bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–05–24
sixty-five papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.
  2. Cardiolipin preserves Treg metabolic fitness and immune homeostasis in the gut.
  3. ATF2 phosphorylation is a core transcriptional driver of neuron apoptosis.
  4. Melas mimicking hydrocephalus.
  5. Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.
  6. The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
  7. Dynamic disorder is crucial for mitochondrial protein import.
  8. Mitoredox Shifts in Mitochondrial Dysfunction.
  9. "SelO"ective NAD+ hydrolysis regulates mitochondrial NAD+ and homeostasis.
  10. Light-Inducible Bispecific DNAzymes Reveal Mitochondrial Fe2+/Fe3+ Dynamics During Ferroptosis.
  11. Expanding the Clinical and Genetic Landscape of UQCRC2-related Mitochondrial Complex III Deficiency: A Case Report and Literature Review.
  12. Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.
  13. Mitochondria transfer in neurological disorders: the key role of neuroglia.
  14. Mitochondria across the globe: Diverse voices, shared energy.
  15. A case of a spinal cord involvement in an adult mitochondrial disease with an m.3243A>G.
  16. Mitochondrial Dynamics and Transfer in Mesenchymal Stromal Cells: Redox Regulation, Therapeutic Mechanisms, and Engineering Strategies.
  17. Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
  18. Electron microscopy visualization of cell-free mitochondrial DNA-associated vesicular structures in human plasma, serum, and saliva.
  19. Before a spinal cord lesion in an m.3243A>G carrier is attributed to mitochondrial disease, all differential diagnoses must be excluded.
  20. Neutrophil-Like Mitochondria Enable Blood-Brain Barrier Transmigration and Neuroprotection.
  21. Mitochondria-derived vesicles with bioenergetic units from brown adipose tissue attenuate cardiac remodeling post-myocardial infarction.
  22. Human iPSC‑based translational and reverse translational research for neurodegenerative diseases: emphasis on ALS and key advances.
  23. Neuroprotective effect of astrocytic dopamine Drd2 receptor on mitochondrial complex I in a mouse model of Parkinson's disease through β-arrestin2-NDUFA10 regulation.
  24. Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.
  25. Leber hereditary optic neuropathy (LHON) in a 6-year-old boy with a transient spinal cord lesion.
  26. A Novel Combination of Biallelic Variants in the VARS2 Gene: A Severe Phenotype.
  27. DDRGK1 regulates muscle development by maintaining mitochondrial calcium homeostasis and oxidative phosphorylation via stabilizing IP3R.
  28. Mavodelpar in patients with primary mitochondrial myopathy: a phase 1 trial.
  29. Crosstalk between endoplasmic reticulum stress and mitochondrial homeostasis: A new perspective on ophthalmic disease treatment.
  30. TACO1 regulates mitochondrial adaptation in hypertension-induced cardiac remodeling and heart failure.
  31. Inhibition of the mitochondrial pyruvate carrier attenuates the integrated stress response activation in a cellular model of Huntington's disease.
  32. Targeting competitive Fe-S regulation to treat Friedreich's ataxia.
  33. Pharmacological rescue of mitochondrial dysfunction, neurite degeneration, and premature death of ALS and AD iPSC-derived neurons.
  34. Mitochondrial Transmembrane β-Barrels: Deducing Thermodynamic Regulators of Folding and Stability.
  35. Mitophagy in cardiovascular diseases: a literature review.
  36. Nrf2 modulates cytosolic and mitochondrial calcium signal.
  37. Challenging mtDNA tRNA variant guidelines: Emphasizing single-cell analysis through four novel variants.
  38. From text to translation: using language models to prioritize variants for clinical review.
  39. A COA8 homozygous mutation presenting as an intermediate CMT with leukopathy.
  40. Aortic Segments-Depending Hypertensive Remodeling Is Driven by Mitochondrial Fusion Dysfunction.
  41. Mitochondrial aminoacyl-tRNA synthetase (ARS)-defects: a review of phenotypes and therapeutic strategies in 899 patients.
  42. Experimental and Computational Approaches to Identify Noncoding Pathogenic Variation in Rare Disease.
  43. Pharmacological restoration of impaired autophagy in retinal ganglion cells prevents abnormal mitochondrial accumulation and glaucomatous neurodegeneration.
  44. Kv2-VAP interactions enhance presynaptic ER and mitochondrial calcium influx and the mobilization of vesicles from the reserve pool.
  45. Mitochondrial metabolic reprogramming, quality control, and intercellular transfer in regulating macrophage plasticity.
  46. The progress of mitochondrial function and transfer in stem cell regulation and therapy.
  47. Mitochondrial Function in Neurons and Glia in Health and Its Alteration in Parkinson's Disease: A Review.
  48. Living donor liver transplantation in a pediatric patient with mitochondrial DNA depletion syndrome caused by two novel POLG1 mutations: a case report and literature review.
  49. Fabrication of fusogenic and magnet-responsive cells for transplantation of an intact mitochondrial network.
  50. Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's disease and Parkinson's disease using polygenic risk scores and Mendelian randomization.
  51. Chromatin- and actin-mediated mitochondrial streaming leads to patterning of mitochondrial distribution in oocytes.
  52. Higher-order structural organization of mitochondrial metabolism.
  53. The Integrated Stress Response Protein, eIF2α, Modulates UPRmt Signaling and Cell Death in Doxorubicin Treated Human Cardiac Cells.
  54. Constrained peptide mimics of the LRRK2 C-terminal Helix inhibits its kinase activity.
  55. Mitochondrially Transcribed dsRNA Mediates Manganese-induced Neuroinflammation.
  56. Revisiting Mitochondrial Temperature: Steady-State Heat Transfer or Non-Steady-State Dynamics?
  57. Twenty years of induced pluripotent stem cells.
  58. Elucidating the molecular interplay between LRRK2 and Rab GTPases.
  59. Genetic architecture of hereditary spastic paraplegia: from monogenic to oligogenic models.
  60. Genome-wide associations of structural variants with human traits through imputation from long-read assemblies.
  61. Nucleoside therapy for thymidine kinase 2 deficiency: Long-term outcomes from a Brazilian cohort.
  62. WeakMitoSAM: competitive prompt aggregation for point-supervised mitochondria segmentation in electron microscopy images.
  63. An engineered viral RNA degrader on mitochondrial surface that mitigates RNA virus infection.
  64. Regulation of Pfh1 helicase activity by nucleic acid interactions and mitochondrial SSB.
  65. A unifying model of stem cell dynamics explains age-related methylation patterns across mammals.
  1. Nature. 2026 May 20.
    Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.
    Ram P Chakrabarty, Jonathan G Van Vranken, Yuki Aoi, Taylor A Poor, Gregory S McElroy, Karthik Vasan, Shimaa H A Soliman, Marta Iwanaszko, Rogan A Grant, Benjamin C Howard, Colleen R Reczek, Anjali D Chandel, Michael Kahl, Zhaofa Xu, Kathryn A Helmin, Qiushi Jin, Dongmei Wang, Peng Gao, Jenna L E Blum, Zachary L Sebo, Feng Yue, Yongchao C Ma, Shawn M Davidson, Steven P Gygi, Samuel E Weinberg, Benjamin D Singer, SeungHye Han, Ali Shilatifard, Navdeep S Chandel.
      L-2-Hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals because the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH) oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation1. In humans, a lack of L2HGDH activity leads to L-2-HG accumulation and causes L-2-hydroxyglutaric aciduria2. Thus, L-2-HG is often classified as a toxic metabolite2-5. However, whether L-2-HG has any physiological function is unclear. Here we investigate whether L-2-HG qualifies as a physiological signalling metabolite by testing three criteria: regulated levels, defined molecular targets and a measurable physiological function. We report that an increase in mitochondrial NADH/NAD+ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-OG into L-2-HG. Moreover, L2HGDH oxidizes L-2-HG back to 2-OG in the mitochondrial matrix without requiring a functional electron transport chain. Through proteome integral solubility alteration assays, we show that the KDM4 family of H3K9 demethylases are L-2-HG-responsive targets. L-2-HG represses the nascent transcription of specific genes in mouse embryonic stem cells and increases H3K9me3 (a repressive histone mark) at these loci. In vivo, early embryonic L2HGDH overexpression in mice systemically reduces L-2-HG levels, impairs postnatal growth, causes mortality and produces selective functional and histological renal vulnerabilities. In postnatal kidneys, this reduction in L-2-HG causes H3K9me3 loss at L1MdTf retrotransposons and their derepression, which coincides with the activation of the integrated stress response and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiological signalling metabolite and indicate that metabolites previously regarded as toxic may also have crucial physiological functions.
    DOI:  https://doi.org/10.1038/s41586-026-10564-x
  2. Nat Metab. 2026 May 18.
    Cardiolipin preserves Treg metabolic fitness and immune homeostasis in the gut.
    Annamaria Regina, Francesca Solagna, Malkon Sanchez Estrada, Maaike M E Jacobs, Daniel Martinez-Martinez, Theodoros Georgomanolis, Irma Alibashikj, Sara Gjurgji, Claire Pearson, Dehui Chang, Chrysanthi Moschandrea, Ana Sagrera Aparisi, Elena Crespo, Jessica Buechel, Farina Schneider, Lea Trojahn, Paulina Pfelzer, Milica Popovic, Elena Potenza, Agnieszka M Kabat, Carien Niessen, Borko Amulic, Niloufar Safinia, Sara Cogliati, David E Sanin, Matteo Villa, Edward J Pearce, Christian Frezza, Erika L Pearce, Filipe Cabreiro, Fiona Powrie, Mauro Corrado.
      Loss of host-microbiota balance promotes gut inflammation, colitis and inflammatory bowel disease. Yet, whether host or microbial factors are the critical driver of the pathology remains unclear. Here, we investigate how cardiolipin maintains metabolic fitness of regulatory T (Treg) cells to preserve gut-immune homeostasis. We discover that deleting the cardiolipin-synthesizing enzyme protein tyrosine phosphatase mitochondrial 1 (PTPMT1) in T cells predisposes mice to colitis due to impaired Treg cell function in the absence of dysbiosis. Subsequent pathobiont infections accelerate the progression and severity of gut inflammation. Mechanistically, the absence of cardiolipin impairs Treg cell metabolic fitness and triggers a maladaptive integrated stress response, which can be reversed pharmacologically or genetically, restoring gut homeostasis and extending lifespan in PTPMT1 ΔT mice. Barth syndrome, a genetic disorder marked by severe cardiolipin deficiency, also exhibits gastrointestinal symptoms and inflammation associated with helper T cell imbalance and an active integrated stress response signature. Overall, these results suggest that a cardiolipin-mediated mitonuclear axis in T cells preserves gut-immune homeostasis and dictates outcome in pathobiont infections.
    DOI:  https://doi.org/10.1038/s42255-026-01533-9
  3. Neuron. 2026 May 19. pii: S0896-6273(26)00330-2. [Epub ahead of print]
    ATF2 phosphorylation is a core transcriptional driver of neuron apoptosis.
    Jorge Gómez-Deza, Matthew Nebiyou, Lara H El Touny, Mor R Alkaslasi, Zhenyu Zuo, Josette J Wlaschin, Francisco M Nadal-Nicolás, Alexandra Stavsky, Xiaotian Zhang, Anastasia L Slavutsky, Ariel Y Zhang, Eliza Y H Lloyd, Peter M Hayashi, Nathan Ashby, Mariella G Brueck, Mira Sohn, Ryan K Dale, Gareth M Thomas, Wei Li, Ken Chih-Chien Cheng, Pedro P Rocha, Claire E Le Pichon.
      Neuronal apoptosis is a key feature of neurodegenerative diseases. Considerable efforts have been made to target this pathway; however, the underlying molecular mechanisms remain incompletely understood. Here, we conducted an unbiased, genome-wide CRISPR inhibition screen in human neurons to discover genes required for cell death. We uncover a multitude of targets required for neuronal apoptosis, some known and many previously unidentified. Among them, three stood out as members of a pro-death cascade: dual leucine zipper kinase (DLK or MAP3K12) and the transcription factors JUN and the lesser-known activating transcription factor 2 (ATF2). Through mechanistic studies, we demonstrate that ATF2 phosphorylation by MAP3 kinases is a critical step in neuronal apoptosis. Surprisingly, JUN phosphorylation is not required. Conversion of the MAP3 kinase signal into a pro-apoptotic transcriptional response requires phospho-ATF2 to upregulate JUN. We show that interfering with ATF2 function prevents neuronal apoptosis in vitro and in vivo. Our work posits ATF2 as a promising target for a wide range of neurodegenerative disorders.
    Keywords:  ATF2; CRISPRi screen; DLK; JUN; LZK; MAP3K12; cytoskeletal stress; neuron death; neuron injury signaling; neuronal apoptosis
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.035
  4. Neurol Sci. 2026 May 20. pii: 506. [Epub ahead of print]47(6):
    Melas mimicking hydrocephalus.
    Matthieu Labriffe, Patrizia Amati-Bonneau, Marco Spinazzi.
      
    Keywords:  Dementia; Hydrocephalus; MELAS; Mitochondrial disease; Neurodegeneration; Ventricular enlargement
    DOI:  https://doi.org/10.1007/s10072-026-09113-1
  5. Pharmacol Res. 2026 May 18. pii: S1043-6618(26)00142-8. [Epub ahead of print] 108227
    Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.
    Julia Brechtel, Christine Lietz, Selin Akpinar Adscheid, Kristina Friedland.
      Mitochondrial dysfunction is considered one of the key drivers of neurodegeneration and pathological aging, characterized by impaired energy production, oxidative stress, disrupted mitophagy, and biogenesis. Because mitochondria regulate bioenergetics, redox balance, and neuronal survival, therapeutic strategies that restore mitochondrial integrity are of growing interest. This review outlines mechanisms of mitochondrial function and failure, links them to Alzheimer's and Parkinson's disease, and summarizes evidence on phytochemicals and mitochondria-targeted small molecules, which enhance biogenesis, mitophagy, respiratory efficiency, and antioxidant defence in preclinical models together with life-style interventions. Although many compounds demonstrate preventive rather than restorative benefit and clinical evidence remains limited, next-generation approaches, including nanoparticles for mitochondrial delivery, mtDNA editing, and mitochondrial transfer, suggest increasing therapeutic potential. We underline that future success will rely on improved delivery, synergistic combinations, and rigorous clinical trials. Mitochondria-directed therapies may ultimately provide disease-modifying or preventive strategies for neurodegenerative disorders.
    Keywords:  Alzheimer’s Disease; Mitochondria-Targeted Therapies; Mitochondrial Dynamics; Mitochondrial Dysfunction; Parkinson’s Disease; Phytochemicals; Small Molecule
    DOI:  https://doi.org/10.1016/j.phrs.2026.108227
  6. Protein Sci. 2026 Jun;35(6): e70622
    The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
    Kira Ritzenhofen, Stefano Rossi, Axel Mogk, Fabian den Brave.
