered different doses of l-arginine to examine its influence on motor ability and lifespan. To evaluate responses under mitochondrial stress, flies were also treated with rotenone, a mitochondrial complex I inhibitor. l-arginine markedly improved climbing performance under baseline conditions and extended lifespan under both baseline and stress conditions. However under rotenone-induced mitochondrial stress, high-dose l-arginine improved survival without a corresponding improvement in locomotor performance. These results support a neuroprotective role for l-arginine in MFN2-deficient Drosophila, possibly through effects on mitochondrial dynamics involving complex I. l-arginine may hold therapeutic promise for CMT2A, meriting further investigation in vertebrate models.
    Keywords:  Drosophila; Mitochondrial dynamics; Mutation; Rotenone; l-arginine
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00900
  41. Elife. 2026 Apr 02. pii: RP106330. [Epub ahead of print]14
    Extracellular vesicle-mediated release of bis(monoacylglycerol)phosphate is regulated by LRRK2 and glucocerebrosidase activity.
    Elsa Meneses-Salas, Moises Castellá, Marianna Arnold, Frank Hsieh, Rubén Fernández-Santiago, Mario Ezquerra, Alicia Garrido, María-José Martí, Carlos Enrich, Suzanne R Pfeffer, Kalpana Merchant, Albert Lu.
      The endolysosomal phospholipid bis(monoacylglycerol)phosphate (BMP) is aberrantly elevated in urine from Parkinson's patients carrying mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GCase). Because BMP resides on, and regulates biogenesis of, endolysosomal intralumenal membranes that become extracellular vesicles (EVs) upon release, we hypothesized that increased urinary BMP reflects enhanced exocytosis of BMP-enriched EVs. We analyzed BMP metabolism and EV-associated BMP release in wild-type (WT) and R1441G LRRK2 mouse embryonic fibroblasts (MEFs). Immunofluorescence and transmission electron microscopy revealed structural alterations in endolysosomes and the antibody-accessible BMP pool, indicating disrupted endolysosomal homeostasis. Biochemical analysis of isolated EV fractions showed increased release of LAMP2-positive EVs by mutant cells, partially restored by LRRK2 kinase inhibition but further, variably, increased by GCase inhibition. Mass spectrometry detected higher total di-22:6-BMP and di-18:1-BMP in mutant LRRK2 MEFs compared to WT. Inhibition of LRRK2 partially restored cellular BMP, whereas GCase inhibition further elevated it. In EVs from mutant cells, LRRK2 inhibition reduced BMP content, while GCase inhibition tended to increase it. Metabolic labeling showed elevated BMP was not due to increased synthesis, despite higher levels of the BMP-synthesizing enzyme CLN5 in mutant MEFs and patient fibroblasts. Finally, pharmacological modulation of EV release and live total internal reflection fluorescence imaging in human G2019S LRRK2 fibroblasts further confirmed that BMP release is likely associated with EV secretion. Together, these results establish LRRK2 as a regulator of BMP in cells and its release through EVs and suggest that GCase activity further modulates this process in LRRK2 mutant cells. Mechanistic insights from these studies have implications for the use of BMP-positive EVs as potential biomarkers for Parkinson's disease.
    Keywords:  bis(monoacylglycero)phosphate; cell biology; endolysosomes; extracellular vesicles; human; human fibroblasts; leucine-rich repeat kinase 2
    DOI:  https://doi.org/10.7554/eLife.106330
  42. Nat Genet. 2026 Mar 30.
    Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy.
    Adam Jackson, Alexander J M Blakes, Bader Alhaddad, Olivia J Henry, Angelica M Delgado-Vega, Elizabeth Wall, Ola Abdelhadi, Shakti Agrawal, Khadijah Bakur, Edward Blair, Angela F Brady, Helen Brittain, Kate E Chandler, Natasha Clarke, Miriana Danelli, Nicholas Drinkall, Irene Duba, Frances Elmslie, Jamie Ellingford, Lisa J Ewans, Andrew P Fennell, Gabriella Gazdagh, Simon P Heller, Anna Hammarsjö, Kristina Karrman, Usha Kini, Nicole Lesko, Anna Lindstrand, Rebecca Macintosh, Sahar Mansour, Lara Menzies, Kay Metcalfe, Alison Milhench, Lina Nashef, Raymond T O'Keefe, Nadja Pekkola Pacheco, Elizabeth E Palmer, Amitav Parida, Katrina Prescott, Melody Redman, Alessandra Renieri, Chiara Fallerini, Caterina Lo Rizzo, Rani Sachdev, Cas Simons, Sanjay M Sisodiya, Helen Stewart, Tommy Stödberg, Benito Banos-Pinero, Fulya Taylan, Huw B Thomas, Flavia Tinella, Samuel Wiafe, Anna Wedell, Nicola Whiffin, Susan Walker, Rocio Rius, Jong Hee Chae, Ann Nordgren, Fowzan Alkuraya, Jenny Lord, Siddharth Banka.
