bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–06–14
63 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial complex I deficiency-associated diseases and models.
  2. Mitochondria-ER contacts function as an iron supply hub.
  3. Mitochondrial capsules mitigate mitochondrial dysfunction.
  4. DRP1 and MID49 co-diffusion scans mitochondria for fission.
  5. Mitochondrial disease: mechanisms, signalling, and therapeutic opportunities.
  6. Mitochondria tethered to the nucleus secure its energy supply.
  7. Expanding the MRPS34 Genotype-Phenotype Correlation: Two Novel Cases and a Cohort Review.
  8. Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.
  9. Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
  10. Omega-3 fatty acid supplementation improves skeletal muscle mitochondrial function in a model of Barth syndrome.
  11. Mitochondrial Dysfunction as a Driver of Neurodegeneration in Parkinson's and Huntington's Disease: Molecular Insights and Emerging Interventions.
  12. Mitophagy: an emerging therapeutic target in mitochondrial diseases.
  13. STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
  14. Folding the message: mRNA structure as a regulatory layer of human mitochondrial gene expression.
  15. Effects of an indole chemical, mitochonic acid 5, in a mouse model of mitochondrial disease onset.
  16. Mitochondrial Dysfunction in Parkinson's Disease: Diagnostic and Therapeutic Advances.
  17. Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
  18. Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
  19. Generation and characterization of the hiPSC line CSSi023-A (16154) from a patient with ADOA caused by an OPA1 variant.
  20. CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
  21. Mitochondria limit coenzyme Q export under cholesterol biosynthetic stress.
  22. A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
  23. Testicular origin of epigenetic inheritance independent of sperm mitochondrial DNA and epididymal exposure.
  24. Expanding the landscape of tRNA pathogenic variants in mitochondrial DNA.
  25. Loss of STMP1 Perturbs Mitochondrial Cristae and Drives Cellular Inflammation and Heart Failure.
  26. Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
  27. STING1 senses mitochondrial damage to promote mitophagy.
  28. Expression of four mitochondrial tRNAs from only two loci.
  29. Mitochondrial permeability transition in redox homeostasis and ferroptosis.
  30. Prevalence and treatment of mitochondrial diabetes in Southwest Finland.
  31. TTC19 and FMNL2 gene variants in a pediatric case of mitochondrial disorder with renal tubular acidosis.
  32. Tracking Gene Expression of Single Mitochondria in Live Neurons Using Nanotweezers.
  33. Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling.
  34. Aberrant TIMM8B alternative splicing compromises mitochondrial respiratory chain integrity and redox homeostasis.
  35. eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in Skeletal Muscle.
  36. Sigma-1 receptor promotes glycolysis in neuronal systems by suppressing GRIM19.
  37. Loss of astrocytic markers and impaired metabolic function in spinocerebellar ataxia type 7 patient-derived neural cultures.
  38. Disruption of Polycystin-1 Cleavage Impairs Mitochondrial Bioenergetics and Calcium Uptake in a Substrate-Dependent Manner.
  39. Alpha-synuclein fibrils induce budding of mitochondrial-derived vesicles.
  40. Distinct age-related pattern of mitochondrial somatic mutations across multiple sclerosis phenotypes.
  41. Quantitative high-content profiling of mitochondrial morphology with automated statistical analysis and integrated data visualization.
  42. Heterozygous OGDH Variants Are Involved in Peripheral Neuropathy With Ataxia and Optical Atrophy.
  43. Why machine learning fails at mass spectrometry for small molecules.
  44. Electron transport chain complex I and mitochondrial fusion regulate ROS for differentiation in Drosophila neural stem cells.
  45. Mitochondrial Transfer from Glia to Neurons: A Novel Protective Mechanism Against Peripheral Neuropathy.
  46. Synaptosomes isolated from cryopreserved MND motor cortex reveal altered calcium handling and reduced complex IV-linked respiration.
  47. SIRT3 regulates PRDX3 acetylation to support mitochondrial peroxide detoxification and limit oxidative stress-associated ferroptosis vulnerability.
  48. Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.
  49. Evaluating a Coenzyme Q10-Based Food for Special Medical Purpose, for Mitochondrial Diseases Management: An Open-Label, Pilot Trial.
  50. Compound heterozygous PINK1 variants including a novel frameshift in a Chinese family with Parkinson's disease.
  51. Reduced Myocardial Serine Synthesis Impairs Functional, Metabolic, and Redox Adaptations to Cardiac Stress.
  52. PARS2 deficiency impairs mitochondrial homeostasis and activates ferroptotic to drive developmental and epileptic encephalopathy.
  53. Scalable hypothalamic neuron differentiation from human pluripotent stem cells suitable for modeling metabolic disorders.
  54. Stem Cell Therapy for Parkinson's Disease: A Mechanistically Distinct Role for Muse Cells.
  55. Drp1-driven fragmentation of scleral mitochondria promotes myopia development.
  56. Molecular Hydrogen as a Regulator of Mitochondrial Quality Control and Metabolic Reprogramming.
  57. Development of a Noncanonical Redox Cofactor Platform in Saccharomyces cerevisiae.
  58. Nitrate-Sialin2 axis couples ER-mitochondrial calcium signaling with fatty acid metabolism to drive white adipose browning.
  59. Fasting requires Peroxiredoxin 2 and Peroxiredoxin 6 to coordinate redox dependent mitochondrial and lipid remodelling in Caenorhabditis elegans.
  60. DHDDS-related juvenile parkinsonism is caused by impaired lipid metabolism, glycosylation, and mitochondrial dysfunction, which can be rescued by NAD⁺ treatment.
  61. The Legionella effector RidL binds the large fission GTPase Drp1 to promote mitochondrial fragmentation.
  62. The pseudokinase domain PK1 of UNC-89/obscurin is required for mitochondrial morphology and function in C. elegans.
  63. Mitochondria directly interact with the nuclear pore complex.
  1. Cell Mol Life Sci. 2026 Jun 10. pii: 249. [Epub ahead of print]83(1):
    Mitochondrial complex I deficiency-associated diseases and models.
    Lena Jentsch, Natascia Ventura.