      Mitochondria are essential organelles of eukaryotic cells, with vital roles in energy production, biosynthesis of macromolecules, and intracellular signaling. Their function depends on a complex proteome with proteins targeted to different mitochondrial sub-compartments. Synthesis of precursors of mitochondrial proteins (mitoPREs) mostly occurs in the cytosol followed by post-translational import. Delay or block of mitochondrial import leads to mitoPRE accumulation in the cytosol, where they interact with cytosolic protein quality control (PQC) factors and might get re-routed to other cellular organelles, including the nucleus. Recent research implies the nucleus as a central hub in cellular PQC. Here, not only nuclear but also proteins from other organelles, including mitochondria or the cytosol, are handled by intra-nuclear PQC factors. In addition, the nucleus controls the expression of mitochondrial proteins and PQC components involved in handling mitoPREs and surveilling the integrity of mitochondrial import channels. In this review, we discuss recent insights from yeast on the dual function of the nucleus in controlling the biogenesis of mitoPREs and as a compartment for quality control of non-imported mitoPREs. We additionally describe how mitochondrial dysfunction and defects in mitochondrial import trigger compensatory stress responses inside the nucleus. Here, nuclear targeting of non-imported mitoPREs may serve as a direct signal to adjust stress response pathways to the status of mitochondrial import.
    Keywords:  chaperones; mitochondria; nucleus; protein quality control; protein sorting; stress response; ubiquitin‐proteasome system
    DOI:  https://doi.org/10.1002/pro.70622
  7. Protein Sci. 2026 Jun;35(6): e70630
    Dynamic disorder is crucial for mitochondrial protein import.
    Jakob Schneider, Undina Guillerm, Caroline Simões Pereira, Paul Schanda.
      The import of proteins into mitochondria poses fundamental mechanistic challenges: aggregation-prone precursor proteins must be maintained in aqueous compartments and threaded through narrow pores without becoming stuck or mislocalized. Recent evidence from mitochondrial protein import studies and other chaperone systems underscores the critical role of dynamics in balancing sufficiently tight binding, promiscuity, specificity, and release. Dynamic binding of client precursor proteins to import machinery components arises naturally from the avidity of their interactions. Conformational entropy enhances their stability, while the multivalent nature of these interactions ensures that client transfer to downstream insertases occurs without a substantial energy barrier. Here, we discuss this emerging paradigm of dynamic protein handling, using examples where dynamic structures have been resolved and highlight outstanding questions.
    Keywords:  avidity; chaperones; import machinery; intrinsic disorder; mitochondria
    DOI:  https://doi.org/10.1002/pro.70630
  8. Free Radic Biol Med. 2026 May 21. pii: S0891-5849(26)00787-2. [Epub ahead of print]
    Mitoredox Shifts in Mitochondrial Dysfunction.
    Walter H Moos, Douglas V Faller, Ioannis P Glavas, Iphigenia Kanara, Krishna Kodukula, Julie Pernokas, Mark Pernokas, Carl A Pinkert, Whitney R Powers, Konstantina Sampani, Kosta Steliou, Demetrios G Vavvas.
      Mitochondrial dysfunction underlies a broad spectrum of primary and secondary disorders, yet current frameworks do not fully capture how diverse genetic, metabolic, and environmental stressors converge on shared pathological outcomes. Here, we propose that mitoredox shifts - bidirectional disruptions in mitochondrial redox homeostasis that alter mitochondrial quality control and genome-stability pathways - serve as a unifying axis linking oxidative stress, mitochondrial quality control failure, heteroplasmy dynamics, and regulated cell death. Both hyperactive and hypoactive mitochondrial states destabilize redox balance, altering PINK1/Parkin-dependent and receptor-mediated mitophagy, disrupting proteostasis, and reshaping mitochondrial network dynamics. These redox-driven perturbations influence the propagation of pathogenic mtDNA variants, modulate tissue-specific threshold effects, and bias cells toward apoptosis, ferroptosis, cuproptosis, and other regulated cell death pathways. We synthesize emerging evidence across mitochondrial genetics, bioenergetics, and redox signaling to outline how mitoredox shifts accelerate disease progression in both primary mitochondrial syndromes and secondary mitochondrial dysfunction. We further evaluate the expanding landscape of diagnostic biomarkers, including FGF21, GDF15, imaging-based oculomics, and high-throughput proteomic and genomic assays. In parallel, we highlight therapeutic strategies aimed at restoring redox balance, enhancing mitophagy, or shifting mitochondrial network composition by diluting dysfunctional organelles through mitochondrial transplantation. By emphasizing mitoredox imbalance as a recurrent feature of disease, this work synthesizes emerging diagnostic and therapeutic approaches across rare and common mitochondrial disorders.
    Keywords:  Biomarkers; cuproptosis; ferroptosis; heteroplasmy; mitochondria; mitophagy; mitoredox medicine; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.307
  9. Cell Chem Biol. 2026 May 21. pii: S2451-9456(26)00147-9. [Epub ahead of print]33(5): 591-593
    "SelO"ective NAD+ hydrolysis regulates mitochondrial NAD+ and homeostasis.
    Qing Zhang, Trina Chia Min Tan, Vincenzo Sorrentino.
      Nicotinamide adenine dinucleotide (NAD+) is a metabolic redox cofactor whose compartmentalization in mitochondria is crucial for cellular function; however, its regulation mechanisms are largely unknown. In a recent Cell publication, Jia et al.1 uncover that the enzyme SelO catalyzes mitochondrial NAD+ hydrolysis to regulate β-oxidation and maintain mitochondrial and liver homeostasis.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.04.012
  10. Angew Chem Int Ed Engl. 2026 May 22. e7378442
    Light-Inducible Bispecific DNAzymes Reveal Mitochondrial Fe2+/Fe3+ Dynamics During Ferroptosis.
    Yang Shi, Rong Wang, Jiaqi Wang, Hang Xing, Jingjing Zhang, Jian-Hui Jiang, Zhenkun Wu.
      Mitochondrial iron redox homeostasis plays critical roles in cellular function and disease progression; however, spatiotemporal measurement of Fe2+ and Fe3+ dynamics in mitochondria remains challenging, largely due to limited analytical tools. Here we report a light-inducible bispecific DNAzyme sensor (LiBD) that enables simultaneous and spatiotemporally controlled imaging of mitochondrial labile Fe2+ and Fe3+ in living cells and in vivo. LiBD integrated two orthogonal iron-specific DNAzymes into a single DNA scaffold, incorporating photocleavable (PC) linkers, rendering DNAzymes inactive until light-triggered activation. Coupled with mitochondria-targeted nanocarriers, LiBD demonstrated high spatial and temporal resolution for monitoring Fe2+ and Fe3+ level changes in mitochondria. We revealed remarkable mitochondrial Fe2+ accumulation in tumor cells during drug-induced ferroptosis, whereas chemotherapy-resistant tumor cells exhibited substantially decreased Fe2+ in mitochondria, both accompanied by slight increases in Fe3+. Moreover, an NIR-activatable LiBD demonstrated in vivo visualization of mitochondrial Fe2+ and Fe3+ level changes during ferroptosis in tumor-bearing mice. Collectively, this work presents LiBD as a powerful platform for investigating mitochondrial iron biology with spatiotemporal precision and provides insights into iron-dependent mechanisms of ferroptosis and chemoresistance.
    Keywords:  DNAzyme; biosensor; cell imaging; functional nucleic acid; mitochondrial Fe2+/Fe3+ detection
    DOI:  https://doi.org/10.1002/anie.7378442
  11. Curr Pediatr Rev. 2026 May 18.
    Expanding the Clinical and Genetic Landscape of UQCRC2-related Mitochondrial Complex III Deficiency: A Case Report and Literature Review.
    Verónica Bindi, Carolina Crespo, Francisco García, Kim Jihye, Hernán Eiroa, Luis Pablo Gravina, Hilda Verónica Aráoz.
       BACKGROUND: Mitochondrial oxidative phosphorylation (OXPHOS) defects are clinically heterogeneous and often challenging to diagnose. Complex III deficiency caused by UQCRC2 variants is exceptionally rare, with only a limited number of patients described worldwide. Reporting new cases is essential to expand the clinical and molecular landscape of this disorder and to provide insights into potential therapeutic strategies.
    CASE PRESENTATION: We describe a female patient with UQCRC2-related complex III deficiency who experienced recurrent episodes of metabolic decompensation characterized by hypoglycemia, hyperlactatemia, and renal tubular dysfunction from early childhood. Brain magnetic resonance imaging revealed white matter lesions associated with mild neurological symptoms. During metabolic crises, management included intravenous glucose infusion and strict avoidance of prolonged fasting. At age 15, supplementation with coenzyme Q10 was introduced, followed by complete cessation of hospitalizations and a sustained clinical stabilization. Genetic testing identified compound heterozygosity for a known missense variant and a novel frameshift variant in UQCRC2. A literature review of previously reported cases confirmed the broad clinical variability, ranging from severe neonatal presentations to milder phenotypes with survival into adolescence.
    CONCLUSION: This case expands the phenotypic spectrum of UQCRC2-related complex III deficiency and suggests that targeted supplementation with coenzyme Q10 may contribute to improved longterm outcomes. Early recognition of metabolic crises, avoidance of fasting, and genetic confirmation are crucial for diagnosis and management. Further reports are needed to clarify genotype-phenotype correlations and to define the therapeutic role of coenzyme Q10 in this rare mitochondrial disorder.
    Keywords:  Mitochondrial disease; UQCRC2 deficiency; coenzyme Q10; complex III deficiency; metabolic crisis; oxidative phosphorylation system
    DOI:  https://doi.org/10.2174/0115733963454034260430145544
  12. Nat Aging. 2026 May;6(5): 987-1006
    Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.
    Arpit Sharma, Aditi Prabhakar, Miriam Valera-Alberni, Jamie D Kraft, Abigail E Ellis, Ryan D Sheldon, Meeta Mistry, Pallas Yao, Yanshan Liang, Sheng Hui, William B Mair.
      Aging impairs coordinated organelle dynamics essential for lipid metabolism, causing a decline in intracellular metabolic flexibility. However, the drivers of organelle collapse and their temporal order remain unclear. Here we identify peroxisomal function as a critical regulator of metabolic flexibility during youth and low-energy states. Using Caenorhabditis elegans, we show that fasting robustly induces peroxisomal function in youth, whereas this response is blunted during aging. Loss of peroxisomal import via PRX-5 declines over age, causing pathological lipid droplet expansion, dysfunctional mitochondrial bioenergetics and metabolic inflexibility. Although targeted PRX-5 degradation recapitulates metabolic aging, its overexpression preserves lipid dynamics and mitochondrial integrity. Notably, dietary restriction maintains peroxisomal pathways and organelle coordination into late life and peroxisomal function causally underpins dietary restriction-mediated longevity. Our findings highlight peroxisomes as central upstream regulators of a dynamic interorganelle cascade driving metabolic plasticity and highlight peroxisomal maintenance as a key determinant of metabolic flexibility during aging.
    DOI:  https://doi.org/10.1038/s43587-026-01122-1
  13. Mol Neurodegener. 2026 May 21.
    Mitochondria transfer in neurological disorders: the key role of neuroglia.
    Jie Jiao, Hui Chen, Alexei Verkhratsky, Yixun Su, Chenju Yi.
      Mitochondria transfer has emerged as a distinctive mechanism for intercellular communication and neuronal homeostasis. Neurones, owing to their unique bioenergetic demands, are particularly vulnerable to mitochondrial dysfunction, a shared pathogenetic feature across many neurological conditions, including neurodegenerative disorders, cerebrovascular diseases, and brain injuries. Intercellular transfer of mitochondria represents a potential adaptive mechanism rectifying compromised mitochondrial function. Neuroglial cells, especially astrocytes and microglia, frequently act as mitochondrial donors, supplying functional mitochondria to stressed neurones to restore bioenergetic capacity and influence disease trajectories. However, mitochondria transfer is intrinsically context dependent and can exert opposing effects. In addition to providing metabolic support, damaged mitochondria may also be transferred, propagating pathological signals, and exacerbating tissue injury. Moreover, in advanced disease states, mitochondrial malfunction often affects all cell types in the nervous system, including neuroglia, limiting the availability of healthy endogenous mitochondrial donors. This review critically examines mitochondria transfer in neurological diseases, with a focus on glial contribution and underlying mechanisms, and outlines key challenges and opportunities for advancing both mechanistic understanding and therapeutic translation.
    Keywords:  Ageing; Extracellular vesicles; Mitochondrial transplantation; Neurodegeneration; Neuroglia; Traumatic brain injury; Tunnelling nanotubes
    DOI:  https://doi.org/10.1186/s13024-026-00953-1
  14. Cell Rep. 2026 May 21. pii: S2211-1247(26)00503-6. [Epub ahead of print]45(6): 117425
    Mitochondria across the globe: Diverse voices, shared energy.
      Like mitochondria themselves, research on this organelle can take many shapes and sizes. This month, to coincide with the Cell Press Symposia: Multifaceted Mitochondria, we are highlighting the diversity of the global mitochondria community with contributions from researchers at all career stages published across Cell Metabolism, Molecular Cell, Cell Reports, and Trends in Endocrinology and Metabolism. Together, these voices showcase the central role of mitochondrial research in metabolism, inflammation, cell biology, and much more.
    DOI:  https://doi.org/10.1016/j.celrep.2026.117425
  15. Rinsho Shinkeigaku. 2026 May 16.
    A case of a spinal cord involvement in an adult mitochondrial disease with an m.3243A>G.
    Ken-Ichi Shibata, Tatsuya Mukai, Hideaki Nakagaki, Sukehisa Nagano.
      
    DOI:  https://doi.org/10.5692/clinicalneurol.cn-002220
  16. Free Radic Biol Med. 2026 May 20. pii: S0891-5849(26)00771-9. [Epub ahead of print]
    Mitochondrial Dynamics and Transfer in Mesenchymal Stromal Cells: Redox Regulation, Therapeutic Mechanisms, and Engineering Strategies.
    XueXia Liu, XiaoXin Wang, FuJun Liu.