      Neurodevelopmental disorders (NDDs) affect 2-4% of the population, are predominantly genetic and remain unsolved in ~50% of individuals. We show that rare biallelic variants in RNU2-2 are enriched and over-transmitted in individuals with unresolved NDDs. We define a recessive RNU2-2 syndrome, delineate its unique genetic architecture and show that it manifests clinically as a severe developmental and epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as a probable pathomechanism. We identify a decreased ratio of U2-2 to its paralog U2-1 as a potential diagnostic biomarker for this condition. We show that the recessive RNU2-2 syndrome is genetically, clinically and mechanistically distinct from the dominant RNU2-2 disorder. Within our cohort, the recessive RNU2-2 syndrome emerges as by far the most frequent recessive NDD, greatly disproportionate to the small genomic footprint of this non-protein-coding gene.
    DOI:  https://doi.org/10.1038/s41588-026-02551-9
  43. bioRxiv. 2026 Apr 01. pii: 2026.03.25.714309. [Epub ahead of print]
    Combinatorial constraints predict that mitochondrial networks contain a large component.
    Raphael Mostov, Greyson R Lewis, Moumita Das, Wallace F Marshall.
      Mitochondria often form branching membrane networks distributed throughout the cell interior. In many, though not all, cell types, these networks are observed to consist of one large connected component together with many smaller fragments. Why does this pattern arise? Does it reflect a specific biological function, an external biophysical constraint, or something simpler? Using results from extremal graph theory, we prove a new theorem which suggests that, under a sufficiently broad sampling of the space of mitochondria-like graphs, the predominance of three-way junctions makes the appearance of a large component likely. This suggests that, in some settings, a large component may serve as a useful null model for mitochondrial network structure rather than requiring a dedicated explanation. More broadly, our result points towards testable predictions, since systematic deviations from this baseline may help reveal additional constraints or mechanisms shaping mitochondrial morphology.
    DOI:  https://doi.org/10.64898/2026.03.25.714309
  44. PLoS One. 2026 ;21(4): e0346295
    Mitochondrial NAD kinase Pos5 is required for CoQ biosynthesis in yeasts.
    Shogo Nishihara, Ikuhisa Nishida, Yasuhiro Matsuo, Tomohiro Kaino, Makoto Kawamukai.
      Coenzyme Q (CoQ) is an essential component of the electron transport chain, and ten genes involved in CoQ biosynthesis have been identified in Schizosaccharomyces pombe. To gain further insight into CoQ biosynthesis, we screened the Bioneer gene-deletion library and found that the Δpos5 strain produced only 0.2-fold of the wild-type CoQ10 level. Pos5 shares homology with Saccharomyces cerevisiae Pos5 (ScPos5), a mitochondrial NADH (or NAD+) kinase that generates NADPH (or NADP+). Heterologous expression of ScPOS5 in the S. pombe Δpos5 strain recovered CoQ content to 0.9-fold of the wild-type level, indicating functional conservation of Pos5 between the two yeasts. Consistently, CoQ6 level in ΔScpos5 was decreased to 0.2-fold of that in the wild-type strain. The Δpos5 strain exhibited several phenotypes characteristic of CoQ-deficient S. pombe, including inability to grow on non-fermentable carbon sources, hypersensitivity to oxidative stress, and high sulfide production. Among CoQ biosynthetic enzymes, Coq6 monooxygenase is thought to utilize NADPH. Supplementation with VA or PHB partially restored CoQ production in the Δpos5 strain, while overexpression of coq6 had negligible effect. These findings suggest that Pos5 is required for the earlier step of CoQ biosynthesis.
    DOI:  https://doi.org/10.1371/journal.pone.0346295
  45. Cell Rep. 2026 Mar 27. pii: S2211-1247(26)00261-5. [Epub ahead of print]45(4): 117183
    STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels.
    Jin-Yi Lin, Ze-Bo Huang, Shi-Qi Zhang, Yong Wu, Ling-Jun Cheng, Xiangzheng Gao, Sofie Lautrup, Shu-Qin Cao, Junping Pan, Dade Rong, Ruixue Ai, Hayden Weng Siong Tan, Liming Wang, Haihe Wang, Han-Ming Shen, Evandro F Fang, Guang Lu.
      PINK1 is a master regulator of PINK1-parkin-mediated mitophagy, a key process for maintaining mitochondrial homeostasis. The precise regulation of PINK1 is therefore essential for orchestrating mitophagy. While proteolytic processing of PINK1 and degradation of cleaved PINK1 via the N-end rule under basal conditions have been extensively characterized, the mechanisms governing full-length PINK1 degradation upon mitochondrial damage remain enigmatic. Here, we demonstrate that PINK1 undergoes ubiquitination and proteasomal degradation during mitophagy through the coordinated action of STUB1 and VCP/p97. Depletion of STUB1 stabilizes full-length PINK1, which paradoxically impairs mitophagy through the acceleration of parkin degradation. At the organismal level, the STUB1-VCP axis plays an important role in neuronal mitophagy-related memory and learning capacities in the roundworm C. elegans. Congruently, this axis is impaired in the postmortem brain tissues from patients with Alzheimer's disease compared with cognitively normal controls. Collectively, our findings support STUB1-VCP as a molecular calibrator that fine-tunes full-length PINK1 levels to enable efficient mitophagy and maintain mitochondrial homeostasis.
    Keywords:  Alzheimer’s disease; CP: metabolism; CP: molecular biology; PINK1; STUB1; VCP/p97; autophagy; mitophagy; parkin; ubiquitination-proteasome system
    DOI:  https://doi.org/10.1016/j.celrep.2026.117183
  46. Genome Med. 2026 Mar 30. pii: 30. [Epub ahead of print]18(1):
    The genomic medicine center Karolinska 10-year report on genome sequencing for rare diseases and a strategy for stepwise clinical implementation.