      Mitochondrial complex I is the first and largest enzyme of the mitochondrial respiratory chain and thus plays a crucial role in cellular energy metabolism. Defects in the mitochondrial respiratory chain, and in particular CI deficiency, are the primary cause of human mitochondrial associated diseases, which most often presents as severe neurometabolic disorders with fatal outcome. Up to this date the diagnosis and treatment of CI deficiency-associated diseases is challenging, only limited symptomatic therapies exist and no cures are available. This review aims at summarizing current knowledge on the genetic basis of CI deficiency-associated diseases and available experimental disease models. Most common human disorders caused by CI deficiency range from Leigh syndrome to MELAS and LHON, all characterized by genetic and symptomatic heterogeneity. So far, in vivo studies on non-mammalian organisms and mouse models, as well as in vitro studies on patient derived fibroblasts, cybrids and human-induced pluripotent stem cells have mainly facilitated the research of CI deficiency. These model systems provide insights on molecular mechanisms in mitochondrial disease and approaches for potential therapeutic intervention strategies. However, current research is limited by translational relevance of existing disease models, varying degrees of heteroplasmy and tissue specific effects characteristic of mitochondrial diseases, so that basic disease mechanisms still remain poorly understood. To overcome these challenges there is an urgent need for in vivo and in vitro human relevant models to aid the development of effective therapeutic interventions and potential cures of CI deficiency-associated diseases.
    Keywords:  Mammalian cell models; Mitochondrial complex I; Mitochondriopathies; Model organisms
    DOI:  https://doi.org/10.1007/s00018-026-06169-2
  2. Nat Cell Biol. 2026 Jun 10.
    Mitochondria-ER contacts function as an iron supply hub.
    Hijiri Oshio, Isshin Shiiba, Naoki Ito, Naozumi Okada, Fuya Yamaguchi, Yuto Ishikawa, Shun Nagashima, Yuuta Fujikawa, Keitaro Umezawa, Yuri Miura, Misaki Shimizu, Yoshiro Saito, Tomoyuki Yamaguchi, Ryoko Inatome, Shigeru Yanagi.
      Mitochondrial iron dynamics are essential for cellular respiration and metabolic homeostasis, yet the molecular mechanisms governing iron supply to mitochondria remain poorly understood. Here we identify a pathway in which haem serves as an iron source for mitochondria, maintaining mitochondrial iron homeostasis and mitochondrial supercomplex integrity, regulated at mitochondria-endoplasmic reticulum contact sites (MERCs). We demonstrate that haem oxygenase 2 (HMOX2), an ER-resident enzyme, is also localized to MERCs and facilitates the supply of haem-derived iron to mitochondria. This process is orchestrated by the mitochondrial ubiquitin ligase MITOL (also known as MARCH5/MARCHF5), which ubiquitinates HMOX2 at K68 with K63-linked polyubiquitin chains, enhancing its haem-degrading activity. Notably, loss of HMOX2 or disruption of MITOL-mediated ubiquitination impairs mitochondrial iron homeostasis and mitochondrial respiration. These findings establish a paradigm in which MERCs function as an iron supply hub, integrating haem metabolism with mitochondrial iron utilization.
    DOI:  https://doi.org/10.1038/s41556-026-01974-0
  3. Nat Genet. 2026 Jun;58(6): 1200
    Mitochondrial capsules mitigate mitochondrial dysfunction.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-026-02651-6
  4. Nat Cell Biol. 2026 Jun 11.
    DRP1 and MID49 co-diffusion scans mitochondria for fission.
    Cristiana Zollo, David Gomez Suarez, Elmira Parvindokht Bararpour, Andreas Jenner, Pratima Verma, Jan Koch, Sabine Wilhelm, Christian Jüngst, Lukas Faber, Faye White, Ana J García-Sáez.
      DRP1 is a dynamin-related large GTPase responsible for mitochondrial fission, which ensures proper mitochondrial distribution, morphology and quality control. Despite its relevance, the mechanism of mitochondrial division, especially regarding the dynamic regulation of DRP1, remains elusive. Here we report that DRP1 oligomers diffuse in helical-like trajectories along mitochondria, browsing the organelle surface and stalling at preconstricted fission sites, in what we call 'mito-scanner' motion. Molecular dynamics simulations support a geometry-mediated diffusion mechanism emerging from surface confinement. Perturbation of DRP1 motility results in elongated mitochondria, underscoring the functional importance of DRP1 scanning dynamics in mitochondrial division. We also show that DRP1 dynamics on mitochondria are differentially regulated by interactions with its adaptors, where co-diffusion of MID49/MID51 with DRP1 promotes its motility. Our findings support a model in which receptor-regulated mitochondrial surveillance by DRP1 enables balanced organelle division, with potential implications for targeting this process in disease.
    DOI:  https://doi.org/10.1038/s41556-026-01986-w
  5. Free Radic Biol Med. 2026 Jun 06. pii: S0891-5849(26)00857-9. [Epub ahead of print]253 749-769
    Mitochondrial disease: mechanisms, signalling, and therapeutic opportunities.
    Samantha Corrà, Luke Young, Anthony L Moore, Carlo Viscomi.
      Mitochondria are central hubs of cellular metabolism and signalling, and their dysfunction underlies a broad spectrum of human diseases, including rare mitochondrial disorders as well as common neurodegenerative and metabolic conditions. Mitochondrial diseases are genetically heterogeneous disorders caused by mutations in nuclear or mitochondrial DNA that impair oxidative phosphorylation (OXPHOS), resulting in reduced ATP production and cellular energy failure. Despite a shared bioenergetic defect, these diseases display marked clinical variability, and the mechanisms underlying this heterogeneity remain poorly understood. At present, no curative therapies are available, although several metabolic and experimental approaches have shown promise in preclinical models. Mitochondrial dysfunction is commonly associated with altered redox homeostasis and increased production of reactive oxygen species (ROS), which can damage mitochondrial components, including mitochondrial DNA, and further impair respiratory chain function. At the same time, ROS also act as context-dependent signalling molecules, with effects that vary according to concentration, localization, and cell type complicating their interpretation in disease mechanisms and therapy development. In this review, we summarize current concepts in mitochondrial disease pathophysiology focusing on unresolved questions that limit mechanistic understanding and clinical translation. We critically evaluate the role of ROS in disease progression and signalling, discuss how the alternative oxidase (AOX) has emerged as a valuable experimental tool to dissect ROS-related mechanisms and reveal unexpected aspects of mitochondrial dysfunction and disease variability.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.013
  6. Nature. 2026 Jun;654(8119): 605-606
    Mitochondria tethered to the nucleus secure its energy supply.