      Mesenchymal stromal cells (MSCs) are metabolically active and redox-sensitive therapeutic cells, with their therapeutic potency tightly linked to mitochondrial integrity and function. Beyond paracrine and immunomodulatory actions, MSCs can transfer functional mitochondria to damaged cells, restoring bioenergetics, maintaining redox homeostasis via ROS regulation, and facilitating tissue repair and regeneration. This review summarizes recent progress in MSC mitochondrial biology, highlighting how metabolic reprogramming, mitochondrial biogenesis, fusion-fission dynamics and mitophagy coordinately regulate MSC stemness, differentiation, senescence and therapeutic capacity. It outlines core redox regulatory networks covering mitochondrial ROS production (ETC Complexes I/III and reverse electron transport), non-mitochondrial oxidases (NADPH oxidases), and canonical antioxidant signaling (Nrf2/Keap1, thioredoxin/peroxiredoxin and glutathione/glutaredoxin). Redox-dependent post-translational modifications governing mitochondrial transfer machinery are emphasized, including cysteine oxidation of connexin 43, redox-regulated Drp1 phosphorylation, and oxidative modulation of Miro1-mediated mitochondrial trafficking. Major intercellular mitochondrial transfer routes, such as tunneling nanotubes, connexin 43-based intercellular communication and extracellular vesicles, are discussed under inflammatory, hypoxic and metabolic stress conditions. Preclinical studies across pulmonary, cardiovascular, neurological, renal, hepatic and immune-mediated diseases validate that MSC-derived mitochondrial transfer preserves ATP production, mitigates oxidative injury and remodels recipient cell immunometabolic phenotypes. Emerging engineering strategies to improve mitochondrial delivery and therapeutic outcomes are also reviewed, alongside translational bottlenecks including cell source heterogeneity, mitochondrial quality control, in vivo tracking, dosage optimization and long-term biosafety. Overall, MSC mitochondrial dynamics and intercellular transfer bridge redox biology, metabolism and regenerative medicine, offering mechanistic insights for next-generation precision regenerative therapies.
    Keywords:  Extracellular vesicles; Mesenchymal stromal cells; Mitochondrial transfer; Redox homeostasis; Regenerative medicine
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.291
  17. Sci Immunol. 2026 May 29. 11(119): eaef0098
    Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
    Sofía C Khouili, Elena Priego, Ignacio Heras-Murillo, Gillian Dunphy, Annalaura Mastrangelo, Sarai Martínez-Cano, Vanessa Nuñez, Manuel Rodrigo-Tapias, Adrián Belinchón-García, Johan Garaude, Salvador Iborra, Navdeep S Chandel, Patricia González-Rodríguez, Michel Enamorado, David Sancho.
      Mitochondrial metabolism modulates immune cell signaling, yet how individual electron transport chain complexes fine-tune dendritic cell (DC) function remains unclear. Here, we identify mitochondrial complex I (CI) as a critical metabolic checkpoint controlling antigen cross-presentation by DCs in mice. Deficiency of the CI subunit NDUFS4 in DCs led to the formation of a nonfunctional CI subcomplex, resulting in mildly impaired mitochondrial respiration without triggering a compensatory glycolytic shift. NDUFS4 deficiency limited endosomal escape of internalized antigens, thereby impairing antigen cross-presentation while largely preserving direct presentation. CI dysfunction lowered the NAD+/NADH ratio, concomitant with decreased ATP levels, and diminished neutral lipid storage and lipid peroxidation. Restoration of the NAD+/NADH ratio rescued cross-presentation in NDUFS4-deficient DCs. NDUFS2-deficient DCs showed similar defects in cross-presentation, which were also rescued by rebalancing the NAD+/NADH ratio. Together, these findings reveal a link between mitochondrial CI integrity, NAD+-driven redox metabolism, and antigen cross-presentation.
    DOI:  https://doi.org/10.1126/sciimmunol.aef0098
  18. Mitochondrion. 2026 May 16. pii: S1567-7249(26)00059-0. [Epub ahead of print] 102169
    Electron microscopy visualization of cell-free mitochondrial DNA-associated vesicular structures in human plasma, serum, and saliva.
    Alexandra Volos, Soah Grace Franklin, Jeremy Michelson, Shannon Rausser, Jonathan R Brestoff, Martin Picard.
      Human biofluids contain cell-free mitochondrial DNA (cf-mtDNA) and extracellular mitochondria (ex-Mito), creating the challenge of defining their origins, destinations, mechanisms of regulation, and purposes. To expand our understanding of vesicular structures across human biofluids, we present a descriptive electron microscopy analysis of circulating particles from cf-mtDNA-enriched plasma (citrate, heparin, and EDTA), serum (red and gold top), and saliva collected from ten healthy participants (5 females, 5 males, mean age 44.9 years). Ex-mito and extracellular vesicles (EVs) were isolated by centrifugation followed by size-exclusion chromatography, imaged by transmission electron microscopy, and morphometrically analyzed. In parallel, cf-mtDNA was quantified in each biofluid to confirm enrichment. The resulting catalog of the most common circulating particles in plasma, serum, and saliva show that circulating double-membrane extracellular particles are present across human biofluids, along with EVs and other particle types. Combining imaging with cf-mtDNA quantification, we show that individuals with higher plasma cf-mtDNA concentrations tend to contain more double-membrane, ex-Mito-like particles. These preliminary and largely qualitative results do not directly demonstrate but are consistent with the concept of mitochondria transfer and/or signaling between cells and tissues. The image inventory provided here expands our knowledge of cell-free mitochondrial biology and provides a resource to inform biofluid selection and technical considerations in future studies quantifying ex-Mito and cf-mtDNA.
    Keywords:  cell-free material; circulating; human; image repository; imaging; microscopy; mitochondria; study design; vesicles
    DOI:  https://doi.org/10.1016/j.mito.2026.102169
  19. Rinsho Shinkeigaku. 2026 May 16.
    Before a spinal cord lesion in an m.3243A>G carrier is attributed to mitochondrial disease, all differential diagnoses must be excluded.
    Josef Finsterer.
      
    Keywords:  m.3243A>G; maternally inherited diabetes and deafness; mitochondrial disorder; spinal cord; transverse syndrome
    DOI:  https://doi.org/10.5692/clinicalneurol.cn-002190
  20. ACS Nano. 2026 May 18.
    Neutrophil-Like Mitochondria Enable Blood-Brain Barrier Transmigration and Neuroprotection.
    Namjo Shin, Yina Wu, Jinwon Park, Junho Byun, Seongsoo Lee, Wooin Lee, Jaiwoo Lee, Yu-Kyoung Oh.
      Mitochondrial transplantation has emerged as a promising therapeutic strategy for neurological diseases associated with mitochondrial dysfunction. However, its application to central nervous system (CNS) disorders remains limited by the restrictive nature of the blood-brain barrier (BBB). Here, we report neutrophil-like mitochondria (nePM@Mito), engineered by coating isolated mitochondria with neutrophil plasma membranes to facilitate CNS delivery. By presenting neutrophil-derived surface adhesion molecules, nePM@Mito interact with endothelial receptors and recapitulate key features of neutrophil transendothelial migration, facilitating BBB crossing via endothelial exocytosis. In a mouse model of Parkinson's disease, intravenous administration of nePM@Mito leads to pronounced CNS accumulation and attenuation of oxidative stress. Delivered mitochondria restore mitochondrial function and increase tyrosine hydroxylase expression in dopaminergic neurons of the substantia nigra, resulting in elevated dopamine levels and improved motor performance. Notably, neutrophil membrane functionalization endows mitochondria with CNS-homing capability while preserving their intrinsic biological activity. The neutrophil-like mitochondrial delivery strategy provides a versatile platform for overcoming BBB limitations and offers a promising therapeutic approach for neurodegenerative diseases involving mitochondrial dysfunction.
    Keywords:  Parkinson’s disease; blood−brain barrier; mitochondrial transplantation; neuroprotection; neutrophil-like mitochondria
    DOI:  https://doi.org/10.1021/acsnano.5c22296
  21. Nat Commun. 2026 May 21.
    Mitochondria-derived vesicles with bioenergetic units from brown adipose tissue attenuate cardiac remodeling post-myocardial infarction.
    Tingting Shi, Feng Chen, Yue Xu, Kai Jiang, Ruhua Deng, Xingbo Yang, Yang Chen, Wenliang Che, John Hwa, Dandan Wang, Yaozu Xiang.
      Post-myocardial infarction remodeling is a major cause of heart failure, with contributions from multiple organs. Brown adipose tissue protects against cardiovascular disease, but the mediators of brown adipose tissue-heart crosstalk and their roles in cardiac remodeling remain elusive. Here, we show that mitochondria-derived vesicles from brown adipose tissue transfer to cardiac macrophages and attenuate pathological remodeling via anti-inflammatory effects. Vesicles containing mitochondrial membranes, rather than mitochondrial matrix, mobilize from brown adipose tissue to the heart in response to stress. VPS35 translocation to mitochondria drives protein packaging into mitochondria-derived vesicles for secretion through extracellular vesicle trafficking machinery. Becn1 deficiency impairs VPS35 translocation, alters mitochondria-derived vesicle cargo, and abolishes brown adipose tissue-mediated cardioprotection. Proteomics identifies mitochondrial respiratory chain complex V as a hallmark of protective mitochondria-derived vesicles. These vesicles enhance reparative cytokine production and oxidative phosphorylation rewiring in macrophages. Purified mitochondria-derived vesicles markedly improve remodeling in male mice. Our study uncovers an interorgan transfer of bioenergetic units that contributes to tissue repair.
    DOI:  https://doi.org/10.1038/s41467-026-73388-3
  22. Jpn J Radiol. 2026 May 18.
    Human iPSC‑based translational and reverse translational research for neurodegenerative diseases: emphasis on ALS and key advances.
    Satoru Morimoto, Shinichi Takahashi, Hideyuki Okano.
      Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) cause progressive loss of specific neuronal populations and currently lack curative therapies. Animal models and immortalized cell lines incompletely recapitulate human pathology and genetic heterogeneity, limiting drug discovery. Human induced pluripotent stem cells (iPSCs) provide a patient‑specific platform for disease modelling, drug screening and studying individual responses. Translational research (TR) uses iPSC models to identify candidate therapies that are subsequently tested in clinical trials, while reverse translational research (rTR) feeds clinical observations back to the bench by analyzing iPSCs derived from trial participants and integrating molecular data with patient phenotypes. This review summarizes recent advances in iPSC‑based TR and rTR for ALS and extends the discussion to other neurodegenerative diseases. Key clinical trials launched from iPSC screens-ropinirole, retigabine and bosutinib-are reviewed alongside emerging rTR efforts that use patient‑derived iPSCs to identify biomarkers and therapeutic mechanisms. We also survey iPSC models for AD, PD and HD, highlighting applications of three‑dimensional (3D) brain organoids and gene‑editing technologies. Finally, we discuss future directions for precision medicine, multimodal integration and technological challenges, with particular attention to how imaging biomarkers may complement iPSC-based TR/rTR frameworks in neurodegenerative diseases.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Imaging biomarkers; Induced pluripotent stem cells (iPSCs); Precision medicine; Translational and reverse translational research; iPSC-based drug discovery
    DOI:  https://doi.org/10.1007/s11604-026-02000-x
  23. Cell Death Differ. 2026 May 22.
    Neuroprotective effect of astrocytic dopamine Drd2 receptor on mitochondrial complex I in a mouse model of Parkinson's disease through β-arrestin2-NDUFA10 regulation.
    Qian-Hui Huang, Nuo-Xi Zhang, Juan-Juan Guo, Chun-Yan Fan, Jian-Hua Ding, Yao Wei, Yang Liu, Gang Hu.
      Parkinson's disease (PD) is a progressive neurodegenerative disease. Current treatment strategies for PD mainly focus on dopamine replacement and regulation of dopaminergic signaling. Here, we reveal the unique role of the astrocytic dopamine D2 (Drd2) receptor in regulating mitochondrial function, thereby improving Parkinson's disease-like symptoms in a mouse model. Transcriptome sequencing and metabolomics suggest that deletion of astrocytic Drd2 receptor significantly aggravates mitochondrial dysfunction. Mechanistically, we demonstrate that the Drd2 receptor regulates mitochondrial complex I activity by recruiting the scaffold protein β-arrestin2, which facilitates its interaction with NDUFA4 and NDUFA10, two subunits of mitochondrial complex I. Notably, the neuroprotective effect of Drd2 activation in vivo was completely abolished upon selective knockdown of NDUFA10 in mouse astrocytes. The identification of this novel mechanistic axis not only elucidates how astrocytes maintain neuronal mitochondrial homeostasis via dopaminergic signaling but also establishes a transformative framework for the development of targeted combination therapies that concurrently address mitochondrial dysfunction and dopamine receptor dysregulation as a promising avenue for advancing PD treatment strategies.
    DOI:  https://doi.org/10.1038/s41418-026-01756-z
  24. Kidney Int. 2026 May 21. pii: S0085-2538(26)00394-7. [Epub ahead of print]
    Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.
    Matthew D Campbell, Monica Sanchez-Contreras, Britta D Sibley, Phoebe Keiser, Carla Ruiz-Sanchez, Carolyn N Mann, Anna A Bakhtina, James E Bruce, David J Marcinek, Behzad Najafian, Mariya T Sweetwyne.
       INTRODUCTION: Whether and how podocytes depend on mitochondria across their long post-mitotic lifespan is unclear. With limited cell numbers and broad kidney distribution, isolation of podocyte mitochondria typically requires first isolating podocytes themselves. Disassociation of podocytes from their basement membrane, however, recapitulates an injured state and stresses mitochondria. Here, we devise a new strategy to examine mitochondria in podocytes.
    METHODS: To address this, we crossed floxed hemagglutinin (HA)-mitochondria tagged (MITO-Tag) mice with those expressing Cre in either podocytes (NPHS2) or mixed tubules (CDH16), thus allowing for rapid, kidney cell-specific, isolation of mitochondria via immunoprecipitation.
    RESULTS: Mitochondrial respiration in fresh isolates from young (4-7 months) and aged (22-26 months) mice of both sexes demonstrated several previously unreported significant differences between podocyte and tubule mitochondria. First, although podocytes contain fewer mitochondria than tubule cells, mitochondria isolated from podocytes averaged twice the respiratory capacity of tubule mitochondria when normalized to mitochondrial content by citrate synthase levels. Second, age-related decline in respiration was detected only in podocyte mitochondria and only in aged male mice. Third, disassociating podocytes for cell culture initiates functional decline in mitochondria as those from cultured primary podocytes have half the respiratory capacity, but twice the hydrogen peroxide production, of podocyte mitochondria isolated directly from fresh kidneys. Finally, conformation of electron transport chain proteins differed between podocyte and tubule mitochondria, suggesting that cell-specific mitochondrial protein conformations dictate cell-specific mitochondrial function.
    CONCLUSIONS: Previous studies suggesting a limited role for mitochondrial regulation of podocytes relied on cell culture. This resulted in artifactual suppression of mitochondrial function and masks the roles of mitochondria in maintenance of podocyte health. Our approach shows that per organelle, podocytes maintain sexually dimorphic mitochondria with greater oxidative phosphorylation capacity than the mitochondria-dependent tubules.
    Keywords:  animal model; distal tubule; mitochondria; podocyte
    DOI:  https://doi.org/10.1016/j.kint.2026.04.016
  25. Turk J Pediatr. 2026 03 11. 68(2): 330-336
    Leber hereditary optic neuropathy (LHON) in a 6-year-old boy with a transient spinal cord lesion.
    Anıl Gök, Gökçe Cırdı, Adnan Deniz, Ayfer Sakarya Güneş, Leman Tekin Orgun, Bülent Kara.