    Anna Lindstrand, Kristina Lagerstedt-Robinson, Anders Jemt, Malin Kvarnung, Sofia Ygberg, Sofie Vonlanthen, Mikael Oscarson, Daniel Nilsson, Nicole Lesko, Angelo Salazar Mantero, Britt-Marie Anderlid, Henrik Arnell, Cecilia Arthur, Svetlana Bajalica-Lagercrantz, Michela Barbaro, Peter Bergman, Erik Björck, Oda Blomqvist Picard, Helene Bruhn, Jonas Carlsten, Sandrina P Correia, Karl De Geer, Angelica M Delgado Vega, Emma Ehn, Jesper Eisfeldt, Marlene Ek, Ingegerd Elvers, Martin Engvall, Christoph Freyer, Sofia Frisk, Caroline Graff, Giedré Grigelioniené, Peter Gustafsson, Anna Hammarsjö, Hafdis T Helgadottir, Maritta Hellström Pigg, Olivia J Henry, Moa Hägglund, Erik Iwarsson, Vincent Janvid, Maria Johansson Soller, Leif Sundin, Ekaterina Kuchinskaya, Anders Kämpe, Anna Leinfelt, Agne Liedén, Hillevi Lindelöf, Anna Lyander, Helena Malmgren, Maria Mannila, Per Marits, Karin Naess, Ramprasad Neethiraj, Karl Nyren, Christoforos Pappas, Martin Paucar, Nadja Pekkola Pacheco, Lucia Peña Perez, Maria Pettersson, Peter Pruisscher, Chiara Rasi, Annick Renevey, Sophia Rössner, Ellika Sahlin, Erik Stenund, Tommy Stödberg, Mikael Sundin, Karl Svärd, Bianca Tesi, Emma Tham, Håkan Thonberg, Virpi Töhönen, Malin Ueberschär, Karin Wallander, Eini Westenius, Johanna Winberg, Nerges Winblad, Josephine Wincent, Malin Winerdal, Anna Wredenberg, Anna Zetterlund, Rolf H Zetterström, Ingegerd Öfverholm, Ann Nordgren, Henrik Stranneheim, Valtteri Wirta, Anna Wedell.
      
    Keywords:  Chromosomal rearrangements; Clinical diagnostics; Genome sequencing; Precision medicine; Rare diseases; Single nucleotide variants; Structural variants
    DOI:  https://doi.org/10.1186/s13073-026-01611-3
  47. Noncoding RNA Res. 2026 Aug;19 28-39
    A conserved mammalian mecciRNA, mecciATP6, regulates mitochondrial homeostasis through interaction with HNRNPA3.
    Xiaoyang Cao, Juzheng Sui, Ge Shan, Xu Liu.
      Circular RNAs (circRNAs) are covalently closed, single-stranded RNA molecules generated from both nuclear and mitochondrial genomes. Several nuclear-encoded circRNAs have been reported to be conserved in sequence and function across animals. However, the evolutionary conservation and physiological significance of mitochondria-encoded circRNAs (mecciRNAs) remain largely unexplored. Here, by analyzing mitochondrial RNA sequencing data from human and mouse cells, we identify a conserved mecciRNA derived from the MT-ATP6 locus, termed mecciATP6. We show that mecciATP6 modulates mitochondrial homeostasis by binding and regulating the protein abundance of an evolutionarily conserved RNA-binding protein (RBP) HNRNPA3. Our data provide a conceptual framework for defining mecciRNA conservation across mammals and uncover a conserved mecciRNA-protein regulatory mechanism linked to mitochondrial homeostasis.
    Keywords:  HNRNPA3; Mitochondria-encoded circRNA; Mitochondrial homeostasis; RNA stability; circRNA
    DOI:  https://doi.org/10.1016/j.ncrna.2026.03.002
  48. Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2508286123
    Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
    Esther García-Domínguez, Cristina García-Domínguez, José Luis Cabrera-Alarcón, María Del Mar Muñoz-Hernández, Pablo Hernansanz-Agustín, Andrea Curtabbi, Julio Domenech-Fernandez, Enrique Calvo, Jesús Vázquez, Antonio L Serrano, Pura Muñoz-Cánoves, Gloria Olaso-González, José Antonio Enríquez, María Carmen Gómez-Cabrera.
      Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural, enzymatic, and functional levels. Our preclinical study included a healthy aging mouse line, a transgenic model of robustness, and a muscle-specific mitochondrial-deficient mutant mice, allowing us to assess both mitochondrial plasticity with aging and the necessity of intact mitochondrial function for exercise-induced adaptations. These findings were corroborated by a cross-sectional human study examining the relationship between skeletal muscle mitochondrial function, age, and physical capacity. We analyzed biopsies from 30 donors (men and women, aged 17 to 99 y) stratified into young and older adults with varying functional statuses. Our results indicate that mitochondrial dysfunction in skeletal muscle is associated with the decline in locomotor muscle function in the elderly, highlighting the potential role of exercise or habitual physical activity in mitigating this phenotype. Notably, we demonstrate that skeletal muscle mitochondria maintain plasticity during aging in mice and humans, and that this preserved adaptability can be leveraged to improve muscle performance and overall functional capacity.