    Philippa Clarke, Sophie Trefely.
      
    Keywords:  Cell biology; Developmental biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-01587-5
  7. JIMD Rep. 2026 Jul;67(4): e70089
    Expanding the MRPS34 Genotype-Phenotype Correlation: Two Novel Cases and a Cohort Review.
    Alberte Aspaas Lundquist, Sumit Parikh, Thomas van Overeem Hansen, Flemming Wibrand, Elsebet Østergaard.
      MRPS34 encodes a mitoribosomal protein essential for mitochondrial translation. Biallelic pathogenic variants in MRPS34 cause Combined Oxidative Phosphorylation Deficiency 32 (COXPD32), a rare mitochondrial disorder within the Leigh syndrome spectrum (LSS), ranging from fatal in infancy to adult survival. The objective is to describe two new individuals with MRPS34-related disease and expand the clinical, genetic, and phenotypic spectrum of COXPD32. Clinical, radiological, biochemical, and molecular evaluations were conducted in two individuals with Leigh Syndrome (LS). Exome and genome sequencing identified presumed biallelic MRPS34 variants. A systematic review of all previously reported cases was performed to assess possible genotype-phenotype correlations (n = 11). Individual 1, who died in infancy with LS, was presumed compound heterozygous for a novel splice-site variant (c.364 + 2 T>C, p.(?)) and a nonsense variant (c.94C>T, p.(Gln32*)). Individual 2 survived into mid childhood and was homozygous for the hypomorphic variant c.322-10G>A, p.(?). Among 11 individuals, key features included developmental delay (100%), lactic acidosis (91%), brainstem lesions (91%), and metabolic acidosis (83%). Homozygosity for c.322-10G>A, p.(?) correlated with longer survival. MRPS34-related disease presents with multisystemic features and genotype-dependent severity. Accurate genetic diagnosis is essential for prognosis and therapeutic strategies.
    Keywords:  MRPS34; combined oxidative phosphorylation deficiency 32; genotype–phenotype correlation; hypomorphic splice variant; leigh syndrome spectrum; mitochondrial disease
    DOI:  https://doi.org/10.1002/jmd2.70089
  8. Nat Commun. 2026 Jun 12.
    Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.
    Angelica E Lang, Chris Stein, Roger Schultz, Catherine M Drerup.
      To maintain a functional mitochondrial population in a long-lived cell like a neuron, mitochondria must be continuously replenished through the process of mitochondrial biogenesis. Because most mitochondrial proteins are nuclear encoded, mitochondrial biogenesis requires communication between mitochondria and the nucleus. This can be a challenge in a large, compartmentalized cell like a neuron in which a significant portion of the mitochondrial population is in neuronal compartments far from the nucleus. Using in vivo assessments of mitochondrial biogenesis in zebrafish neurons, we determined that mitochondrial transport between distal axonal compartments and the cell body is required for sustained mitochondrial biogenesis. Estrogen-related receptor transcriptional activation links transport with nuclear expression of mitochondrial genes. Together, our data support a role for retrograde feedback between axonal mitochondria and the nucleus for regulation of mitochondrial biogenesis in neurons.
    DOI:  https://doi.org/10.1038/s41467-026-74127-4
  9. CNS Neurol Disord Drug Targets. 2026 Jun 08.
    Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
    Shalini Singh, Anisha Sharma, Ravi Kumar Rajan, Manodeep Chakraborty, Ananya Bhattacharjee.
       INTRODUCTION: Mitochondrial dysfunction plays a crucial role in the pathogenesis of Parkinson's disease (PD). PINK1-Parkin-mediated mitophagy is a quality-control system for mitochondria that protects neurons by getting rid of damaged mitochondria. The OMA1-DELE1-HRI axis has recently been recognized as a vital regulatory checkpoint that limits excessive mitophagy and prevents metabolic failure during mitochondrial stress. The aim of this review is to analyze the mechanistic interplay between the PINK1-Parkin pathway and the OMA1-DELE1-HRI signaling axis. This study aims to synthesize current research on the influence of the stress-response pathway on the initiation of mitophagy, maintenance of mitochondrial homeostasis, and neuronal survival in PD.
    METHODS: A comprehensive literature review was conducted of molecular, genetic, and pharmacological studies on OMA1, DELE1, and HRI. A thorough analysis of data from kinome-wide screening assays, genetic knockdown experiments, multi-omics profiling, and structural biology studies was performed to elucidate the regulatory interactions between HRI and PINK1 under mitochondrial stress conditions.
    RESULT: The OMA1-DELE1-HRI pathway stops PINK1 from being stable by controlling how mitochondria make proteins and how they respond to stress. This inhibition serves as a metabolic safeguard that regulates mitophagy levels, preventing harmful overactivation. HRI seems to change PINK1-dependent mitophagy while having little effect on other pathways that clear things at the same time. This suggests that HRI has different substrate preferences and signaling specificity.
    DISCUSSION: The OMA1-DELE1-HRI axis is an important negative regulator of mitophagy that PINK1 and Parkin mediate. It stops too much mitochondrial clearance and metabolic failure in Parkinson's disease. This mechanism preserves bioenergetic homeostasis and promotes neuronal survival, suggesting that HRI is a promising therapeutic target. Inhibitors like ISRIB or heme mimetics may selectively restore mitophagy, thereby enhancing neuroprotection and enabling precision therapies guided by biomarkers such as phosphorylated eIF2.
    CONCLUSION: The OMA1-DELE1-HRI axis is a distinctive regulatory mechanism for mitochondrial quality control, significantly impacting neuroprotection in Parkinson's disease. Understanding its dual role in controlling mitophagy and maintaining bioenergetic homeostasis opens new possibilities for targeted drug development. Subsequent research should focus on structural and pharmacological modifications of HRI to enhance mitophagy while preventing mitochondrial depletion.
    Keywords:  DELE1; HRI (heme-regulated inhibitor kinase); ISR (integrated stress response); OMA1; PINK1; Parkin; Parkinson’s Disease (PD).; mitophagy
    DOI:  https://doi.org/10.2174/0118715273469080260515103009
  10. JCI Insight. 2026 Jun 09. pii: e196134. [Epub ahead of print]
    Omega-3 fatty acid supplementation improves skeletal muscle mitochondrial function in a model of Barth syndrome.