       BACKGROUND: Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder that predominantly manifests as bilateral, painless vision loss in young males. While traditionally associated with the optic nerves, a subset of patients exhibits additional neurological symptoms, referred to as LHON-plus syndrome. Involvement of the spinal cord is uncommon, particularly among the pediatric population, and may result in diagnostic challenges, potentially leading to confusion regarding acquired demyelinating diseases.
    CASE PRESENTATION: We report a 6-year-old boy with near-complete vision loss in the right eye and blurred vision in the left eye. Demyelinating diseases were suspected in the case of acute bilateral optic neuropathy. Cranial and orbital magnetic resonance imaging (MRI) showed no demyelinating lesions, whereas spinal MRI revealed a T2-hyperintense lesion at the C3-C6 levels. Due to unresponsiveness to conventional treatment for demyelinating diseases, genetic testing confirmed the homoplasmic m.11778G>A variant in NADH dehydrogenase subunit 4 (MT-ND4), establishing an LHON diagnosis. Spinal cord involvement supported the LHON-plus syndrome classification. Idebenone therapy was initiated, and follow-up was scheduled. During the 1.5-year follow-up, right eye visual loss persisted, while the left eye showed gradual vision decline. A second spinal MRI performed at 6 months showed complete resolution of the previous lesion without new lesions.
    CONCLUSION: Since optic neuropathy and spinal cord involvement typically indicate demyelinating diseases, these should be prioritized in initial evaluation due to their frequency and need for early immunomodulatory treatment. However, spinal cord involvement can occur in mitochondrial diseases, as demonstrated in this case. The presence of a transient and asymptomatic spinal cord lesion in this patient expands the recognized spectrum of central nervous system involvement in LHON. Therefore, LHON-plus syndrome should be considered when spinal cord involvement accompanies optic neuropathy after excluding other demyelinating diseases.
    Keywords:  LHON-plus syndrome; Leber hereditary optic neuropathy; MT-ND4 m.11778G>A mutation; mitochondrial disease; optic neuropathy
    DOI:  https://doi.org/10.24953/turkjpediatr.2026.6882
  26. Acta Med Port. 2026 May 18.
    A Novel Combination of Biallelic Variants in the VARS2 Gene: A Severe Phenotype.
    Joana Capela, Mariana Reis, Inês Almeida, Marta Novo, Ana Ramalho, Patrícia Lipari, Márcia Rodrigues.
      To our knowledge, only 29 individuals have been described in the literature with biallelic pathogenic variants in the valyl-tRNA synthetase 2 (VARS2) gene, responsible for changes in the mitochondrial respiratory chain complex. We report two siblings with a novel combination of biallelic variants in the VARS2 gene (c.1079C>T p.Ala360Val, likely pathogenic, and c.1258G>A p.Ala420Thr, likely pathogenic). Both presented early hypertrophic cardiomyopathy and lactic acidosis, with fatal outcomes within the first year of life. The first also presented severe fetal growth restriction and a ventricular septal defect; the second developed epilepsy, respiratory failure, and psychomotor delay. This genotype may be linked to a particularly severe cardiac phenotype. Our report broadens the clinical and genetic spectrum of VARS2-related mitochondrial disease, highlights the variability of phenotypic expression, and reinforces the importance of early molecular diagnosis in neonatal-onset cardiomyopathy. Genetic confirmation enables accurate genetic counselling and consideration of prenatal or preimplantation diagnosis in future pregnancies.
    Keywords:  Cardiomyopathy; Epilepsy; Hypertrophic; Mitochondrial Diseases; Valine-tRNA Ligase/genetics
    DOI:  https://doi.org/10.20344/amp.23831
  27. Mol Biol Rep. 2026 May 22. pii: 817. [Epub ahead of print]53(1):
    DDRGK1 regulates muscle development by maintaining mitochondrial calcium homeostasis and oxidative phosphorylation via stabilizing IP3R.
    Ping Li, Lingfei Li, Mali Guo, Junjie Xu, Yafei Cai.
       BACKGROUND: Mitochondrial calcium homeostasis is essential for oxidative phosphorylation (OXPHOS) and cellular energy production. DDRGK1 is an ER‑localized adaptor protein, which is critical for maintaining ER homeostasis, protein stability, and organelle communication. However, the role of DDRGK1 in regulating mitochondrial function remains largely unknown. This study aims to define the role of DDRGK1 in mitochondrial calcium signaling and bioenergetics.
    METHODS AND RESULTS: Through biochemical analyses in cellular models, we identify DDRGK1 as a direct interactor and stabilizer of IP3R, preventing its ubiquitin-mediated degradation. DDRGK1 deficiency reduces IP3R protein levels, impairing mitochondrial calcium uptake and OXPHOS activity, as assessed by respirometry and ATP measurements. Consequent bioenergetic deficits are accompanied by calcium overload-induced ER stress, which activates C/EBP-homologous protein (CHOP) and suppresses the PGC‑1α pathway, thereby inhibiting mitochondrial biogenesis.
    CONCLUSIONS: The DDRGK1-IP3R axis constitutes a critical regulatory module in mitochondrial calcium signaling and energy metabolism. Disruption of this axis underlies bioenergetic failure and provides mechanistic insight into the pathogenesis of skeletal muscle metabolic disorders and related mitochondrial diseases.
    Keywords:  DDRGK1; ER-mitochondrial crosstalk; inositol 1,4,5-trisphosphate receptor; mitochondrial calcium homeostasis; oxidative phosphorylation
    DOI:  https://doi.org/10.1007/s11033-026-12009-0
  28. Sci Rep. 2026 May 18.
    Mavodelpar in patients with primary mitochondrial myopathy: a phase 1 trial.
    Renae J Stefanetti, Chiara Pizzamiglio, Alasdair P Blain, Oliver M Russell, Lisa Alcock, Gavin Hudson, Jane Newman, Naomi Thomas, Charlotte Warren, Huizhong Su, Helen A L Tuppen, Philip Brown, David Houghton, Heather Hunter, Albert Z Lim, Yi Shiau Ng, Catherine Feeney, Iwona Skorupinska, Louise Germain, Enrico Bugiardini, Michael G Hanna, Robert McFarland, Robert D S Pitceathly, Gráinne S Gorman.
      Primary mitochondrial myopathies (PMM) are rare, genetically-defined disorders characterised by defects of oxidative phosphorylation, predominantly affecting skeletal muscle. This Phase 1b open-label trial evaluated mavodelpar, a selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, over 12 weeks (Part A), with an optional 36 week extension (Part B) in adults with PMM. The primary objective was to assess safety and tolerability, with secondary assessments of pharmacokinetics, pharmacodynamics, and exploratory performance, patient-reported, and muscle biopsy outcomes. Of the 23 participants who received mavodelpar, 17 completed Part A; none completed Part B due to premature study termination during the COVID-19 pandemic. Adverse events were mild-moderate severity, with headache and constipation most common (4/23 participants; 17.4% each). Exploratory measures showed a mean increase of 104 m in the twelve minute walk test (95% CI: 53 to 156) and a mean reduction of -10.5 points in patient-reported fatigue (95% CI: -16.3 to -4.6). No consistent changes in mitochondrial function were detected in muscle biopsies (n = 10), while transcriptomic profiling (n = 6) revealed modest upregulation of fatty acid-metabolism pathways. Although findings from this Phase 1b trial supported progression to later-phase evaluation, the subsequent Phase 2b trial did not demonstrate clinical efficacy for mavodelpar. The results reported here should be interpreted as exploratory and not indicative of therapeutic benefit. Nevertheless, this Phase 1b trial provides important methodological insights to inform future PMM clinical trial design and outcome measure development.
    Keywords:  Mitochondrial disease; Mitochondrial myopathy; Outcome measures; Peroxisome proliferator-activated receptor delta (PPARδ) agonist; Phase 1 trial; Rare disease
    DOI:  https://doi.org/10.1038/s41598-026-43287-0
  29. J Cell Commun Signal. 2026 Jun;20 e70080
    Crosstalk between endoplasmic reticulum stress and mitochondrial homeostasis: A new perspective on ophthalmic disease treatment.
    Luyang Jiang, Gongsang Cuomu, Sang Jijia, Yumei Yang, Jufen Liu, Yumin Tao.
      Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are hallmarks of many ophthalmic diseases; however, they have traditionally been examined as isolated pathological processes. Recent evidence indicates that these organelles are inextricably coupled through mitochondria-endoplasmic reticulum contact sites, also known as mitochondria-associated membranes (MAMs), which coordinate Ca2+ signaling, lipid transfer, mitochondrial dynamics, redox balance, and cell death decisions. Consequently, dysregulated ER-mitochondria communication has emerged as a key vulnerability that links the cellular stress responses among diverse ocular tissues, including lens epithelial cells, retinal ganglion cells, the retinal pigment epithelium, and corneal endothelial cells. In this review, we summarize the recent advances involving the molecular architecture and regulatory function of ER-mitochondria crosstalk. We focus on how the unfolded protein response signaling, pathological MAM remodeling, Ca2+ dysregulation, and disrupted mitochondrial quality control collectively drive disease progression. By integrating evidence from cataract, glaucoma, diabetic retinopathy, age-related macular degeneration, and Fuchs endothelial corneal dystrophy, we reveal that these disorders are not driven by a uniform mechanism of organelle failure, but rather by the dominance of pathological nodes along the ER-mitochondria axis. We propose that ophthalmic diseases should be stratified based on these distinct failure nodes, which provides a mechanistic framework for developing therapeutics. Within this context, interventions targeting maladaptive ER stress, MAM destabilization, bioenergetic failure, or defective mitophagy should be considered complementary and context-dependent strategies. By reframing ophthalmic disorders as diseases of inter-organelle stress integration, this review positions the ER-mitochondria axis as a modifiable upstream determinant of ocular cell fate, which provides a foundation for stage-specific precision therapies.
    Keywords:  calcium signaling; endoplasmic reticulum–mitochondria crosstalk; mitochondrial dynamics; mitochondria‐associated membranes; mitophagy; ophthalmic diseases; unfolded protein response
    DOI:  https://doi.org/10.1002/ccs3.70080
  30. Res Sq. 2026 May 05. pii: rs.3.rs-9589283. [Epub ahead of print]
    TACO1 regulates mitochondrial adaptation in hypertension-induced cardiac remodeling and heart failure.
    Berwin Singh Swami Vetha, Ronald McMillan, James Marchant, Mohd Mabood Khan, Joyonna Gamble George, Jeremiah Afolabi, Edgar Garza Lopez, Andrea G Marshall, Calixto Pablo Hernandez Perez, Dillon Garbrandt, Bret Mobley, Jenny Schafer, Max Kushner, Oleg Kovtun, Debra D Murray, Tonya Zeczycki, Annet Kirabo, Alexandre Colas, Celestine Wanjalla, Dao Fu Dai, Melanie McReynolds, Azeez Aileru, Antentor Hinton.
      Mitochondrial dysfunction drives hypertensive heart failure and reflects impaired oxidative phosphorylation and altered organelle structure. The mechanisms linking hypertensive signaling to mitochondrial translation and architecture remain unclear. TACO1 is a mitochondrial translational activator required for cytochrome c oxidase subunit I synthesis and may regulate respiratory chain assembly. We tested whether angiotensin II type 1 receptor activation disrupts TACO1-dependent translation and drives inner membrane remodeling. Using mRen also known as (mRen2)27 hypertensive rat hearts, we assessed mitochondrial function, ultrastructure, and metabolism. AT1R activation reduced TACO1-dependent COX I translation and produced a selective deficiency in complex IV activity. This impaired oxidative phosphorylation and increased the production of reactive oxygen species. Mitochondria exhibited reduced volume, increased fragmentation, and disrupted cristae organization with lower integrity scores. Hypertensive hearts also showed reduced expression of OPA1 and MICOS components. Metabolomic profiling separated control and heart failure groups and revealed enrichment of amino acid, nucleotide, and mitochondrial energy pathways. Lipidomic analysis identified coordinated changes across lipid classes consistent with altered membrane composition. Pharmacological AT1R inhibition restored COX I translation, rescued complex IV activity, and improved cristae structure. These findings establish a mechanistic link between hypertensive signaling, mitochondrial translation, cristae organization, and metabolic remodeling in heart failure.
    DOI:  https://doi.org/10.21203/rs.3.rs-9589283/v1
  31. Mol Cell Biochem. 2026 May 21.
    Inhibition of the mitochondrial pyruvate carrier attenuates the integrated stress response activation in a cellular model of Huntington's disease.
    Ângela Oliveira, Liliana M Almeida, Jorge M A Oliveira, Brígida R Pinho.
      Mitochondrial pyruvate carrier (MPC) inhibition was found protective in models of neurodegenerative diseases, such as Alzheimer's and Parkinson's. However, little is known about MPC as a potential therapeutic target in Huntington's disease (HD), a neurodegenerative disorder with dysregulation of the pro-survival pathway integrated stress response (ISR). Here, we investigate if MPC inhibition modulates the ISR and mitigates mutant huntingtin (mut-Htt) proteotoxicity in a cellular HD model. We treated cells expressing N-terminal fragments of wild-type- (wt-) or mut-Htt with two MPC inhibitors (mitoglitazone and UK5099) or solvent control. Metabolism was assessed analysing resazurin reduction, oxygen consumption, extracellular acidification, and ATP levels. ISR activation and huntingtin proteostasis were assessed using western-blot and filter-trap assays. Mut-Htt-expressing cells showed decreased resazurin reduction and ATP levels, and increased eIF2α phosphorylation, indicating metabolic stress and ISR activation. MPC inhibitors (100 µM) increased resazurin reduction and decreased respiration. The latter was rescued by the membrane-permeant methyl pyruvate, which bypasses MPC inhibition. In wt-Htt-expressing cells, MPC inhibitors increased levels of ATP and ISR markers, suggesting metabolic adaptation and ISR activation. In mut-Htt-expressing cells, MPC inhibitors preserved ATP levels and attenuated mut-Htt-induced eIF2α phosphorylation but without changing soluble or aggregated mut-Htt levels. This work showed that MPC inhibition differentially modulates the ISR: it activates ISR in control cells and attenuates overactive ISR in mut-Htt-expressing cells. However, MPC inhibition did not impact the proteostasis of N-terminal fragment mut-Htt. Further studies are essential to explore MPC inhibition in less severe full-length mut-Htt-expressing models to better understand its therapeutic potential in HD.
    Keywords:  Aggregation; Huntingtin; Huntington’s disease; Integrated stress response; Metabolism; Mitochondrial pyruvate carrier
    DOI:  https://doi.org/10.1007/s11010-026-05573-3
  32. Trends Pharmacol Sci. 2026 May 18. pii: S0165-6147(26)00108-2. [Epub ahead of print]
    Targeting competitive Fe-S regulation to treat Friedreich's ataxia.
    Juliane C Campos, Julio C B Ferreira.
      Recent discoveries reveal that frataxin (FXN) and ferredoxin 2 (FDX2) competitively regulate mitochondrial iron-sulfur (Fe-S) cluster biosynthesis through their binding to the cysteine desulfurase NFS1 and the iron-sulfur cluster scaffold protein ISCU2 complex. Here, we discuss the potential of rationally designed peptide inhibitors targeting the FDX2-NFS1 interaction as a strategy to mitigate FXN deficiency and restore Fe-S cluster biosynthesis.