    Keywords:  frailty; health span; mitochondrial function; proteomics; sarcopenia
    DOI:  https://doi.org/10.1073/pnas.2508286123
  49. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250076. [Epub ahead of print]381(1947):
    Why selection for mitochondrial quality drives the evolution of sexes.
    Nick Lane, Andrew Pomiankowski.
      The evolution of sexes is closely tied to uniparental inheritance (UPI) of mitochondrial DNA (mtDNA), where only females transmit mtDNA. Unlike nuclear DNA, mtDNA is highly polyploid and never evolved to be part of meiotic sex. Modelling shows that UPI increases mtDNA mutational variance, enhancing selection for high-quality mtDNA and promoting the emergence of sexes from mating types in unicellular eukaryotes. Paternal control of mitochondrial transfer favours some degree of mtDNA leakage, whereas maternal control favours strict UPI, leading to sexual conflict driving turnover in transmission mechanisms. In multicellular organisms, mitotic segregation of mtDNA increases variance in gametes, again facilitating selection. Surprisingly, germline evolution seems to reflect mtDNA mutation rates: plants and sessile metazoans have low rates and produce gametes from somatic cells, while bilaterians and ctenophores with higher rates sequester germlines with restricted cell division. High mtDNA ploidy in oocytes allows early embryonic cell division without replication, reducing mutational variance across tissues and enhancing somatic fitness. Germline mtDNA quality is maintained by mitotic over-proliferation of germ cells and the selective transfer of mtDNA into primordial oocytes linked with massive apoptotic germ-cell atresia. Overall, selection for mtDNA quality elucidates the evolution of sexes and the architecture of the female germline. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  Balbiani body; germline; mitochondria; mitochondrial mutation; mtDNA; oogenesis; sexes; uniparental inheritance
    DOI:  https://doi.org/10.1098/rstb.2025.0076
  50. Aging Cell. 2026 Apr;25(4): e70462
    Pck1 Deficiency Drives Mitochondrial Dysfunction and Cellular Senescence in Adipocytes.
    Yiting Lei, Meng Yang, Xiaoyun Jiang, Yujie Zhang, Yuzhi Chen, Weiheng Xie, Qihui Dai, Weihong Qin, Xiuqin Deng, Xiaojun Zhang, Zhongjun Zhou, Gonghua Huang, Xinguang Liu.
      Cellular senescence of white adipose tissues (WAT) represents an early hallmark of aging; however, the involved mechanisms remain incompletely understood. Here, we identified the cytosolic phosphoenolpyruvate carboxykinase (Pck1) as a key regulator of mitochondrial function and inflammaging in WAT. Pck1 expression was downregulated in both gonadal WAT and inguinal WAT during aging, and adipocyte-specific Pck1 deficiency accelerated inflammaging and metabolic disorders. Untargeted metabolomic and isotope-tracing analyses revealed that loss of Pck1 impaired cataplerosis, the export of tricarboxylic acid (TCA) cycle intermediates, resulting in accumulation of fumarate in adipocytes. Supplementation with exogenous fumarate disrupted mitochondrial homeostasis of adipocytes, promoted oxidative stress and triggered cytosolic release of mitochondrial DNA (mtDNA), leading to the activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway that may contribute to inflammaging and chronic obesity. These were phenocopied with Pck1-deficient adipocytes. Conversely, overexpression of fumarate hydratase (Fh1) reduced fumarate level substantially and attenuated adipocyte inflammaging. Collectively, these findings identify Pck1 as a pivotal regulator of mitochondrial metabolic homeostasis and suggest that targeting Pck1 may represent a promising therapeutic strategy for age-related diseases.
    Keywords:  Pck1; TCA cycle; aging; cGAS/STING signaling; cellular senescence; white adipose tissue
    DOI:  https://doi.org/10.1111/acel.70462
  51. Front Biosci (Landmark Ed). 2026 Mar 19. 31(3): 49714
    NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.
    George B Stefano.
      Alzheimer's disease (AD) is increasingly associated with mitochondrial dysfunction and disrupted metabolism. Thus, the maintenance of nicotinamide adenine dinucleotide (NAD+) homeostasis is proposed as a potential therapeutic strategy. Toward this end, we suggest that AD-related mitochondrial dysfunction might be viewed as a regulatable, redox-dependent vulnerability rather than an inherently degenerative and irreversible process. This perspective advances an evolutionary model in which NAD+-mediated redox systems represent a conserved regulatory axis, and that destabilization of this axis during aging may increase susceptibility to degeneration. Here, we assess the potential of a therapeutic approach that combines this understanding of mitochondrial energy metabolism with results from preclinical studies demonstrating the impact of pharmacologic correction of NAD+ homeostasis (e.g., P7C3-A20) as contextual motivation. We explicitly elevate redox balance, rather than absolute NAD+ abundance, as the mechanistically dominant variable that shapes mitochondrial resilience, inflammatory tone, and neurovascular stability. Accordingly, the key unresolved issue is whether specific physiologic benefits might accrue from increased NAD+ availability per se or rather, the restoration of the NAD+/NADH redox ratio, with important implications for the interpretation of the results of directed metabolic interventions. Within this framework, metabolic failure in AD can be understood as an upstream permissive condition that explains, rather than replaces, canonical amyloid-β and tau-associated pathologies. While extended human lifespan may expose late-life vulnerabilities in otherwise conserved metabolic systems, claims of causal primacy, disease reversibility, and cross-neurodegenerative generalization remain premature, underscoring the need for redox-resolved, genetic, and clinical validation.