    Katharina B Kuentzel, Ana Vranešević, Samuel Aj Trammell, Fabian Finger, Jesper F Havelund, Yvette L Schooneveldt, Ivan Bradić, Nicoline R Andersen, Anna S Hassing, Katja T Michler, Martin R Larsen, Zachary Gerhart-Hines, Steven M Claypool, Jonas T Treebak, Andreas M Fritzen, Matthew P Gillum, Steen Larsen, Nils Færgeman, Trisha J Grevengoed.
      The composition of mitochondrial membrane lipids is crucial to cellular respiration, as seen in Barth syndrome (BTHS), a rare disease affecting skeletal muscle, heart, and neutrophils. In BTHS, mutations in the tafazzin (TAZ) gene reduce remodeling of the mitochondrial phospholipid, cardiolipin, causing mitochondrial dysfunction in skeletal muscle and heart. Here, we investigated effects of altering polyunsaturated fatty acid content in cardiolipin using preclinical models of BTHS. In vitro, the absence of TAZ did not impair omega-3 fatty acid incorporation into cardiolipin and resulted in increased turnover of these acyl chains. To examine this in a functional model, we generated a muscle-specific knockout mouse of TAZ (TAZ MKO), which recapitulated the human phenotype in skeletal muscle. Supplementing the diet of TAZ MKO with fish-oil-derived omega-3 fatty acids prevented lean mass loss, improved mitochondrial respiration, altered mitochondrial structure, and revealed moderate improvements in the stress response. Surprisingly, no diet-induced changes to cardiolipin species were observed in the TAZ MKO, but other phospholipids were altered by both genotype and diet, revealing complex regulation and potential compensation. Overall, this work provides evidence that omega-3 fatty acid supplementation is beneficial in muscle lacking TAZ to improve quality of life when added to current BTHS treatments.
    Keywords:  Lipidomics; Metabolism; Mitochondria; Muscle biology
    DOI:  https://doi.org/10.1172/jci.insight.196134
  11. Mol Neurobiol. 2026 Jun 10. pii: 685. [Epub ahead of print]63(1):
    Mitochondrial Dysfunction as a Driver of Neurodegeneration in Parkinson's and Huntington's Disease: Molecular Insights and Emerging Interventions.
    Omkar Kumar Kuwar, Sarila Khan, Ayushi Maloo, Chetna Singh, Mansi Sharma, Kousik Maparu, Mamta Sachdeva Dhingra, Vipul Sharma.
      Mitochondrial dysfunction has emerged as a central contributor to the pathogenesis of major neurodegenerative disorders, such as Parkinson's and Huntington's disease. In Parkinson's disease, mitochondrial abnormalities are often linked to mutations in genes like PINK1 and Parkin, which regulate mitochondrial quality control, while α-synuclein aggregation further exacerbates mitochondrial damage. In Huntington's disease, mutant huntingtin protein impairs mitochondrial dynamics, transport, and ATP production, contributing to selective neuronal vulnerability. The convergence of mitochondrial impairments across both diseases highlights a common pathological axis that can be therapeutically targeted. This review critically examines the molecular underpinnings of mitochondrial dysfunction in PD and HD and explores emerging strategies to restore mitochondrial function. These include antioxidants, metabolic modulators, mitophagy activators, and gene therapy approaches. Despite promising preclinical findings, several translational challenges remain, underscoring the need for continued investigation. Understanding the shared and unique mitochondrial-related mechanisms in PD and HD will be essential for developing targeted, disease-modifying therapies that may improve outcomes and quality of life for affected individuals.
    Keywords:  Antioxidants; Huntington’s disease; Mitochondrial dysfunction; Neuroinflammation; Neuronal loss; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-026-05991-w
  12. Biochem J. 2026 Jul 08. 483(7): 1193-1220
    Mitophagy: an emerging therapeutic target in mitochondrial diseases.
    Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira.
      Mitophagy is a crucial autophagic process that degrades dysfunctional or unnecessary mitochondria, thereby maintaining cellular homeostasis. Mitophagy occurs through both basal mitophagy and stress-induced pathways, highly regulated by a complex network of proteins. In mitochondrial diseases, which are genetic disorders lacking effective treatments, mitophagy is often defective or insufficient. This permits the accumulation of dysfunctional mitochondria that negatively impact cell homeostasis. While some experimental therapeutic strategies have enhanced mitophagy in mitochondrial disorders by targeting broadly acting signaling pathways, such as mTORC1 inhibition or AMPK activation, pharmacological approaches directly targeting the mitophagy process remain underexplored in these disorders. Given the growing understanding of mitophagy regulation, targeting key proteins involved in this process may offer novel therapeutic opportunities for mitochondrial diseases. Here, we explore the molecular mechanisms of mitophagy, examining distinct pathways and regulatory checkpoints that might present potential therapeutic targets. Additionally, we review recent studies evaluating the effects of mitophagy modulation in mitochondrial diseases.
    Keywords:  autophagy; mitochondria; pathway; pharmacology; receptors; ubiquitins
    DOI:  https://doi.org/10.1042/BCJ20260161
  13. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00593-0. [Epub ahead of print]45(6): 117515
    STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Yong Wu, Xiang-Zheng Gao, Yichi Zhang, Guan-Lin He, He-Yu Ling, Hayden Weng Siong Tan, Yuxiong Guo, Chuang Wang, Haihe Wang, Evandro F Fang, Han-Ming Shen, Guang Lu.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an essential role in innate immunity. While recent studies have revealed its critical role in non-canonical autophagy independent of its immune function, its role in selective autophagy remains elusive. Here, we identify the cGAS-STING pathway as an upstream positive regulator of mitophagy. We demonstrate that activation of TANK-binding kinase 1 (TBK1) during mitophagy is strictly dependent on the cGAS-STING pathway. Mechanistically, TBK1 activation involves the mitochondrial recruitment of STING, which requires valosin-containing protein (VCP)/p97-mediated degradation of outer mitochondrial membrane proteins. Activated TBK1 then phosphorylates optineurin (OPTN), resulting in the efficient clearance of damaged mitochondria via the autophagosome-lysosome pathway. Disruption of the STING-OPTN axis impairs mitophagy, which switches cellular response from mitophagy to apoptosis. Our work thereby defines a non-canonical, pro-survival function of the cGAS-STING pathway in mitochondrial quality control.