    Keywords:  genetic disease; mitochondria; neurodegeneration; pharmacology; protein–protein interaction
    DOI:  https://doi.org/10.1016/j.tips.2026.04.010
  33. bioRxiv. 2026 May 05. pii: 2026.04.30.722019. [Epub ahead of print]
    Pharmacological rescue of mitochondrial dysfunction, neurite degeneration, and premature death of ALS and AD iPSC-derived neurons.
    Neelam Shahani, Rupkatha Banerjee, Courtney MacMullen, Neelam Sharma, Mohammad Habibi, Henry D Wasserman, Nathaniel C Noyes, Puhan Zhao, Bahaa Elgendy, Michael D Cameron, Thomas D Bannister, Lamees Hegazy, Brian N Finck, Ronald L Davis.
      Mitochondrial (MT) dysfunction is a key driver of ALS pathology. Without a healthy MT system, motor neurons (MN) function at sub-optimal levels and die. In addition, other effects of ALS, like axon/dendrite degeneration, may occur from a pathophysiological cascade spurred by MT dysfunction. A phenotypic screen identified Dipyridamole (DPM), an FDA-approved and safe drug, as having extraordinary effects on ALS patient induced pluripotent stem cell (iPSC)-derived MNs. The drug prevented MT fragmentation, loss of MT content, impaired MT bioenergetics, axon/dendrite degeneration, and premature MN death, extending neuronal survival by more than fivefold. Importantly, its efficacy extended across iPSC-derived neurons representing two different familial forms of ALS (C9orf72, TDP43) and Alzheimer's disease (PSEN1), implying broad neuroprotection across ALS forms and other neurodegenerative diseases. DPM increased MT respiration and pyruvate uptake in a mechanism requiring the Mitochondrial Pyruvate Carrier (MPC), mechanistically explaining its biological activities. Thus, DPM is a promising drug to repurpose or refine for treating neurodegenerative diseases or other diseases that would benefit by augmenting pyruvate uptake into MT.
    Teaser: Dipyridamole, an FDA-approved drug, restores mitochondrial function and protects neurons in ALS and Alzheimer's disease.
    DOI:  https://doi.org/10.64898/2026.04.30.722019
  34. Methods Mol Biol. 2026 ;3001 833-861
    Mitochondrial Transmembrane β-Barrels: Deducing Thermodynamic Regulators of Folding and Stability.
    Udit Kumar Dash, Kinjal Mazumder, Radhakrishnan Mahalakshmi.
      Biophysical characterization of membrane protein folding and stability provides a direct molecular correlation of folding and stability with protein function. Here, we describe how mitochondrial outer membrane β-barrels can be overproduced, and how structures of folding intermediates and per-residue thermodynamic stability are measured using intrinsic tryptophan fluorescence in near-native membranes.
    Keywords:  End-state stability; Folding kinetics; Gibbs free energy; Mitochondrial OMPs; Stopped flow; Tryptophan fluorescence; β-barrels
    DOI:  https://doi.org/10.1007/978-1-0716-5054-7_30
  35. Cardiovasc Diagn Ther. 2026 Apr 24. 16(2): 35
    Mitophagy in cardiovascular diseases: a literature review.
    Ran Zhang, Junyan Zhang, Shuangliang Ma, Li Rao, Zhongxiu Chen.
       Background and Objective: Mitochondria generate nearly 90% of cellular adenosine triphosphate (ATP) and are essential for maintaining cardiac energetic homeostasis. Mitophagy, a selective autophagic process that removes damaged mitochondria, is critical for preserving mitochondrial quality and ensuring cardiomyocyte survival under stress. Given that cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide and are profoundly influenced by mitochondrial dysfunction, understanding mitophagy has become increasingly important. This review aims to summarize the current mechanistic findings related to mitophagy, examine its roles across major CVDs, and evaluate emerging mitophagy-targeted interventions with potential clinical application.
    Methods: A comprehensive literature search of PubMed was conducted using keywords, including "mitophagy", "cardiovascular disease", "myocardial ischemia-reperfusion", to retrieve relevant studies published in English between January 2020 and March 2025. Original studies, reviews, and clinically relevant reports were included in the literature review to ensure broad coverage of mechanistic and translational findings.
    Key Content and Findings: The review synthesizes current knowledge on canonical and noncanonical mitophagy pathways, as well as their roles in myocardial ischemia-reperfusion injury, heart failure, cardiomyopathies, and metabolic cardiomyopathy. Recent evidence highlights the dual nature of mitophagy, where both insufficient and excessive activation impair cardiac function. The review further discusses innovative therapeutic strategies, including mitochondrial-targeted nanoparticles, small-molecule mitophagy activators, and exercise-induced mitochondrial remodeling, along with their potential benefits and limitations. Key knowledge gaps have been identified, including the tissue-specific regulation of mitophagy and uncertainties surrounding dose-dependent therapeutic activation.
    Conclusions: Mitophagy is a pivotal determinant of mitochondrial homeostasis and cardiac health. While emerging interventions show promise, precise modulation remains challenging. Advancing quantitative assessment tools, defining safe activation thresholds, and developing cell-type-specific targeting strategies will be essential for clinical translation. This review provides a comprehensive framework that may guide future research and inform the development of mitophagy-based therapies for CVDs.
    Keywords:  Mitochondria quality control; cardiovascular diseases (CVDs); mitophagy; mitophagy-targeted therapy
    DOI:  https://doi.org/10.21037/cdt-2025-438
  36. Redox Biol. 2026 May 15. pii: S2213-2317(26)00211-9. [Epub ahead of print]94 104213
    Nrf2 modulates cytosolic and mitochondrial calcium signal.
    Alessandra Preziuso, Artyom Y Baev, Fozila R Rustamova, Sharadha Dayalan Naidu, Lauren Millichap, Plamena R Angelova, Vincenzo Lariccia, Albena T Dinkova-Kostova, Andrey Y Abramov.
      Nrf2 is a transcription factor which regulates ∼1% of the mammalian genome and is responsible for orchestrating the cellular defense against oxidative, inflammatory and metabolic stress. Calcium (Ca2+) is a ubiquitous intracellular messenger which controls most cellular processes, from fertilization to cell death. Nrf2 and Ca2+ are involved in a large number of similar physiological processes, but it is not clear if they can regulate each other. Here, using primary co-cultures of neurons and astrocytes we asked if Nrf2 activation or deficiency alters physiological Ca2+ signaling and mitochondrial Ca2+ handling in brain cells. We found that activation of Nrf2 leads to an increase in the amplitude of Ca2+ peak and a faster Ca2+efflux in response to glutamate and ATP in neurons and astrocytes. Interestingly, Nrf2-deficient neurons and astrocytes also had higher Ca2+ peaks in response to glutamate and ATP, but the recovery in neurons was significantly delayed. Genetic (Keap1-knockdown) or pharmacological (ovameloxolone, RTA-408) activation of Nrf2 increases mitochondrial Ca2+ uptake and mitochondrial Ca2+ capacity, and this correlates with increased activity of the Na+/Ca2+/Li+ exchanger (NCLX) and inhibition of the mitochondrial permeability transition pore (mPTP). Conversely, mitochondria in neurons and astrocytes from Nrf2-knockout mice had a lower Ca2+ uptake, lower mitochondrial Ca2+ capacity and lower mitochondrial Ca2+efflux, making these cell vulnerable to Ca2+-induced cell death. Thus, Nrf2 modulates cytosolic calcium signaling and activates the mitochondrial NCLX, increasing the mitochondrial Ca2+ capacity, which adds another critical aspect to the multifaceted nature of Nrf2-mediated cytoprotection.
    Keywords:  Astrocyte; Calcium signal; Keap1; Mitochondria; Neuron; Nrf2
    DOI:  https://doi.org/10.1016/j.redox.2026.104213
  37. Mitochondrion. 2026 May 17. pii: S1567-7249(26)00060-7. [Epub ahead of print]90 102170
    Challenging mtDNA tRNA variant guidelines: Emphasizing single-cell analysis through four novel variants.
    Prosper Chloé, Zereg Elamine, Chaussenot Annabelle, Bannwarth Sylvie, Lannes Béatrice, Nathalie Streichenberger, Kaphan Elsa, Nadaj-Pakleza Aleksandra, Villa Luisa, Sacconi Sabrina, Masingue Marion, Eléonore Birgy, Francou Bruno, Ait-El-Mkadem Saadi Samira, Fragaki Konstantina, Paquis-Flucklinger Véronique, Rouzier Cécile.
      The broad clinical and genetic heterogeneity of mitochondrial diseases makes diagnosis challenging. Accurate characterization of novel variants is crucial to reduce diagnostic uncertainty, guide treatment, and enable reliable genetic counseling. In this study, we validated a single-cell NGS-based analysis approach by comparison with conventional PCR-RFLP and applied it to five mtDNA variants identified in patients evaluated at our national reference center for mitochondrial disorders (CALISSON). Variant interpretation was assessed using multiple frameworks, including Yarham's scoring, Wong's specifications, and the ClinGen guidelines. We report four novel variants (m.9998 T > C in MT-TG, m.7530A > G in MT-TD, and m.4271G > C and m.4305A > G in MT-TI), including three for which single-fiber analysis provided strong evidence supporting pathogenicity. However, these functional results alone were not sufficient to enable reclassification under the current ClinGen framework. These findings highlight differences between the various scoring systems and illustrate the limitations of current recommendations in fully integrating functional evidence and tissue segregation data. We therefore suggest that adjusted weighting of existing criteria may improve variant classification. Nevertheless, classification frameworks must preserve reproducibility across laboratories, and the criteria proposed here should be considered preliminary points for reflection requiring further validation in larger cohorts, as well as the establishment of standardized criteria for functional studies, including single-fiber analyses.
    Keywords:  0m.7530A>G inMT-TD; 0m.9998T>C inMT-TG; And m.4271G>C and m.4305A>G inMT-TI; Mitochondrial DNA heteroplasmy; Next-Generation Sequencing (NGS); Single-fiber analysis; mitochondrial tRNA; mtDNA guidelines
    DOI:  https://doi.org/10.1016/j.mito.2026.102170
  38. Genome Med. 2026 May 19.
    From text to translation: using language models to prioritize variants for clinical review.
    Weijiang Li, Xiaomin Li, Ethan Lavallee, Alice Saparov, Marinka Zitnik, Christopher Cassa.
       BACKGROUND: Despite rapid advances in genomic sequencing, most rare coding variants remain insufficiently characterized for clinical use, limiting the potential of personalized medicine. When classifying whether a variant is pathogenic, clinical labs adhere to diagnostic guidelines that integrate many forms of evidence, including case data, computational predictions, and functional screening data. While a great deal of clinical evidence has been curated for many variants, the majority still cannot be definitively classified as 'pathogenic' or 'benign', and thus persist as 'Variants of Uncertain Significance' (VUS). Variant Curation Expert Panels (VCEPs) are tasked with analyzing the available evidence for each variant to reach a classification.
    METHODS: To make use of previously curated evidence, we processed over 2.3 million free-text variant summaries from ClinVar, employing sentence-level classification to restrict to sentences that contain different forms of evidence, and removing uninformative or similar summaries. We then used labeled text summaries to train ClinVar-BERT, a model that can discern evidence of pathogenicity or benignity within variant text summaries.
    RESULTS: We validated ClinVar-BERT model predictions for variant summaries that are classified as uncertain using variants curated by expert panels, orthogonal functional screening data, and computational predictions. ClinVar-BERT model predictions of VUS had significantly different estimates of functional impact in clinically actionable genes, including BRCA1 (p = [Formula: see text]), TP53 (p = [Formula: see text]), and PTEN (p = [Formula: see text]) with an AUROC = 0.927 when classifying whether variants are damaging or are expected to retain function. Similarly, ClinVar-BERT model predictions of VUS had significantly different AlphaMissense computational scores: BRCA1 (p = [Formula: see text]), TP53 (p = [Formula: see text]), and PTEN (p = [Formula: see text]). In genes screened for secondary findings or included on ClinGen expert panels, ClinVar-BERT prioritizes 7,644 variants for expert review, where 2 or more clinical summaries related to the same VUS were model-predicted to contain pathogenic evidence, and 7,042 variants with 2 or more summaries predicted to contain benign evidence. This would result in the average VCEP having 143 variants prioritized for review, ranging from 8 to 907 variants across VCEPs.
    CONCLUSIONS: These findings suggest that ClinVar-BERT can discern evidence from diagnostic reports, useful for prioritizing variants for re-assessment by expert curation panels.
    Keywords:  ClinVar; Genetic diagnostics; Large language models; Variant classification
    DOI:  https://doi.org/10.1186/s13073-026-01661-7
  39. Neuromuscul Disord. 2026 May 05. pii: S0960-8966(26)00110-0. [Epub ahead of print]64 106442
    A COA8 homozygous mutation presenting as an intermediate CMT with leukopathy.
    A Dupic, T Evangelista, B Labella, P Gaignard, P H Becker, H Turmel, M Konyukh, M Masingue.
      Patients with cytochrome c oxidase (COX) deficiency exhibit clinical heterogeneity, with onset ranging from infancy to adulthood. COA8-related disorders typically present in childhood with acute symptoms and cavitating posterior leukoencephalopathy, though milder, muscle-predominant forms have recently been reported. We describe a 54-year-old woman with a neuropathy with slow conduction velocities and leukoencephalopathy, associated with hearing loss and migraine. Neurological examination showed mildly high-arched feet, mild dysmetria without lateralization, and distal hypoesthesia. There was no gastro-intestinal involvement. Targeted NGS for hereditary neuropathies was unremarkable. The neurometabolic workup was negative. Whole genome sequencing identified a homozygous COA8 mutation (c.476 + 1G > A), confirmed by muscle biopsy showing COX deficiency and significantly reduced complex IV activity. This case expands the phenotypic spectrum of COA8-related diseases and suggests that a mitochondrial etiology should be considered in cases of neuropathy with intermediate conduction velocities associated with leukoencephalopathy, even with late onset.
    Keywords:  COA8; COX deficiency; Leukoencephalopathy; Mitochondrial diseases; Sensory-motor neuropathy
    DOI:  https://doi.org/10.1016/j.nmd.2026.106442
  40. FASEB J. 2026 May 31. 40(10): e71937
    Aortic Segments-Depending Hypertensive Remodeling Is Driven by Mitochondrial Fusion Dysfunction.
    Alexis Richard, Alicia Baptista Vicente, Clara Gourhand, Antoine Ducroix, Pauline Robert, Bertrand Toutain, Linda Grimaud, Emilie Vessières, Agnès Toutain-Barbelivien, Guy Lenaers, Juan-Manuel Chao de la Barca, Olivier Fouquet, Daniel Henrion, Céline Fassot, Laurent Loufrani.