    Keywords:  Alzheimer’s disease; cognition; evolution; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammatory diseases; nicotinamide adenine dinucleotide
    DOI:  https://doi.org/10.31083/FBL49714
  52. bioRxiv. 2026 Mar 28. pii: 2026.03.27.711928. [Epub ahead of print]
    ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.
    Amber Crabtree, Mohd Mabood Khan, Estevao Scudese, Calixto Pablo Hernandez Perez, Prasanna Venkhatesh, Andrea G Marshall, Benjamin Rodriguez, Edgar Garza Lopez, Okwute M Ochayi, Estélio Henrique Martin Dantas, Pamela Martin, Matheus Baffi, Fabiana Scartoni, Margaret Mungai, Kit Neikirk, Jennifer Streeter, Renata Oliveira Pereira, Dao Fu Dai, Han Le, Harrison Mobley, Jeremiah Afolabi, Bret C Mobley, Celestine N Wanjalla, Duane Hall, Julia Berry, Oleg Kovtun, Jenny C Schafer, Sean Schaffer, Prasanna Katti, Chantell Evans, Andre Kinder, Joyonna Gamble George, Melanie McReynolds, Annet Kirabo, Sepiso Kenias Masenga, Antentor Hinton.
      Aging is associated with a progressive loss of skeletal muscle function, known as sarcopenia; however, the molecular mechanisms coordinating cellular stress responses and structural adaptations remain incompletely understood. The aim of this study was to investigate the role of activating transcription factor 4 (ATF4), a master regulator of the integrated stress response (ISR), in aging muscle using complementary human population and mouse model approaches. Older adults exhibited a marked decrease in aerobic capacity, muscle strength, and endurance when compared with young participants. These results paralleled findings in aged mice, with significant loss of muscle mass across multiple hindlimb muscles. Ultrastructural analysis revealed substantial age-related changes in mitochondrial morphology, including decreased volume, surface area, and branching index, as well as a shift toward smaller, more fragmented, and spherical mitochondria. These structural changes likely impair oxidative capacity and drive a feed-forward cycle of mitochondrial dysfunction and ISR activation. Our findings indicate that ATF4 coordinates transcriptomic and structural adaptations in aging muscle, identifying the ISR pathway as a potential therapeutic target for preserving muscle function in older adults.
    DOI:  https://doi.org/10.64898/2026.03.27.711928
  53. Nature. 2026 Apr 01.
    The 1000 Chinese Pangenome empowers medical and population genetics.
    Yifei Wang, Zhongqu Duan, Dan Chen, Dandan Shi, Yi Ding, Zhibin Wang, Baoqing Li, Zhiyi Wang, Minmin Guo, Wen Yang, Junren Hou, Wenhao Chen, Yazhou Guo, Wenjie Wei, Yujie Cao, Xiwei Sun, Weiyang Bai, Mingdong Lu, Ting Qi, Xian Shen, Jian Yang.
      Pangenomes are revolutionizing our ability to resolve genomic regions with complex variations1. However, existing human pangenomes2,3, constrained by small sample sizes, provide limited utility for medical and population genetic applications. Here we generated 1,116 diploid genome assemblies (55 de novo and 1,061 pangenome-informed) with an average size of 2.98 Gb and a mean quality value of 46 as part of the 1000 Chinese Pangenome (1KCP) project. On the basis of these assemblies, we constructed a pangenome comprising 405.3 million base pairs of sequences absent from the current references GRCh38 and CHM13, including 26.2 million base pairs of functional genic and predicted regulatory elements. We catalogued a full spectrum of genetic variation, including 35.4 million small variants, 110,530 structural variants (SVs), 485,575 tandem repeats (TRs) and 0.86 million nested variants embedded in non-reference sequences. This extensive dataset enabled detailed characterization of multiscale genic variations relevant to medical genetics, including gene-altering SVs, TR expansions, gene cluster variations and HLA gene haplotypes. Coupled with the 1KCP gene expression data, we conducted pan-variant expression quantitative trait locus (eQTL) mapping to analyse diverse variant types. We identified 3,256 eQTLs involving complex variants (SVs, TRs and nested variants) and elucidated their regulatory complexity. Finally, we developed a 1KCP pan-variant imputation reference panel, which provides multitype genetic markers to enhance the resolution of future association studies. This resource advances our understanding of complex variants and their functional implications to provide new insights into human health.
    DOI:  https://doi.org/10.1038/s41586-026-10315-y
  54. Sci Adv. 2026 Apr 03. 12(14): eaea4279
    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, Eric Hwang, Claire S Chung, Jaye L Weinert, 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 life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. 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 prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. 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/10.1126/sciadv.aea4279
  55. Nat Genet. 2026 Mar 30.
    Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder.