    Keywords:  CP: cell biology; OPTN; PINK1; TBK1; VCP/p97; cGAS-STING; cell death; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117515
  14. Biochim Biophys Acta Mol Cell Res. 2026 Jun 09. pii: S0167-4889(26)00069-8. [Epub ahead of print] 120171
    Folding the message: mRNA structure as a regulatory layer of human mitochondrial gene expression.
    Ahram Ahn, Seungwoo Hong, Michele Brischigliaro, Flavia Fontanesi, Antoni Barrientos.
      Mammalian mitochondrial gene expression operates within an unusually compact genomic architecture in which most regulatory information must be encoded within or immediately adjacent to protein-coding sequences. In this context, mitochondrial mRNAs function not merely as templates for translation but as structured molecules whose folding landscape contributes to multiple stages of gene expression. Recent advances in chemical probing, mutational profiling, and mitoribosome profiling have begun to disclose the human mitochondrial mRNA structurome in its native organellar context, revealing a transcriptome that is broadly accessible yet punctuated by localized structural elements and alternative conformational states. These studies indicate that RNA structure contributes to translation initiation on leaderless transcripts, elongation kinetics, translational coupling across bicistronic junctions, and dynamic remodeling during membrane protein synthesis. They also highlight the role of RNA-binding proteins, including LRPPRC-SLIRP and related factors, in maintaining a translation-competent folding environment. In this review, we discuss the structural organization of mitochondrial mRNAs, the experimental approaches that enabled its analysis, and emerging mechanistic links between RNA folding, translational regulation, and respiratory chain biogenesis. We further discuss how alterations in mt-mRNA structure may represent an underappreciated determinant of mitochondrial disease and consider implications for future diagnostic and therapeutic strategies.
    Keywords:  Bicistronic transcripts; Mitochondrial RNA folding; Mitochondrial RNA processing; Mitochondrial RNA structurome; Mitochondrial gene expression; Mitochondrial translation
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120171
  15. Sci Rep. 2026 Jun 10.
    Effects of an indole chemical, mitochonic acid 5, in a mouse model of mitochondrial disease onset.
    Emi Ogasawara, Haruna Tani, Chitose Suzuki, Yuji Owada, Masaki Ogata, Naotada Ishihara, Takaaki Abe, Kazuto Nakada.
      This study tested the effects of mitochonic acid 5 (MA-5) using a mouse model of mitochondrial disease onset (mito-mice∆), with disease resulting from the accumulation of pathogenic mitochondrial DNA harboring a large deletion (∆mtDNA). Administration of MA-5 to mito-mice∆ inhibited the progression of clinical symptoms, such as low body weight and lactic acidosis. In the kidneys, MA-5 protected against mitochondrial respiration defects and subsequent renal failure, even when ∆mtDNA accumulated to > 80%. In the heart, MA-5 also resolved the mitochondrial respiration defects. Our findings suggested that administration of MA-5 would be effective in delaying the progression of some mitochondrial diseases caused by mutant mtDNA and especially in mitochondrial-mediated renal failure.
    Keywords:  Mitochondria; Mitochondrial DNA (mtDNA); Mitochondrial diseases; Mitochonic acid 5 (MA-5); Mouse model; Respiratory chain
    DOI:  https://doi.org/10.1038/s41598-026-57342-3
  16. CNS Neurol Disord Drug Targets. 2026 Jun 08.
    Mitochondrial Dysfunction in Parkinson's Disease: Diagnostic and Therapeutic Advances.
    Gang Wu, Xiao-Lin Dong, Rui Li, Fu-Rong Jin, Jing-Ting Lu, Lian-Bing Lin.
      Parkinson's Disease (PD) is a neurodegenerative disorder in which mitochondrial dysfunction plays a central role in pathogenesis. This review summarizes key mitochondrial abnormalities involved in PD, including respiratory chain impairment, dysregulation of mitochondrial dynamics, defective mitophagy, and mitochondrial DNA (mtDNA) damage. It further examines how these processes interact with α-synuclein (α-syn) pathology, contributing to increased vulnerability of dopaminergic neurons. In addition, current diagnostic approaches are transitioning from isolated biomarkers to an integrated Mitochondrial Health Index (MHI) for improved early detection. Finally, a critical appraisal of therapeutic interventions is presented, emphasizing the shift from monotherapies to multifaceted combination strategies. This review delineates a strategy for transformative PD therapies.
    Keywords:  Parkinson's disease; biomarkers; mitochondrial; neuroimaging; therapeutics strategies
    DOI:  https://doi.org/10.2174/0118715273454275260601070029
  17. Neuron. 2026 Jun 09. pii: S0896-6273(26)00386-7. [Epub ahead of print]
    Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
    Yongqing Liu, Yingzhi Ye, Minghua Fan, Henry Yi Cheng, Shuying Sun, Zhaozhu Qiu.
      Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer's disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5×FAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of cytidine/uridine monophosphate kinase 2 (Cmpk2), a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease β-amyloid burden, restore synaptic plasticity, and improve cognitive function in 5×FAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a potential therapeutic target for AD.
    Keywords:  Alzheimer’s disease; CMPK2; KAT7; cGAS-STING; microglia; mitochondrial DNA; neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuron.2026.05.015
  18. bioRxiv. 2026 Jun 07. pii: 2026.06.03.729837. [Epub ahead of print]
    Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
    Alexandra M Perez, Jason D Fivush, Bailey M Cordill, Nathan Ferguson, Yu Zhang, Allison T Mezzell, Ushodaya Mattam, Omar Chaudhry, Karleigh G Porter, Saanvi Maadaadi, Dina Secic, Megan Bischoff, Karthickeyan Chella Krishnan, Rhett Kovall, Tom Cunningham, Maria Czyzyk-Krzeska, Katherine E Vest.