      OPA1 haploinsufficiency exacerbates severe hypertension-induced aortic remodeling in a segment-specific manner, revealing differential vulnerability between the suprarenal abdominal aorta (SRAA) and the descending thoracic aorta (DTA). In the SRAA, hypertension activates mitochondrial fission pathways (DRP1, FIS1) and mitophagy markers (PINK1, PARKIN), without triggering full autophagic flux (LC3B, p62). Respiratory chain complexes I and IV are upregulated in hypertensive Opa1+/- mice across both segments, reflecting a compensatory mitochondrial stress response. Apoptotic analysis shows increased TUNEL staining in both regions, while caspase-3 and 9 activation is restricted to the SRAA. Inflammatory profiling reveals a predominance of M1 macrophages, specifically in the SRAA. Morphometric assessment highlights major impacts in SRAA, such as luminal dilation and adventitial thickening, confirmed by in vivo representative ultrasound images. These findings underscore the pivotal role of OPA1 in mitochondrial homeostasis and reveal, for the first time, a region-specific protective function of OPA1 within the aortic wall under severe hypertensive stress. This differential impact, according to aortic segment anatomy and physiology, opens new avenues for hypertension and pathological aorta remodeling therapies.
    Keywords:  Opa1 haploinsufficiency; aortic remodeling; hypertension; mitochondrial dysfunction; segmental vascular vulnerability
    DOI:  https://doi.org/10.1096/fj.202503667R
  41. Genet Med. 2026 May 20. pii: S1098-3600(26)00926-3. [Epub ahead of print] 102608
    Mitochondrial aminoacyl-tRNA synthetase (ARS)-defects: a review of phenotypes and therapeutic strategies in 899 patients.
    Eva M M Hoytema van Konijnenburg, Jingjing Ying, Gajja S Salomons, Saskia B Wortmann, Irena J J Muffels, Sabine A Fuchs.
       PURPOSE: Aminoacyl-transfer RNA (tRNA) synthetases (ARSs) are crucial for protein translation. The number of identified patients with mitochondrial (mt)ARS-deficiencies is rapidly increasing, but treatment is limited to supportive care. Recently, cognate amino acid supplementation has been explored. Early diagnosis and insights into the natural history are necessary to evaluate potential treatment effects.
    METHODS: We performed a scoping literature search for patients with mtARS-deficiencies focusing on phenotype (using Human Phenotype Ontology (HPO) terms), disease progression, death rate and targeted treatments.
    RESULTS: We identified 899 patients with 19 different mtARS-deficiencies with a wide variation in age of disease presentation (0-63 years), clinical symptoms and death rate (0-57%). Although neurological problems were common across many mtARS-deficiencies, symptoms were surprisingly different and highly specific for one or a few ARS-deficiencies. Supplementation with cognate amino acids, has been explored in 11 patients, but studies were largely observational and the observed effects were variable.
    CONCLUSION: MtARS-deficiencies are an important subgroup within primary mitochondrial disorders with already 899 patients reported. The genotype-phenotype correlation between specific symptoms and mtARS-deficiencies is not yet understood. Treatment with cognate amino acids is a theoretically appealing potential disease-modifying treatment modality that needs to be explored further with well-designed controlled studies.
    Keywords:  Aminoacyl-transfer RNA (tRNA) synthetase; mitochondrial disorder; mtARS-deficiency
    DOI:  https://doi.org/10.1016/j.gim.2026.102608
  42. Annu Rev Genomics Hum Genet. 2026 May 21.
    Experimental and Computational Approaches to Identify Noncoding Pathogenic Variation in Rare Disease.
    Laura E Covill, Lindsay Romo, Anne O'Donnell-Luria.
      Noncoding variants occur within noncoding genes as well as within the regulatory nontranslated regions of protein-coding genes. It is important to be aware that these variants have been increasingly implicated in developmental disease through a variety of mechanisms. However, they remain difficult to interpret clinically due to their unclear effect on transcript or protein abundance compared with coding variants. Here, we review methods to identify pathogenic noncoding variants in rare disease, which can present challenges due to the inaccessibility of disease-relevant tissue for many conditions. We explore experimental approaches such as high-throughput functional assays, omic data integration, and long-read sequencing. We also review computational methods for annotating and filtering variants, as well as machine learning methods for predicting variant effect and pathogenicity. We discuss the recent discovery of several developmental syndromes caused by noncoding variants and propose an integrated approach to identifying pathogenic noncoding variants within this patient cohort.
    DOI:  https://doi.org/10.1146/annurev-genom-111124-024627
  43. Mol Neurodegener. 2026 May 16.
    Pharmacological restoration of impaired autophagy in retinal ganglion cells prevents abnormal mitochondrial accumulation and glaucomatous neurodegeneration.
    Prabhavathi Maddineni, Balasankara Reddy Kaipa, Bindu Kodati, Karthikeyan Kesavan, Linya Li, J Cameron Millar, Sam Yacoub, Ramesh B Kasetti, Abbot F Clark, Gulab S Zode.
       BACKGROUND: Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve (ON) axons are the key pathological hallmarks of glaucoma, the leading cause of irreversible blindness. Elevated intraocular pressure (IOP), primarily due to dysfunction of the trabecular meshwork (TM), remains the most significant and only known modifiable risk factor. However, vision loss persists in some patients despite effective IOP control, highlighting the critical need to elucidate the mechanisms driving glaucomatous neurodegeneration. Emerging evidence links mitochondrial dysfunction to glaucomatous neurodegeneration, yet the precise mechanisms remain poorly defined. Here, we investigate whether defective autophagy/mitophagy, which removes damaged mitochondria, contributes to mitochondrial accumulation, oxidative stress, and neurodegeneration in glaucoma. We further explore the therapeutic potential of enhancing autophagy to improve mitochondrial turnover, mitigate RGC loss, and preserve visual function.
    METHODS: Glucocorticoid (GC)-induced and myocilin (MYOC)-associated glaucoma mouse models were used to assess the expression of mitochondrial markers (TOM20/COX IV), oxidative DNA damage (8-OHdG), and mitophagy/autophagy-related proteins (p62, LC3, Phospho-ubiquitin (Ser65), and LAMP1) in retinal tissues. Transmission electron microscopy (TEM) was employed to analyze mitochondrial accumulation in glaucomatous ON. Mitophagy flux was assessed at early and late stages of neurodegeneration using mitophagy reporter Mt-Keima mice. The effect of RGC-specific autophagy deficiency on mitochondrial accumulation and neurodegeneration was further investigated using Atg5flox/flox mice, in which Atg5 deletion was induced by AAV2-Cre delivery. Additionally, the therapeutic effect of enhancing autophagy with Torin 2 to restore mitochondrial turnover and prevent glaucomatous neurodegeneration was evaluated in both GC-induced and myocilin-associated glaucoma models, as well as in ex vivo human retinal explants.
    RESULTS: Chronic IOP elevation led to increased mitochondrial accumulation, oxidative DNA damage, and impaired mitophagy/autophagy in glaucomatous retina. TEM analysis further confirmed the accumulation of structurally abnormal mitochondria in glaucomatous ON. In Mt-Keima mice, chronic IOP elevation significantly reduced mitophagy flux prior to RGC loss, indicating that mitophagy impairment precedes neurodegeneration. RGC-specific Atg5 deletion induced the accumulation of damaged mitochondria, leading to neurodegeneration in Atg5 flox/flox mice. Notably, pharmacological restoration of impaired autophagy with Torin 2 prevented mitochondrial accumulation and preserved the structural and functional integrity of RGCs and their axons in glaucoma mouse models and ex vivo human retinal explant cultures.
    CONCLUSION: Our study indicates impaired autophagy contributes to damaged mitochondrial accumulation and oxidative stress, leading to glaucomatous neurodegeneration. Enhancing autophagy in RGCs represents a promising therapeutic strategy to prevent glaucomatous neurodegeneration.
    Keywords:  Autophagy; Glaucoma; Intraocular pressure; Mitochondrial dysfunction; Mitophagy; Mouse models of glaucoma; Neurodegeneration; Optic neuropathy; Oxidative DNA damage; Torin 2
    DOI:  https://doi.org/10.1186/s13024-026-00950-4
  44. bioRxiv. 2026 May 07. pii: 2026.05.04.722784. [Epub ahead of print]
    Kv2-VAP interactions enhance presynaptic ER and mitochondrial calcium influx and the mobilization of vesicles from the reserve pool.
    Cameron D Paton, Michael B Hoppa.
      In neurons, the endoplasmic reticulum (ER) forms an extensive network that establishes membrane contact sites (MCSs) with various organelles including the plasma membrane (PM). While MCSs are known to regulate lipid exchange and Ca 2+ signaling, their specific roles in synaptic transmission remain poorly understood. Here, we demonstrate that the ER resident proteins VAPA and VAPB are essential for organizing presynaptic Ca 2+ exchange and mobilizing synaptic vesicles. We show that the loss of VAP impairs Ca 2+ loading into both the ER and mitochondria during electrical activity. This regulation occurs primarily through VAP interactions with voltage-gated potassium channels (Kv2) at the PM. Our data suggest that the Kv2-VAP complex organizes presynaptic Ca 2+ signaling outside of the active zone. Without this scaffold, synaptic vesicles become trapped in the reserve pool and fail to participate in exocytosis. These findings reveal a novel role for Kv2-VAP MCSs in coordinating organelle Ca 2+ signaling and the synaptic vesicle cycle.
    DOI:  https://doi.org/10.64898/2026.05.04.722784
  45. Front Physiol. 2026 ;17 1721230
    Mitochondrial metabolic reprogramming, quality control, and intercellular transfer in regulating macrophage plasticity.
    Guanheng He, Qian Sun.
      Macrophage functional plasticity is intrinsically linked to metabolic reprogramming, including mitochondrial function, substrate utilization, and redox signaling. In response to hypoxia, infection, or tissue injury, macrophages rely on mitochondria not only for energy provision but, critically, for metabolic intermediates and reactive oxygen species (ROS) that serve as signaling molecules to guide gene expression reprogramming. While macrophage activation exists along a continuous spectrum, this review summarizes the distinct metabolic paradigms characterizing the classical M1-like (glycolysis-dominant) and M2-like (oxidative phosphorylation, OXPHOS-dominant) extremes, highlighting the molecular mechanisms where metabolic events-specifically tricarboxylic acid (TCA) cycle truncation and succinate accumulation-drive inflammatory polarization. Furthermore, we discuss the role of mitochondrial quality control, particularly dynamics and mitophagy, in maintaining macrophage homeostasis. Notably, recent evidence identifies "intercellular mitochondrial transfer" as a novel mode of immune microenvironment regulation, enabling damaged macrophages to restore function by acquiring exogenous mitochondria. A deeper understanding of these mechanisms offers new intervention targets for metabolic immunotherapy in sepsis, cancer, and chronic inflammatory diseases. Importantly, we emphasize that many of these metabolic and mitochondrial regulatory mechanisms are highly context-dependent, varying significantly across different tissues and disease microenvironments.
    Keywords:  intercellular mitochondrial transfer; macrophage polarization; metabolic reprogramming; mitochondria; mitophagy
    DOI:  https://doi.org/10.3389/fphys.2026.1721230
  46. J Physiol Biochem. 2026 May 21. pii: 53. [Epub ahead of print]82(1):
    The progress of mitochondrial function and transfer in stem cell regulation and therapy.
    Yubing Zhang, Zhuojian Qu, Zhiliang Guo, Lijuan Zhang, Hong Li, Xiaoyun Zhang, Xiumei Guan, Xiaodong Cui, Wenxu Wang, Min Cheng.
      Mitochondria, serving as central organelles for energy metabolism, play a critical regulatory role in stem cell self-renewal and differentiation-a function increasingly supported by accumulating evidence and closely linked to various aging-related diseases. Central to their function in stem cell pluripotency are several key mechanisms, such as the control of reactive oxygen species, mitophagy, and mitochondrial-endoplasmic reticulum communication. Mitochondrial transfer, as an emerging intercellular communication mechanism, can enhance stem cell pluripotency and function by replacing damaged mitochondria or activating mitophagy in recipient cells. However, different transfer mechanisms can induce distinct effects on recipient cells. The development of artificial mitochondrial transfer technology, compared to traditional cell transplantation, reduces immune rejection and offers new strategies for stem cell therapy. This review examines the interplay between mitochondrial function and stem cell fate determination, discusses the therapeutic potential of mitochondrial transfer in stem cell-based regenerative strategies, and establishes a theoretical framework for understanding and treating mitochondrial dysfunctions and aging-associated pathologies.
    Keywords:  Mitochondrial function; Mitochondrial transfer; Mitophagy; Reactive oxygen species; Stem cell regulation
    DOI:  https://doi.org/10.1007/s13105-026-01192-0
  47. Curr Neuropharmacol. 2026 May 15.
    Mitochondrial Function in Neurons and Glia in Health and Its Alteration in Parkinson's Disease: A Review.
    Monika Kaushik, Mrugendra Potdar, Prathap Madeswaraguptha, Murugesan Vanangamudi, Md Abubakar, Manoj Kumar Mishra, Sachchida Nand Rai.
       INTRODUCTION: Mitochondria play an important role in maintaining redox balance, energy, calcium, and the viability of neurons. The mitochondrial dysfunction is one of the primary sources of glial activation and dopaminergic neuron loss in Parkinson's disease (PD). The key biochemical elements of the pathogenesis of PD include impaired oxidative phosphorylation, elevated generation of reactive oxygen species (ROS), and impaired mitophagy.
    METHODS: This review is a synthesis and stringent evaluation of recent experimental, clinical and genetic studies relating mitochondrial dysfunction and Parkinson's disease (PD). We examined information on bioenergetics, mitochondrial dynamics, calcium homeostasis, and interactions between neurons and glia. The molecular and therapeutic importance of therapies, such as mitophagy modulators, bioenergetic enhancers, and mitochondrial antioxidants, was investigated. The absence of Complex I, excess ROS, mitochondrial DNA damage, and nonfunctioning fusionfission cycles leads to neurodegeneration. The glial metabolic abnormalities worsen the oxidative stress and neuroinflammation, weakening the support of the neurons. The effects of impaired mitophagy are the accumulation of dysfunctional mitochondria, and the effects of calcium overload disrupt energy metabolism. Neuroprotective effects of such substances as spermidine, urolithin A, resveratrol, αlipoic acid, MitoQ, SkQ1, or CoQ10 have been shown using preclinical research. Sacrifices such as exercising and proper dieting enable the mitochondria to perform better and become stronger.
    DISCUSSION: Mitochondrial dysfunction enhances the progression of PD through oxidative stress, bioenergetic breakdown, and inflammatory signalling. Attention to these related systems is an entire way to alter the direction of a disease.
    CONCLUSION: PD can be treated using an increase in mitochondrial quality control, redox regulation, and metabolic efficiency. Continued studies in the framework of precision medicine are required to validate the safety and effectiveness of mitochondrial-targeted medications.