    Undiagnosed Diseases Network
      We recently showed that mutations in the snRNA genes RNU4-2 and RNU2-2 are prevalent causes of dominant neurodevelopmental disorders (NDDs). Here, by genetic association, we demonstrate the existence of a recessive form of RNU2-2 syndrome. We inferred a log Bayes factor for a recessive model of association of 18.2. Conditional on that model, 17 rare variants had a posterior probability of pathogenicity >0.8. This conservative threshold identified 18 probands and 5 affected siblings, each carrying two alleles in trans at these variants. A relaxed threshold of >0.6 identified a further 13 candidate probands. We identified nine further cases in replication collections. Affected individuals have intellectual disability, global developmental delay and seizures. Recessive RNU2-2 syndrome accounts for ~10% of families with a recessive NDD presently diagnosable by sequencing and affects ~60% as many families as the dominant RNU4-2-related NDD ReNU syndrome. The variants are predicted to destabilize stem loops and binding domains of U2-2 snRNA. Whole-blood RNA sequencing data showed a >90% reduction in the expression of pathogenic U2-2 alleles in biallelic cases and monoallelic carriers, albeit with wild-type compensation in carriers, pointing to a loss-of-expression mechanism.
    DOI:  https://doi.org/10.1038/s41588-026-02539-5
  56. Nat Genet. 2026 Mar 30.
    Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.
    Elsa Leitão, Amandine Santini, Benjamin Cogne, Miriam Essid, Maria Athanasiadou, Christy W LaFlamme, Pierre Marijon, Virginie Bernard, Kevin Jousselin, Nicolas Chatron, Giulia Barcia, Boris Keren, Cyril Mignot, Perrine Charles, Thomas Besnard, Robin Paluch, Jean-Madeleine de Sainte Agathe, Edith P Almanza Fuerte, Soham Sengupta, Mathieu Milh, Francis Ramond, Talia Allan, Isabelle An, Camila Araujo, Stéphanie Arpin, Christina Austin-Tse, Stéphane Auvin, Sarah Baer, Nadia Bahi-Buisson, Mads Bak, Magalie Barth, Stéphanie Baulac, Nathalie Bednarek-Weirauch, Matthias Begemann, Mark F Bennett, Uriel Bensabath, Stéphane Bézieau, Rakia Bhouri, Margaux Biehler, Trine Bjørg Hammer, Julie Bogoin, Emilie Bonanno, Simon Boussion, Céline Bris, Adelaide Brosseau-Beauvir, Ange-Line Bruel, Audrey Briand-Suleau, Julien Buratti, Tristan Celse, Pascal Chambon, Nicole Chemaly, Bertrand Chesneau, Estelle Colin, Maxime Colmard, Cindy Colson, Solène Conrad, Thomas Courtin, Isabelle Creveaux, Anne-Charlotte Cullier, Louis T Dang, Anne de Saint Martin, Caroline de Vanssay de Blavous Legendre, Bénédicte Demeer, Anne-Sophie Denommé-Pichon, Philine Diekhoff, Stephanie DiTroia, Martine Doco-Fenzy, Christèle Dubourg, Charlotte Dubucs, Stéphanie Ducreux, Louis Dufour, Romain Duquet, Benjamin Durand, Salima El Chehadeh, Miriam Elbracht, Laurence Faivre, Marie Faoucher, Anne Faudet, Sylvie Forlani, Mélanie Fradin, Pauline Gaignard, Benjamin Ganne, Aurore Garde, Justine Géraud, Deepak Gill, Alice Goldenberg, David Grabli, Coraline Grisel, Sophie Gueden, Paul Gueguen, Anne-Marie Guerrot, Agnès Guichet, Tobias B Haack, Nina Härting, Martin Georg Häusler, Solveig Heide, Theresia Herget, Bénédicte Héron, Delphine Héron, Johanna Herwig, Mathilde Heulin, Tess Holling, Clara Houdayer, Bertrand Isidor, Aurélia Jacquette, Louis Januel, Nolwenn Jean-Marçais, Frank J Kaiser, Sabine Kaya, Chontelle King, Marina Konyukh, Florian Kraft, Jeremias Krause, Rémi Kirstetter, Alma Kuechler, Ingo Kurth, Kerstin Kutsche, Audrey Labalme, Jean-Serene Laloy, Vincent Laugel, Floriane Le Bricquir, Anne-Sophie Lèbre, Marine Lebrun, Eric Leguern, Jonathan Levy, Nico Lieffering, Stanislas Lyonnet, Kevin Lüthy, Sian M W Macdonald, Lamisse Mansour-Hendili, Julien Maraval, Iris Marquardt, Carolin Mattausch, Sandra Mercier, Olfa Messaoud, Godelieve Morel, Jérémie Mortreux, Arnold Munnich, Rima Nabbout, Sophie Nambot, Vincent Navarro, Ashana Neale, Laetitia Nguyen, Mathilde Nizon, Frédérique Nowak, Melanie C O'Leary, Sylvie Odent, Naomi Meave Ojeda, Valérie Olin, Simone Olivieri, Katrin Õunap, Lynn S Pais, Eleni Panagiotakaki, Olivier Patat, Laurence Perrin-Sabourin, Florence Petit, Christophe Philippe, Amélie Piton, Marc Planes, Céline Poirsier, Antoine Pouzet, Clément Prouteau, Sylvia Quéméner-Redon, Mathilde Renaud, Anne-Claire Richard, Marlène Rio, Clotilde Rivier, Florence Robin-Renaldo, Paul Rollier, Massimiliano Rossi, Agathe Roubertie, Valentin Ruault, Maïlys Rupin-Mas, Pascale Saugier-Veber, Aline Saunier, Russell Saneto, Elisabeth Sarrazin, Catherine Sarret, Elise Schaefer, Caroline Schluth-Bolard, Amy Schneider, Isabell Schumann, Vladimir B Seplyarskiy, Stephanie Spranger, Thomas Smol, Marc Sturm, Shamil R Sunyaev, Brian Sperelakis-Beedham, Sarah L Stenton, Friedrich Stock, Mylène Tharreau, Deniz Torun, Joseph Toulouse, Harshini Thiyagarajah, Stéphanie Valence, Sophie Valleix, Julien Van-Gils, Laurent Villard, Dorothée Ville, Nathalie Villeneuve, Antonio Vitobello, Aurélie Waernessyckle, Jan Wagner, Yvonne Weber, Dagmar Wieczorek, Tom Witkowski, Manya Yadavilli, Tony Yammine, Khaoula Zaafrane-Khachnaoui, Maha S Zaki, Alban Ziegler, Nuria C Bramswig, Alban Lermine, Gael Nicolas, Joseph G Gleeson, Lynette G Sadleir, Michael S Hildebrand, Ingrid E Scheffer, Nicola Whiffin, Anne O'Donnell-Luria, Heather C Mefford, Pierre Blanc, Julien Thevenon, Camille Charbonnier, Clément Charenton, Christel Depienne, Gaetan Lesca, Caroline Nava.
      Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with the high mutability of snRNA genes. Dominant and recessive RNU2-2 NDDs share overlapping clinical features, with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome.
    DOI:  https://doi.org/10.1038/s41588-026-02547-5
  57. Science. 2026 Apr 02. 392(6793): eaea8782
    Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response.
    Lucas C Reineke, Ping Jun Zhu, Udit Dalwadi, Sean W Dooling, Yuwei Liu, I-Ching Wang, Sara Young-Baird, James Okoh, Santosh Kumar Kuncha, Hongyi Zhou, Akshara Kannan, Hyekyung Park, Nicolas A Debeaubien, Tristan Croll, D John Lee, Christopher Arthur, Thomas E Dever, Peter Walter, Jin Chen, Adam Frost, Mauro Costa-Mattioli.
      The integrated stress response (ISR) is essential for cellular homeostasis and cognitive function. We investigated how persistent ISR activation affects cognitive performance by studying the PPP1R15BR658C genetic variant associated with intellectual disability. To model this condition, we generated a mouse line with the pathogenic allele inserted. This variant destabilized the PPP1R15B•PP1 phosphatase complex, causing persistent ISR activation, impaired protein synthesis, and long-term memory deficits. We demonstrated that the cognitive and synaptic impairments in Ppp1r15bR658C mice arise directly from ISR activation. Furthermore, we characterized DP71L, a viral ortholog of PPP1R15B, which acted as a potent pan-ISR inhibitor. DP71L reversed the cognitive and synaptic deficits across mouse models of Down syndrome, Alzheimer's disease, and aging, and enhanced synaptic plasticity and memory in healthy mice.
    DOI:  https://doi.org/10.1126/science.aea8782
  58. bioRxiv. 2026 Mar 26. pii: 2026.03.24.713976. [Epub ahead of print]
    MLL3/4 methyltransferases regulate the differentiation of pluripotent stem cells via cellular respiration.
    Suza Mohammad Nur, Yunbo Jia, Muyi Ye, Caylin A Lepak, Issam Ben-Sahra, Kaixiang Cao.
      Enhancer-regulating epigenetic modifiers play critical roles in normal physiological processes and human pathogenesis. The major enhancer regulator paralogs MLL3 and MLL4 (MLL3/4) belong to the lysine methyltransferase 2 (KMT2) family, which catalyzes the methylation of lysine 4 on histone H3 (H3K4me). MLL3/4 are required for enhancer activation and are essential for mammalian development and stem cell differentiation. Recent studies have linked MLL3/4 with different metabolic pathways in the context of stem cell self-renewal and cancer cell growth; however, the underlying mechanisms remain elusive. Here, we utilize Seahorse extracellular flux analysis, stable isotope tracing, stem cell biology techniques, and transcriptomic analysis to investigate the functional relationship of MLL3/4, cellular respiration, and stem cell differentiation. Our results indicate that the loss of MLL3/4 impairs glycolytic activity and mitochondrial respiration in murine embryonic stem cells by downregulating the rate-limiting glycolytic enzyme Hexokinase 2 (HK2) and impairing the function of the Alpha-ketoglutarate dehydrogenase (OGDH) complex. Furthermore, simultaneously overexpression of HK2 and OGDH rescues defects in both cellular respiration and differentiation caused by MLL3/4 loss. Taken together, our study reveals a novel mechanism by which epigenetic machineries such as MLL3/4 govern the differentiation of pluripotent stem cells and facilitates the understanding of disease pathogenesis driven by enhancer malfunction.
    DOI:  https://doi.org/10.64898/2026.03.24.713976
  59. bioRxiv. 2026 Mar 28. pii: 2026.03.27.714830. [Epub ahead of print]
    Dynamic UFMylation governs cellular fitness by coordinating multi-organelle proteostasis.
    Guy B Kunzmann, William E Leiter, Sophie E Durn, Amy M Weeks, Jason R Cantor.
      Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like protein (UBL) covalently attached to substrates through a dedicated enzymatic cascade (UFMylation) and removed by specific proteases. Despite a key role in endoplasmic reticulum (ER)-ribosome homeostasis, the basis by which this UBL supports cell fitness remains elusive, as the essentiality of UFMylation machinery varies widely across hundreds of cancer lines. Here, we trace a conditional dependence on the UFMylation pathway to the availability of alanine, an amino acid provided by human plasma-like medium but absent from most conventional synthetic media. We show that by facilitating the clearance of stalled ribosomes at the ER, dynamic UFMylation maintains cellular levels of glutamic-pyruvic transaminase 2 (GPT2), the primary enzyme responsible for de novo alanine synthesis in most human cancer lines. This buffering preserves the alanine pools required to sustain protein synthesis under alanine-restricted conditions. Beyond GPT2, UFM1 deficiency leads to widespread proteomic remodeling that spans diverse processes, including mitochondrial translation. Our results reveal that despite primarily targeting ER-localized ribosomes, the UFMylation system orchestrates a multi-organelle proteostasis network whose client composition and contributions to cell fitness are shaped by intrinsic factors and nutrient conditions.
    DOI:  https://doi.org/10.64898/2026.03.27.714830
  60. bioRxiv. 2026 Mar 26. pii: 2026.03.23.712647. [Epub ahead of print]
    Mitochondrial protein translation is a heightened dependence and therapeutic vulnerability of chemo-refractory triple negative breast cancer.
    Mariah J Berner, Steven W Wall, Mokryun L Baek, Audra Lane, Allison S Greer, Karen Wang, Lacey E Dobrolecki, Ivy Strope, Qian Zhu, Bing Zhang, Jonathan T Lei, Michael T Lewis, Gloria V Echeverria.
      Triple negative breast cancer (TNBC) patients harboring residual cancer burden following completion of conventional neoadjuvant chemo-immunotherapy regimens have poor relapse-free and overall survival rates despite recent advances in immunotherapies and antibody drug conjugates. We and others have demonstrated the requirement of mitochondrial function for survival of chemo-refractory TNBC, as well as its pervasive association with chemoresistance in human and patient-derived xenograft (PDX) cohorts. We sought to gain new mechanistic insights into the mitochondrial vulnerability of TNBC. Analyses of human and PDX mass spectrometry proteomics datasets revealed that mitochondrial protein translation-related signatures were among the top significantly associated with chemoresistance. Those signatures encompassed many core mitoribosome components as well as the mitoribosome accessory protein, Oxidase (Cytochrome C) Assembly 1-Like (OXA1L), which was consistently enriched in chemoresistant versus chemosensitive TNBCs across datasets. OXA1L, while not yet characterized in cancer, has been reported to be crucial for the termination of translation of the 13 mtDNA-encoded electron transport chain (ETC) proteins and for the insertion of those proteins, as well as nDNA-encoded ETC proteins, into the inner mitochondrial membrane. Together, those functions are crucial for the proper formation and function of the ETC. Therefore, we hypothesized that mitochondrial translation supported by OXA1L supports mitochondrial dependence and chemoresistance in TNBC. Knockdown (KD) of OXA1L in human TNBC cells reduced ETC protein levels, mitochondrial 'respirasome' supercomplex levels, ATP production, and oxidative phosphorylation (oxphos). Of note, OXA1L was required for the characteristic oxphos elevation induced by carboplatin (CRB), and KD significantly enhanced CRB sensitivity. To explore the translational potential of targeting the mitoribosome in TNBC, we leveraged the bacterial ancestry of mitochondria to repurpose the FDA-approved antibiotic tigecycline (TIG) as a chemo-sensitizing drug based on its mitoribosome inhibitory function. Direct measurement of mitochondrial nascent peptide levels revealed that, while CRB elevated mitochondrial translation, TIG potently diminished mitochondrial translation as monotherapy and when combined with CRB or docetaxel (DTX). Further, TIG abolished CRB-induced oxphos, decreased oxphos in combination with DTX, and significantly improved sensitivity to chemotherapies in human TNBC cell lines, PDX-derived spheroids, and in an in vivo PDX trial. These findings identify OXA1L-dependent mitochondrial translation and ETC formation as critical determinants of mitochondrial function that support TNBC chemoresistance, justifying further exploration of the clinical potential of repurposed antibiotics for TNBC.
    DISCLOSURES: GVE is co-founder, Chief Scientific Officer, and an equity stakeholder of Nemea Therapeutics. G.V.E. formerly received sponsored research funding from Chimerix Inc. G.V.E. receives experimental compounds from the Lead Discovery Center of Germany and from Jazz Pharmaceuticals. MLB is a co-inventor at Nemea Therapeutics. MTL is a founder and limited partner in StemMed Ltd. and a manager in StemMed Holdings, its general partner. He is a founder and equity stakeholder in Tvardi Therapeutics Inc. Some PDX models, including BCM-4272 and BCM-7649, are exclusively licensed to StemMed Ltd., resulting in royalty income to MTL when used for commercial purposes. LED is a compensated employee of StemMed Ltd. Some PDX models, none of which are included in this study, are exclusively licensed to StemMed Ltd., resulting in royalty income to LED. All other authors have nothing to disclose.
    DOI:  https://doi.org/10.64898/2026.03.23.712647
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