      Differentiation of skeletal muscle is associated with increased mitochondrial biogenesis and reliance of oxidative phosphorylation (OXPHOS). The terminal enzyme complex in the electron transport chain, cytochrome c oxidase (COX), requires copper for its assembly and activity, and copper delivery to mitochondria is essential for OXPHOS. However, when mitochondrial copper becomes essential during skeletal myoblast differentiation is not known. Here, we show that genetic deficiency of the mitochondrial copper and phosphate carrier SLC25A3 induced prior to myoblast differentiation leads to the formation of smaller myotubes, but SLC25A3 deficiency induced in mature myotubes leads to cell death and detachment. Both phenotypes are recapitulated upon genetic knockdown of COX17, a critical assembly protein for both COX copper cofactors, or by chemical inhibition of COX. Importantly, myotube death caused by SLC25A3 deficiency is rescued by copper supplementation or expression of an SLC25A3 variant that transports copper but not phosphate. Taken together these data support a model wherein copper transport by SLC25A3 and copper delivery to COX is critical for survival in mature myotubes.
    DOI:  https://doi.org/10.64898/2026.06.03.729837
  19. Stem Cell Res. 2026 Jun 01. pii: S1873-5061(26)00118-2. [Epub ahead of print]94 104022
    Generation and characterization of the hiPSC line CSSi023-A (16154) from a patient with ADOA caused by an OPA1 variant.
    Angela Maria Giada Giovenale, Ilaria Ferrone, Silvia Tomaselli, Elisa Maria Turco, Martina Mazzoni, Barbara Torres, Paola Zanfardino, Edvige Vulcano, Daniela Ferrari, Devid Damiani, Filippo M Santorelli, Alessandro De Luca, Maria Pennuto, Angelo Luigi Vescovi, Vittoria Petruzzella, Jessica Diana Rosati.
      Autosomal Dominant Optic Atrophy plus syndrome (ADOA, OMIM #125250) is a mitochondrial optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs), leading to worsening visual impairment. The disease is caused by pathogenic variants in the Optic Atrophy 1 (OPA1) gene, a member of the guanosine triphosphatase (GTPase) family that plays a central role in mitochondrial fusion and fission, mitophagy regulation, and mitochondrial DNA (mtDNA) maintenance. To model this disorder, we generated and characterized a human induced pluripotent stem cell (hiPSC) line from primary fibroblasts obtained from a patient affected by ADOA syndrome.
    DOI:  https://doi.org/10.1016/j.scr.2026.104022
  20. Nat Commun. 2026 Jun 09. pii: 5072. [Epub ahead of print]17(1):
    CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
    Chengquan Huang, Yixue Zhang, Han Gao, Yuxin Song, Shunchang Hu, Chaoyue Sun, Shiwen Duan, Dongxiao Ma, Xiumei Jiang, Gang Liu.
      Mitochondrial proteostasis-maintaining mechanisms are crucial for protecting cells from the toxicity of misfolded protein accumulation. Although excessive stress is known to inactivate these mechanisms and thereby induce mitophagy in cancer cells, the detailed molecular mechanisms coordinating these mitochondrial quality control processes remain unclear. Herein, we identify CLPX, a mitochondrial protease subunit, as an iron-sulfur protein, which requires a [4Fe-4S] cluster to bind with CLPP to exert proteolysis function. Iron chelation impairs the assembly of the [4Fe-4S] cluster onto CLPX, thereby disrupting mitochondrial proteostasis maintenance and inducing mitophagy. Furthermore, cysteine deprivation caused by excessive reactive oxygen species accumulation hinders iron-sulfur cluster biosynthesis, thereby undermining CLPX function and inducing mitophagy. Our research elucidates an iron-sulfur cluster-dependent mechanism sustaining mitochondrial proteostasis.
    DOI:  https://doi.org/10.1038/s41467-026-74080-2
  21. J Cell Biol. 2026 Aug 03. pii: e202507174. [Epub ahead of print]225(8):
    Mitochondria limit coenzyme Q export under cholesterol biosynthetic stress.
    Marjana Ndoci, Sharanya Bhattacharya, Ishita Agrawal, Yvonne Hinze, Kathrin Lemke, Anna-Lena Schumacher, Esther Uijttewaal, Ulrich Elling, Steffen Lawo, Patrick Giavalisco, Thomas Langer, Soni Deshwal.
      Coenzyme Q (CoQ) is a hydrophobic lipid primarily synthesized in the mitochondria, though it is also present in non-mitochondrial membranes. However, the metabolic pathways that regulate intracellular CoQ distribution are unknown. This study identifies a key role for the mevalonate pathway in regulating CoQ distribution. The mevalonate pathway synthesizes isopentenyl pyrophosphate (IPP) as the precursor metabolite for both CoQ and cholesterol. We show that CoQ synthesis remains stable regardless of whether the mevalonate pathway is upregulated or downregulated. Upregulation of HMG-CoA reductase (HMGCR), indicative of increased mevalonate flux, enhances cholesterol ester synthesis without altering CoQ levels. When the pathway is downregulated, cholesterol synthesis declines, yet mitochondrial CoQ levels are preserved. Under these limiting conditions, mitochondria reduce CoQ export to maintain their internal CoQ pool. While this adaptation sustains mitochondrial respiration, it diminishes extramitochondrial CoQ availability and sensitizes cells to ferroptosis. These findings uncover a mitochondria-driven mechanism that preserves respiratory function by prioritizing CoQ retention during metabolic stress.
    DOI:  https://doi.org/10.1083/jcb.202507174
  22. Nat Commun. 2026 Jun 10.
    A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
    Sarin Segev-Nakar, Itay Koren.
      Peroxisomes are essential organelles involved in lipid and reactive oxygen species metabolism, and their function requires proper targeting of peroxisomal membrane proteins (PMPs). When peroxisome biogenesis fails, as occurs in peroxisome biogenesis disorders, PMP levels decrease markedly, yet the underlying mechanisms remain unclear. Here, using quantitative proteomics and transcriptomics in peroxisome-deficient cells, we observe widespread post-transcriptional downregulation of PMPs driven by increased protein turnover via ubiquitination and proteasomal degradation. An unbiased CRISPR screen uncovers a mitochondrial quality control axis. PMPs that fail to reach their native peroxisomal destination are rerouted to mitochondria, where the mitochondrial outer membrane E3 ligases MUL1 and MARCH5 act redundantly to promote their degradation. Importantly, the transmembrane domain of PMPs is sufficient to drive their mitochondrial turnover. Functionally, simultaneous loss of peroxisomes and mitochondrial E3 ligases severely impairs cell proliferation, underscoring the essential role of this pathway. Together, these findings provide insight into the pathology of organelle dysfunction and reveal an inter-organelle quality control axis in which mitochondria act as a surveillance hub to clear PMPs and maintain cellular proteostasis when peroxisomes are absent.