    Keywords:  Astrocytes; Parkinson’s disease; calcium ions; free fatty acid oxidation; glycolysis; microglia; mitochondria; neuroinflammation; neurons; oligodendrocytes; oxidative stress
    DOI:  https://doi.org/10.2174/011570159X415585260303184042
  48. Transl Pediatr. 2026 Apr 30. 15(4): 161
    Living donor liver transplantation in a pediatric patient with mitochondrial DNA depletion syndrome caused by two novel POLG1 mutations: a case report and literature review.
    Yanhao Li, Fuxiao Xie, Lin Wei, Zhijun Zhu.
       Background: Mitochondrial DNA depletion syndrome (mtDDS) is a rare genetic disorder caused by mutations in nuclear genes responsible for mitochondrial DNA maintenance, most notably POLG1. The disease is characterized by diverse clinical manifestations, including myopathy, hepatopathy, and neurological deficits. Due to its phenotypic heterogeneity, diagnosing mtDDS in pediatric populations remains a significant clinical challenge, often leading to delays in life-saving interventions.
    Case Description: We report the case of an 11-month-old male infant presenting with acute liver failure and recurrent hypoglycemia. Laboratory findings revealed elevated liver enzymes, jaundice, and persistent metabolic distress. Notably, the patient lacked the neurological symptoms typically associated with POLG1 mutations, complicating the initial clinical picture. Genetic analysis via whole exome sequencing (WES) identified two novel compound heterozygous mutations in the POLG1 gene (695G>A and 1735C>T), confirming the diagnosis of mtDDS. Following the diagnosis, the patient underwent a successful liver transplantation, which resulted in significant clinical stabilization and improved quality of life.
    Conclusions: This case expands the known mutational spectrum of the POLG1 gene and highlights an atypical presentation of mtDDS isolated to hepatic dysfunction. Our findings underscore the critical importance of early genetic testing, such as WES, in infants with unexplained liver failure or metabolic crises. Timely diagnosis is essential to guide surgical interventions like liver transplantation, which can effectively improve outcomes. Clinicians should maintain a high index of suspicion for underlying mitochondrial genetic defects in pediatric hepatopathy to facilitate early intervention and long-term management.
    Keywords:  Mitochondrial DNA depletion syndrome (mtDDS); POLG1 gene mutation; case report; liver dysfunction; living donor liver transplantation (LDLT)
    DOI:  https://doi.org/10.21037/tp-2025-1-883
  49. Acta Biochim Biophys Sin (Shanghai). 2026 May 11.
    Fabrication of fusogenic and magnet-responsive cells for transplantation of an intact mitochondrial network.
    Liqun Xu, Xiao Li, Xing Fan, Wei Yan, Wanfei Wu, Junwei Li, Ronghao Deng, Haibao Zhu, Aihua Mao, Pingnan Sun, Xin Zhang, Wencan Xu, Chi-Ju Wei.
      Mitochondrial transplantation is a promising treatment for many diseases associated with mitochondrial defects or aging; however, a reliable method for mitochondrial transfer remains urgently needed. In this study, we assemble fusogenic and magnet-responsive cells (FMRCs), which are enucleated stem cells loaded with Fe 3O 4 nanoparticles and further incorporated fusogenic vesicular stomatitis virus glycoprotein G (VSV-G). Mitochondrial transplantation from FMRCs via fusion in the presence of a magnetic force restores normal mitotic activity, mitochondrial membrane potential, ROS levels and ATP production in cells subjected to partial mtDNA depletion or in cybrids harboring mtDNA with a 4977-bp deletion. SNP tracing and qPCR analysis of the mitochondrial and nuclear genomes unequivocally demonstrate that exogenous mitochondria are able to reside stably and predominately. Mitochondrial transplantation stimulate autophagy and thus the clearance of defective endogenous counterparts, resulting in lower mtDNA heteroplasmy. These results suggest that FMRCs are excellent vehicles for mitochondrial transplantation and could be used for the treatment of aging and mitochondria-associated diseases.
    Keywords:  143B cell; SNP analysis; VSV-G; autophagy; cell fusion; fusogenic and magnet-responsive cell; mitochondrial transplantation
    DOI:  https://doi.org/10.3724/abbs.2026031
  50. Alzheimers Dement. 2026 05;22(5): e71469
    Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's disease and Parkinson's disease using polygenic risk scores and Mendelian randomization.
    Alzheimer's Disease Genetics Consortium and the Alzheimer's Disease Neuroimaging Initiative
       INTRODUCTION: Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genomes per nucleated cell, has an unclear causal relationship with Alzheimer's disease (AD) and Parkinson's disease (PD). We integrated genetic correlation, polygenic risk scores (PRSs), and Mendelian randomization (MR) to assess whether mtDNAcn influences the risk of AD and PD, and evaluate how study-specific factors in mtDNAcn genome-wide association studies (GWASs) distort these causal estimates.
    METHODS: Using GWASs of four mtDNAcn measures, AD, AD/dementia, and PD, we evaluated genetic correlations, generated ancestry-normalized PRS in the Alzheimer's Disease Genetics Consortium (N = 27,383), and applied MR methods including latent heritable confounder-MR (LHC-MR).
    RESULTS: Across the four mtDNAcn GWASs, only one was consistently associated with AD/dementia and PD, with genetic correlations and PRSs showing negative correlations and MR indicating that higher mtDNAcn reduced AD/dementia and PD risk.
    DISCUSSION: Higher blood-based mtDNAcn was causally associated with reduced risk of AD/dementia and PD, with limited evidence to suggest a bidirectional effect.
    Keywords:  Alzheimer's disease; Mendelian randomization; Parkinson's disease; genetic correlations; mitochondrial DNA copy number; polygenic risk scores
    DOI:  https://doi.org/10.1002/alz.71469
  51. Nat Commun. 2026 May 18.
    Chromatin- and actin-mediated mitochondrial streaming leads to patterning of mitochondrial distribution in oocytes.
    In-Won Lee, Morteza Nazari, Jazmine Yuson, Sanjeev Uthishtran, Ross Stocker, Deepak Adhikari, Zhong-Wei Wang, Gyorgy Szabadkai, Michael R Duchen, Senthil Arumugam, Reza Nosrati, John Carroll.
      Mitochondria are highly dynamic organelles, and their spatiotemporal organization is strictly regulated. While it has long been recognized that mitochondria in ovulated oocytes are concentrated in the spindle hemisphere, the mechanism remains unknown. Through live cell imaging and modeling, we have discovered that mitochondrial polarization in MII oocytes is achieved through two distinct mechanisms: (i) a mechanism in which mitochondria are transported by actin-driven cytoplasmic streaming that is delimited to the spindle hemisphere; (ii) an active, MYO19 dependent channeling mechanism that directs mitochondria from beneath the spindle to the polarized cortex bilaterally and perpendicular to the long axis of the MII spindle. This directionality in mitochondrial streaming patterns the ooplasm of the spindle hemisphere, creating mitochondria-rich and mitochondria-poor regions. These features explain the establishment of the polar gradient of mitochondria in MII oocytes and may provide new insight into the spatiotemporal organization of mitochondria in cells.
    DOI:  https://doi.org/10.1038/s41467-026-73192-z
  52. J Biol Chem. 2026 May 20. pii: S0021-9258(26)02046-6. [Epub ahead of print] 113174
    Higher-order structural organization of mitochondrial metabolism.
    Greg Kafetzopoulos, Jonas Döbler, Panagiotis L Kastritis.
      The mitochondrion embeds numerous metabolic, biosynthetic, and signaling pathways occurring within its specialized compartments that collectively define eukaryotic biology. To visualize these, cryogenic electron microscopy (cryo-EM) is now utilized, particularly for resolving biomolecular complexes that were notoriously hard to study with other structural methods. Our review synthesizes recent cryo-EM-based discoveries, analyzes structures related to mitochondrial metabolism and explains related functional aspects of core energy metabolism, biosynthetic processes, transport and regulatory systems. We report on recent data on mitochondrial enzyme filamentation, higher-order metabolons, enzyme gating mechanisms, and contact-site nanostructures. In addition to single-particle cryo-EM results, we discuss emerging in situ cryo-tomography data, the integration of traditional structural biology approaches, and the use of in silico models for less-studied pathways. By mapping hundreds of recent mitochondrial structures, we provide a roadmap that connects structural biochemistry with cell physiology disclosing the molecular basis of mitochondrial disease. Our collected resource may guide future integrative research aiming to elucidate mitochondrial architecture and function across organisms and conditions.
    Keywords:  conformational landscape; dynamic protein complexes; filamentous enzyme regulation; integrative structural modeling; lipid-protein interactions; metabolic modularity; mitochondrial metabolons; scaffolding; structural and molecular biology; supramolecular assemblies
    DOI:  https://doi.org/10.1016/j.jbc.2026.113174
  53. Cardiovasc Toxicol. 2026 May 20. pii: 53. [Epub ahead of print]26(6):
    The Integrated Stress Response Protein, eIF2α, Modulates UPRmt Signaling and Cell Death in Doxorubicin Treated Human Cardiac Cells.
    Kienan P O'Dwyer, Perry E Bauer, Subhankhi Pal, Kathleen Brundage, Sundararajan Venkatesh.
      Doxorubicin (DOX), is an indispensable first-line chemotherapeutic. Despite this first-line indication, clinical use of DOX is limited by severe, off-target, and often irreversible cardiotoxicity. DOX induces cytotoxicity in rapidly dividing cancer cells via inhibition of Topoisomerase IIα. However, the underlying mechanisms by which DOX causes cell death in non-replicative, terminally differentiated cardiomyocytes remain poorly understood. Emerging evidence suggests that mitochondrial uptake of DOX is contributory to cardiotoxicity. Whether mitochondrial stress pathways, including the mitochondrial unfolded protein response (UPRmt), are activated and critical for mediating DOX cardiotoxicity is poorly understood. Moreover, whether phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), a mediator of the Integrated Stress Response, regulates potential UPRmt signaling during DOX treatment is also unknown. Here, using human AC-16 cardiac cells, we examined the role of eIF2α phosphorylation during DOX treatment. Our data suggest that DOX triggers a transient increase in eIF2α phosphorylation, followed by a progressive decline. Further, knockdown of eIF2α decreased key transcriptional regulators of UPRmt signaling such as C/EBP Homologous Protein and ATF5, blunted the induction of UPRmt genes (AFG3L2, CLPP, HSPA9, HSPD1, LONP1, SPG7), and aggravated DOX induced cytotoxicity. Together, these findings identify eIF2α as a critical upstream regulator of UPRmt signaling, and suggest that activation of the UPRmt may confer cardio-protection against DOX-induced mitochondrial stress in human cardiac cells.
    Keywords:  ATF5; CHOP; Cardiomyocytes; Cardiotoxicity; Doxorubicin; Mitochondria; UPRmt ; eIF2α
    DOI:  https://doi.org/10.1007/s12012-026-10124-9
  54. Bioorg Chem. 2026 May 15. pii: S0045-2068(26)00530-4. [Epub ahead of print]179 109994
    Constrained peptide mimics of the LRRK2 C-terminal Helix inhibits its kinase activity.
    Tiancheng Chen, Krista K Alexander, Juliana A Martinez Fiesco, Yahaira Naaldijk, Rachel Fasiczka, Besma Brahmia, Astrid Alvarez de la Cruz, Timothy J LeClair, Emma G Steude, Ping Zhang, Sabine Hilfiker, Eileen J Kennedy.
      Leucine-rich repeat kinase 2 (LRRK2) is the most frequently mutated gene in Parkinson's disease (PD), a neurodegenerative disorder affecting over 10 million people. PD-related pathogenic mutations in LRRK2 increase its kinase activity, thereby contributing to disease pathology. While elevated LRRK2 activity is a recognized contributor to PD, the precise mechanisms by which its various domains regulate kinase activation remain unclear. To address this, we developed hydrocarbon-constrained peptides that mimic the C-terminal helix of LRRK2, a region implicated in modulating its kinase activity. These peptides are cell-penetrant, directly bind LRRK2, and inhibit kinase function. Consequently, they suppress downstream LRRK2-associated pathological phenotypes, including centrosomal and ciliary defects. Unlike many ATP-competitive LRRK2 inhibitors that induce LRRK2 mislocalization, these peptides do not alter LRRK2 localization. Our findings highlight a potentially critical regulatory role of the LRRK2 C-terminal helix and suggest a novel, alternative strategy for modulating pathogenic LRRK2 activity as relevant in PD.
    Keywords:  Constrained peptide; Kinase; LRRK2; Parkinson's disease; Stapled peptide
    DOI:  https://doi.org/10.1016/j.bioorg.2026.109994
  55. J Neurosci. 2026 May 21. pii: e1936252026. [Epub ahead of print]
    Mitochondrially Transcribed dsRNA Mediates Manganese-induced Neuroinflammation.
    Hadassah Mendez-Vazquez, Avanti Gokhale, Maureen M Sampson, Felix G Rivera Moctezuma, Adriana Harbuzariu, Anson Sing, Stephanie A Zlatic, Anne M Roberts, Milankumar Prajapati, Blaine R Roberts, Thomas B Bartnikas, Levi B Wood, Steven A Sloan, Victor Faundez, Erica Werner.
      Manganese is an essential trace element required for various biological functions, but in excess is neurotoxic and leads to significant health concerns. The mechanisms underlying manganese neurotoxicity remain poorly understood. Neuropathological studies of affected brain regions reveal astrogliosis, neuronal loss, and neuroinflammation. Here, we present a novel manganese-dependent mechanism linking mitochondrial dysfunction to neuroinflammation. We found that manganese disruption of the mitochondrial transcriptome processing results in the accumulation of double-stranded RNA (dsRNA). This dsRNA is released into the cytoplasm, where it activates the cytosolic sensor MDA5, triggering type I interferon responses and inflammatory cytokine production. This mechanism is evident in 100-day human cerebral organoids, where manganese-increased mitochondrial dsRNA and induced inflammatory responses in mature astrocytes. Similarly, we observed an increase in mitochondrial dsRNA content, the activation of an inflammatory transcriptome and the production of cytokines in female and male mouse brains carrying mutations in the Slc30a10 gene, a model for human hypermanganesemia with dystonia 1 disorder. These findings highlight a previously unrecognized role for mitochondrial dsRNA in manganese-induced neuroinflammation and provide insights into the molecular pathogenesis of manganism. We propose that this mitochondrial dsRNA-induced inflammatory pathway could be active in other neurological diseases caused by environmental or genetic factors.Significance Statement Environmental exposures and genetic defects that perturb manganese homeostasis are an underappreciated cause of neurodegeneration and neuroinflammation. We describe a new paradigm for inducible neuroinflammation, where manganese disruption of mitochondrial transcriptome processing leads to the accumulation of mitochondrial double-stranded RNA (dsRNA), which activate antiviral responses in the cytoplasm driving type I interferon-dependent inflammation. This manganese-dsRNA axis is induced in cell lines in vitro and a subpopulation of mature astrocytes in exposed human cerebral organoids. Brain cortex of mice deficient in the manganese efflux transporter Slc30a10, a genetic model of chronic manganese accumulation, show dsRNA accumulation, and up-regulation of type I interferon response and astrogliosis markers, supporting a role for this pathway in neurotoxicity and parkinsonism.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1936-25.2026
  56. Acta Physiol (Oxf). 2026 Jun;242(6): e70252
    Revisiting Mitochondrial Temperature: Steady-State Heat Transfer or Non-Steady-State Dynamics?
    Chérif F Matta.
      
    DOI:  https://doi.org/10.1111/apha.70252
  57. Nat Rev Drug Discov. 2026 May 20.
    Twenty years of induced pluripotent stem cells.
    Asher Mullard.
      
    DOI:  https://doi.org/10.1038/d41573-026-00084-8
  58. bioRxiv. 2026 May 05. pii: 2026.04.30.722110. [Epub ahead of print]
    Elucidating the molecular interplay between LRRK2 and Rab GTPases.
    Hanwen Zhu, Liam Eade, Dario R Alessi, Ji Sun.
      Gain-of-function mutations in LRRK2 are a major cause of inherited Parkinson's disease. LRRK2 encodes a multidomain kinase, whose bidirectional interplay with Rab GTPases regulates critical cellular processes like lysosomal homeostasis. Certain Rabs, including Rab12 and Rab29, recruit LRRK2 to organelle membranes and stimulate its kinase activity; activated LRRK2 phosphorylates a subset of Rabs in their Switch-II motifs. Molecular basis governing selective Rab recognition by LRRK2 remains unclear. Here we structurally characterize LRRK2 interactions with representative Rab GTPases and identify three novel Rab-binding sites: site 4 for Rab8A/10, site 5 for Rab43, and site 6 for Rab5A, defining a total of six distinct binding sites that account for known LRRK2-interacting Rabs. Additionally, we elucidated the binding site of GABARAP, an ATG8 member that recruits LRRK2 to stressed lysosomes. Our findings provide a framework for therapeutic targeting of LRRK2 recruitment for Parkinson's.
    DOI:  https://doi.org/10.64898/2026.04.30.722110
  59. J Neurogenet. 2026 May 18. 1-7
    Genetic architecture of hereditary spastic paraplegia: from monogenic to oligogenic models.
    Giuseppe Pedullà, Maurizio Morelli, Monica Gagliardi, Radha Procopio, Andrea Quattrone, Enrico Fratto, Antonio Gambardella.
      Hereditary spastic paraplegia (HSP) encompasses a clinically and genetically heterogeneous group of neurodegenerative disorders, characterized by progressive lower limb spasticity due to corticospinal tract degeneration. While traditionally regarded as monogenic, recent genomic advances have revealed more complex inheritance models, including oligogenic and polygenic contributions. This mini-review examines the evolving genetic landscape of HSP, integrating established monogenic forms with emerging evidence of cumulative variant burden. Importantly, current evidence remains insufficient to establish oligogenic inheritance as a validated or broadly applicable pathogenic mechanism in HSP, and most available data should be considered exploratory and hypothesis-generating rather than conclusive. Monogenic subtypes such as SPG4, SPG7, and SPG11 remain central to current understanding, but analyses of large sequencing cohorts show that up to 40% of cases lack a single-gene explanation. Both statistical analyses and illustrative reports, such as ultra-rare variant enrichment involving SYNE1, CAPN1, and PGAP1, suggest that oligogenic inheritance may operate in a subset of unresolved cases, although current evidence remains preliminary and not yet broadly validated. Pathogenic mechanisms converge on shared molecular pathways including microtubule dynamics, endoplasmic reticulum shaping, lipid metabolism, mitochondrial maintenance, and vesicular trafficking. Recognition of these multilayered mechanisms informs diagnostic strategies, favoring whole-exome or genome sequencing, variant burden analysis, and refined genetic counselling. Functional studies in cellular and animal models, coupled with biomarker discovery, are crucial to unravel gene-gene interactions and identify therapeutic targets. HSP exemplifies a genetic continuum ranging from high-penetrance monogenic forms to genetically unresolved phenocopies and putative oligogenic cases influenced by cumulative variant burden. Accordingly, diagnosis should incorporate multi-locus models as a hypothesis-testing framework in selected unresolved cases rather than as an established default explanation, counselling must address probabilistic inheritance, and therapeutic development should prioritize pathway-based interventions. Multidisciplinary integration of genomic, mechanistic, and clinical insights is essential to achieve precise diagnoses and personalized therapies.
    Keywords:  Axonal degeneration; Hereditary spastic paraplegia; neurogenetics; oligogenic inheritance; precision medicine; variant burden
    DOI:  https://doi.org/10.1080/01677063.2026.2671912
  60. Nat Genet. 2026 May 20.
    Genome-wide associations of structural variants with human traits through imputation from long-read assemblies.
    Wei-Yang Bai, Shuli Liu, Zhongqu Duan, Ji-Jian Yang, Jie Chen, Junren Hou, Lianfeng Wu, Nan Li, Ting Qi, Jian Yang.
      Structural variants (SVs) are a major type of genetic variation, yet their role in human traits remains largely uncharacterized, primarily due to challenges in genotyping them on a genome-wide scale in large cohorts. Here we identified 171,233 high-quality, genome-wide SVs from 482 haplotype-resolved genome assemblies derived from PacBio HiFi long-read sequencing of 241 individuals. We developed a reference panel and a web application (ImputeSV) to impute these SVs from single-nucleotide polymorphism (SNP) data and demonstrated high imputation accuracy at both the individual and cohort levels. Using this tool, we imputed 54,578 common SVs (minor allele frequencies (MAFs) ≥1%) in 456,643 UK Biobank (UKB) participants of European ancestry. Through analysis of UKB data and simulations, we estimated that SVs contributed to at least 4.7% of the common genetic variation for complex traits. Genome-wide association analyses of SVs for 2,624 UKB traits identified 17,335 SV-trait associations, including 958 unlikely to be driven by small genetic variants. Our study demonstrates the power of using long-read assemblies for imputing SVs from SNPs, unveils the role of SVs in complex trait variation and provides a catalog of SV associations in the UKB.
    DOI:  https://doi.org/10.1038/s41588-026-02612-z
  61. J Neuromuscul Dis. 2026 May 20. 22143602261432401
    Nucleoside therapy for thymidine kinase 2 deficiency: Long-term outcomes from a Brazilian cohort.
    Cristiane Araujo Martins Moreno, Tatiana Ribeiro Fernandes, Clara Gontijo Camelo, Gabriel Keller, Filipe Di Pace, Gabriella Corrêa Dousseau, Alulin Tácio Quadros Santos Monteiro Fonseca, Eliene Dutra Campos, Ana Paula Dos Anjos Lança, Mariana Cunha Artilheiro, André Macedo Serafim da Silva, Michelle Abdo Paiva, Andres Nascimento, Edmar Zanoteli.
      BackgroundThymidine Kinase 2 deficiency (TK2d) is a rare, mitochondrial DNA (mtDNA) depletion/deletions syndrome leading to a severe and progressive myopathic disorder. Nucleoside supplementation (deoxythymidine and deoxycytidine) has been shown to favorably alter the disease's course, particularly in severe infantile-onset cases. Long-term data on efficacy and safety, especially in the adult patient population, remain limited.MethodsThis is a retrospective, long-term follow-up study of 14 TK2d patients (five children and nine adults with childhood-onset disease) treated with nucleosides. Patients were systematically evaluated over a period ranging from 9 to 36 months, with assessments conducted every 3 months during the first year of treatment, and every 6 months thereafter. Comprehensive functional assessments of motor, respiratory, and bulbar function were performed. Periodic measurements of liver and pancreatic function monitored safety and tolerability.ResultsAll 14 TK2d patients showed beneficial effects across motor, respiratory, and bulbar function domains. Among pediatric patients, a rapid treatment response was observed early on, with functional gains sustained and continuing beyond 12 months of therapy. Adults experienced substantial improvements in motor and respiratory capacity but most of them reported severe gastrointestinal symptoms. Liver and pancreatic enzymes abnormalities were noticed mainly in adults.ConclusionsDeoxythymidine and deoxycytidine were found to be safe and beneficial in this long-term cohort of TK2d patients, but elevation in liver and pancreatic enzymes were present and required regular monitorization. This study provided valuable evidence supporting this therapy as an effective and safe, long-term disease-modifying treatment option for both pediatric and adult patients.
    Keywords:  Mitochondrial Myopahty; TK2 deficiency; deoxythymidine and deoxycytidine; mtDNA depletion syndrome; nucleosides therapy
    DOI:  https://doi.org/10.1177/22143602261432401
  62. Biomed Opt Express. 2026 May 01. 17(5): 2262-2281
    WeakMitoSAM: competitive prompt aggregation for point-supervised mitochondria segmentation in electron microscopy images.
    Yuanwei Li, Xinliang Zhang, Hangzhou He, Kaiwen Li, Shuang Zeng, Chuqiao Yang, Lei Zhu, Yanye Lu.
      Mitochondrial morphology is a critical indicator of cellular metabolic status and disease pathogenesis, requiring high-resolution visualization and precise segmentation in electron microscopy (EM) images. While fully supervised deep learning models have achieved significant progress, their reliance on dense pixel-wise annotations presents a major bottleneck due to the labor-intensive labeling process and expert variability near the optical diffraction limit. Existing weakly supervised methods, primarily designed for densely packed instances, often fail to generalize to the sparse distribution of mitochondria in EM data. In this paper, we propose WeakMitoSAM, a novel weakly supervised framework for high-precision mitochondria segmentation using sparse point annotations. Our approach introduces the competitive aggregation of multiple prompts strategy, which employs a Bias-augmented Softmax mechanism to reconcile semantic ambiguities and suppress background noise, effectively converting sparse priors into high-fidelity pseudo-labels. Subsequently, segment anything model is specialized for mitochondrial ultrastructures via low-rank adaptation, ensuring parameter-efficient domain adaptation. Experimental results across four public EM datasets demonstrate that WeakMitoSAM achieves state-of-the-art performance in point-supervised scenarios and even outperforms several fully supervised benchmarks, providing an efficient and robust solution for large-scale mitochondrial morphofunctional analysis.
    DOI:  https://doi.org/10.1364/BOE.592074
  63. Nat Commun. 2026 May 19.
    An engineered viral RNA degrader on mitochondrial surface that mitigates RNA virus infection.
    Chih-Wei Chen, Wei-Ting Liao, Tung Chao, Yi-Han Chen, Shih-Che Weng, Shin-Hong Shiao, Ching-Yang Kao, Yun-Jung Li, Kai-An Cheng, Zee-Fen Chang.
      Infections by RNA viruses cause diseases. Host factor(s) that restrain viral propagation offer new anti-virus strategies. We use vesicular stomatitis virus (VSV) as a model and observe the synthesis of VSV RNAs at mitochondria/endoplasmic reticulum (Mito/ER) spheres, accompanied by the leakage of endonuclease G (ENDOG), a mitochondrial nuclease, to the cytosol. We provide evidence that ENDOG released from mitochondria is a host anti-viral factor by eliminating viral RNAs for replication. However, ENDOG outside mitochondria can translocate to nuclei and cause nuclear DNA damages. We engineer an ENDOG expressed on mitochondrial outer membrane (MOM), namely MOM-ENDOG, to increase the accessibility to viral RNA transcripts synthesized at mitochondrial sites without damaging nuclear DNA (nDNA). Delivery of modified mRNA of wild-type but not catalytic-dead MOM-ENDOG markedly suppresses not only the propagation of VSV, but also Dengue and Zika virus. Thus, this organelle-specific viral RNA degrader may be developed as a broad-spectrum anti-viral agent.
    DOI:  https://doi.org/10.1038/s41467-026-73487-1
  64. Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2602528123
    Regulation of Pfh1 helicase activity by nucleic acid interactions and mitochondrial SSB.
    María Ortiz-Rodríguez, Saurabh P Singh, Francisco J Cao-García, Roberto Galletto, Borja Ibarra.
      Pif1-family helicases are essential for proper nuclear and mitochondrial genome maintenance, yet the regulation of their activities remains incompletely understood. Here, we use single-molecule manipulation and visualization techniques to dissect the real-time mechanochemical behavior of Pfh1, the sole Pif1-family helicase in Schizosaccharomyces pombe. We systematically varied force, ATP concentration, fork composition, and the single-stranded DNA-binding protein spRim1, to quantify the unwinding and single-stranded DNA translocation properties of Pfh1. We find that Pfh1 operates through unwinding-rewinding cycles during which coordinated interactions with both DNA strands at the fork optimize ATP utilization. Contacts with the translocating strand modulate ATP affinity, while interactions with the displaced strand control maximum unwinding velocity. Binding of spRim1 to the displaced strand disrupts the latter interactions, increasing the unwinding velocity. Stable interactions of the helicase with both strands at the fork may limit unwinding processivity to ~20 bp, eventually triggering transition to rewinding. Rewinding proceeds through an ATP-dependent process that is incompatible with strand switching, in which ATP turnover modulates DNA contacts and rewinding rate. Binding of spRim1 to the displaced strand further accelerates rewinding, possibly by competing with helicase-DNA interactions, and facilitates recovery of the active unwinding conformation once the fork has rewound. Together, these findings suggest that Pfh1 balances unwinding and rewinding through coordinated ATP-dependent strand interactions, providing insight into how Pif1-family helicases are controlled at replication forks.
    Keywords:  ATP-dependent helicase activity; DNA unwinding kinetics; Pfh1 helicase; mitochondrial SSB interactions; single-molecule manipulation
    DOI:  https://doi.org/10.1073/pnas.2602528123
  65. Nat Aging. 2026 May 19.
    A unifying model of stem cell dynamics explains age-related methylation patterns across mammals.
    Samuel J C Crofts, Caleb M Grenko, Riccardo E Marioni, Eric Latorre-Crespo, Tamir Chandra.
      DNA methylation changes are reliable biomarkers of aging, but the driving mechanisms remain poorly understood. Here we present SCARLET (Stem Cells and Age-ReLated Epigenetic Trajectories), a parsimonious mathematical model that describes how methylation changes in blood arise and propagate through hematopoietic stem cell divisions. Using a large human cohort, we demonstrate that seemingly distinct age-related methylation patterns can be explained by a unifying mechanistic model. We show that SCARLET captures known drivers of epigenetic aging, with accelerated individuals showing reduced ratios of stem cell pool size to division rate (N/s). Applying SCARLET to methylation data from 11 mammalian species reveals that N/s scales with maximum lifespan, suggesting that evolutionary adjustments to stem cell dynamics, rather than epigenetic maintenance efficiency, drive the previously observed relationship between methylation rates and lifespan. Our findings provide a quantitative framework for understanding epigenetic aging and suggest that stem cell dynamics may be a key driver of aging across mammals.
    DOI:  https://doi.org/10.1038/s43587-026-01125-y
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒24 at 8:43.