    DOI:  https://doi.org/10.1038/s41467-026-74117-6
  23. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2611096123
    Testicular origin of epigenetic inheritance independent of sperm mitochondrial DNA and epididymal exposure.
    Zhuqing Wang, Yasuhiro Yamauchi, Sheng Chen, Huili Zheng, Monika A Ward, Wei Yan.
      Paternal epigenetic inheritance remains mechanistically unresolved. Recent studies propose that environmental exposures induce mitochondrial DNA (mtDNA)-dependent transcription in sperm during epididymal transit, altering small RNA content and offspring phenotypes. Here, we show that mature murine sperm are effectively devoid of mtDNA, precluding mtDNA-dependent transcription, and that sperm-borne mitochondrial RNAs originate during spermatogenesis. Testicular sperm transmitted diet-induced metabolic traits as efficiently as, and in most cohorts more efficiently than, epididymal sperm. These findings establish testicular inheritance independent of sperm mtDNA transcription and epididymal exposure.
    Keywords:  epigenetic inheritance; mitochondrial DNA; small RNA; sperm epigenome
    DOI:  https://doi.org/10.1073/pnas.2611096123
  24. Brain Commun. 2026 ;8(3): fcag178
    Expanding the landscape of tRNA pathogenic variants in mitochondrial DNA.
    Salvatore Loris Siragusa, Santino Blando, Claudio Fiorini, Alberto Pietro Pasti, Danara Ormanbekova, Francesco Casadei, Luca Morandi, Elena Pegoraro, Rocco Liguori, Valerio Carelli, Chiara La Morgia, Leonardo Caporali, Maria Lucia Valentino.
      We present a comprehensive molecular and histopathological characterization of nine patients with mitochondrial myopathy, predominantly manifesting progressive external ophthalmoplegia (PEO), associated with heteroplasmic variants in mitochondrial tRNA genes (mt-tRNA). Among the ten variants identified, four were novel and previously unreported in MITOMAP. Using laser capture microdissection and deep next-generation sequencing, we quantified heteroplasmy at the single-muscle-fibre level, demonstrating that cytochrome c oxidase (COX)-deficient fibres consistently reached near-homoplasmic mutant loads, whereas COX-positive fibres remained heteroplasmic with lower variant fractions. These findings firmly support the pathogenic role of all variants. Furthermore, digital droplet PCR revealed an increased mitochondrial DNA (mtDNA) content in COX-deficient fibres, indicating compensatory mitochondrial biogenesis. Of particular note, one patient harboured two novel heteroplasmic variants, m.10009G > A and m.15961G > A, for which long-read sequencing identified mitogenomes carrying both variants also in cis, suggesting the occurrence of mtDNA recombination in human tissue. By applying refined American College of Medical Genetics and Genomics (ACMG) criteria specific for mt-tRNA, we reclassified several variants as pathogenic or likely pathogenic, including three previously deemed of uncertain significance. Overall, our integrative approach-combining single-fibre molecular dissection, mtDNA quantification, and long-read sequencing-broadens the mutational spectrum of pathogenic mt-tRNA variants, highlights the diagnostic value of single-fibre analyses in confirming pathogenicity, and provides new insights into mitochondrial genome dynamics and compensatory responses in mitochondrial disease.
    Keywords:  mitochondrial DNA; mitochondrial myopathy; mt-tRNA variant; mtDNA recombination; single muscle fibre microdissection
    DOI:  https://doi.org/10.1093/braincomms/fcag178
  25. Circulation. 2026 Jun 10.
    Loss of STMP1 Perturbs Mitochondrial Cristae and Drives Cellular Inflammation and Heart Failure.
    Francesco Paolo Ruberto, Chang Jie Mick Lee, Matthew Ackers-Johnson, Pooja Sridharan, Vartika Khanchandani, Lik Hang Wu, Ling Xuan Goh, Tuan Danh Anh Luu, Leroy Sivappiragasam Pakkiri, Isabelle Bonne, Thong Beng Lu, Daniel J Buss, Tell Lovelace, Vivek Subramanian, Erielle Villanueva, Yang Hu, Prasanna Vidyasekar, Rijan Gurung, Jie Min Lee, Wai Khang Yong, Zhe Li, Dennis Kappei, Lena Ho, Chester Lee Drum, Roger S Y Foo.
       BACKGROUND: Heart failure is a leading cause of morbidity and mortality worldwide, particularly among the growing elderly population. In degenerative aging and autoimmune diseases, the cytoplasmic leak of mitochondrial DNA, resulting from mitochondrial cristae compromise, triggers persistent low-grade cellular inflammation through activation of the cGAS (cyclic GMP [guanosine monophosphate]-AMP [adenosine monophosphate] synthase)-STING (stimulator of interferon genes) pathway and the IFN-I (type I interferon) response. However, how and whether mitochondrial architectural components and cardiomyocyte inflammation drive cardiac aging and failure are not yet well understood.
    METHODS: We investigated the function of STMP1 (short transmembrane mitochondrial protein 1), a 47-amino acid nuclear-encoded mitochondrial-localized peptide featuring a distinctive GxxxGxxxG glycine zipper domain. A mouse with cardiomyocyte-specific knockout of Stmp1 (Stmp1-KO) was generated to investigate its role in cardiac function. We profiled the transcriptome, proteome, and metabolome of Stmp1-KO hearts to determine its functional mechanism of action. Electron microscopy was used to assess the impact of STMP1 depletion and functional rescue after adeno-associated virus 9-mediated gene restoration in the Stmp1-KO mouse.
    RESULTS: STMP1 is downregulated specifically in cardiomyocytes, and not other cardiac cell types, in aged mice and humans. Genetic loss of Stmp1 in cardiomyocytes resulted in heart failure in vivo. STMP1 interacts with components of the cristae organizing complexes MICOS (mitochondrial contact site and cristae organizing complex) and SAM (sorting and assembly machinery). Consequent to Stmp1 loss, mitochondrial cristae were destabilized, mitochondrial DNA was mislocalized to the cytosol, and the cGAS-STING pathway was activated, with ensuing cellular inflammation and cardiomyocyte cell death. Restoration of wild-type Stmp1 or STING inhibition significantly rescued cardiac function in vivo.
    CONCLUSION: Our work reveals a mechanism connecting the micropeptide STMP1 to mitochondrial cristae architecture and cardiomyocyte cellular inflammation, both of which are present as potential drivers of heart failure and cardiac aging.
    Keywords:  heart failure; inflammation; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.073677
  26. Curr Neuropharmacol. 2026 Jun 08.
    Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
    Katerina Kitopoulou, Antonis Roussos, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.
      Ageing and neurodegeneration are characterized by the progressive breakdown of organellar communication between mitochondria, the endoplasmic reticulum (ER), and lysosomes. Recent findings underline mitophagy as a central modulator of this interconnected network. Impaired mitophagy induces ER fragmentation, lysosomal dysfunction, imbalanced mitochondrial dynamics, and deregulation of calcium homeostasis, suggesting that mitochondrial turnover is essential for the maintenance of global organellar architecture. Conversely, restoring mitophagy re-establishes structural integrity and functional coordination across subcellular compartments. Notably, Urolithin A (UA) rejuvenates inter-organelle crosstalk through a defined calcium-dependent mechanism. UA promotes ER-derived calcium release via ITR-1/ITPR/InsP3R, EMC-3/EMC3, and TMCO-1/TMCO1, and enhances calcium uptake into mitochondria through MCU-1/MCU. This calcium flux activates DRP-1/DRP1-mediated mitochondrial fission, facilitating mi-tophagy initiation. In parallel, calcium-dependent activation of the UNC-43/CaMKII-SKN-1/Nrf2 axis stimulates mitochondrial biogenesis and metabolic adaptation. Furthermore, UA increases ER-mitochondrial contact sites (MAMs) and restores lysosomal activity, thereby re-establishing functional inter-organellar communication in nematodes and mammalian cells. These findings establish mitophagy as a central node of cellular and tissue homeostasis, acting through the stabilization of the organellar communication network to promote healthspan and lifespan while highlighting the need for future studies to validate these mechanisms across human tissues and disease-relevant cellular contexts.
    Keywords:  Ageing; ER; MAMs; lysosome; mitochondria; mitophagy; neurodegeneration; urolithin A.
    DOI:  https://doi.org/10.2174/011570159X473929260605103158
  27. Autophagy. 2026 Jun 13.
    STING1 senses mitochondrial damage to promote mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Hayden Weng Siong Tan, Han-Ming Shen, Guang Lu.
      The cGAS-STING1 pathway is essential for innate immunity, while its functions beyond immune activation have emerged as a key research topic. Recent studies have revealed the non-canonical roles of this pathway in autophagy. However, whether it participates in organelle quality control through selective autophagy processes such as mitophagy remains largely unexplored. In our study, we identify the cGAS-STING1 pathway as an essential upstream regulator of PINK1-PRKN-dependent mitophagy. We demonstrate that upon mitochondrial damage, STING1 is recruited to damaged mitochondria in a process requiring PINK1- and VCP/p97-mediated degradation of outer mitochondrial membrane proteins. STING1 at damaged mitochondria then activates TBK1, which phosphorylates the mitophagy receptor OPTN at Ser177, enhancing its recruitment to damaged mitochondria and driving efficient mitophagy. Disruption of the STING1-TBK1-OPTN axis impairs mitophagy and shifts the cellular response from pro-survival mitophagy to apoptosis. Our findings therefore uncover a non-canonical, pro-survival function of the cGAS-STING1 pathway in mitophagy, extending its role beyond innate immunity to the regulation of selective autophagy and cell fate decisions. Abbreviations: BafA1: bafilomycin A1; cGAS: cyclic GMP‑AMP synthase; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; NAC: N-Acetylcysteine; Nec-1: Necrostatin-1; OMM: outer mitochondrial membrane; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; VCP/p97: valosin containing protein; Z-VAD-FMK: benzyloxycarbony (Cbz)-l-ValAla-Asp (OMe)-fluoromethylketone.
    Keywords:  Cell death; OPTN; PINK1-PRKN-dependent mitophagy; cGAS-STING1 pathway; innate immunity; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2689463
  28. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2534946123
    Expression of four mitochondrial tRNAs from only two loci.
    Jessica M Warren, Kasavajhala V S K Prasad, Anistynn M Mendez, Stephanie Temnyk, John P McCutcheon.
      Transfer RNAs (tRNAs) are among the few genes retained in animal mitochondrial genomes after more than a billion years of gene loss. These ancient bacterial vestiges are often structurally aberrant and less stable than their bacterial or cytosolic tRNA counterparts. In some lineages, mitochondrial tRNAs (mt-tRNAs) have become so truncated that the loss of one or both arms has expanded our understanding of what constitutes a functional tRNA. Here, we report another radical departure from canonical tRNA gene architecture: two overlapping tRNAs produced from opposite strands of the same locus. These "mirror" tRNA pairs eliminate the need to retain separate loci for all tRNA genes, as a single locus can produce tRNAs to decode two different amino acids. We show that these mirror tRNAs are aminoacylated and demonstrate their presence in mitoribosomes. Furthermore, mirror tRNAs display strand-specific patterns of nucleotide modification and RNA editing, reflecting specific posttranscriptional maturation that depends on transcriptional orientation. This demonstration of functional, bidirectional tRNA expression reveals an unexpected strategy by which mitochondrial genomes maintain a complete set of tRNAs in the face of unrelenting gene loss. The presence of mirror tRNAs has broad implications for the evolution of tRNA-interacting enzymes, mitochondrial biology, and even the origins of the protein synthesis machinery itself.
    Keywords:  bidirectional transcription; mitochondrial genome evolution; mitochondrial tRNAs
    DOI:  https://doi.org/10.1073/pnas.2534946123
  29. J Biol Chem. 2026 Jun 12. pii: S0021-9258(26)02116-2. [Epub ahead of print] 113244
    Mitochondrial permeability transition in redox homeostasis and ferroptosis.
    Lishu Guo.
      Mitochondria are major sources of intracellular reactive oxygen species (ROS), and act as central signaling hubs in maintaining homeostasis of cellular oxidative states. Mitochondrial permeability transition (MPT) is coordinately mediated by mitochondrial outer membrane permeabilization (MOMP) and opening of the permeability transition pore (PTP). MPT is highly sensitive to ROS, and serves as a critical checkpoint in redox balances and cell death. This review will summarize the regulatory systems of mitochondrial and intracellular redox homeostasis, as well as the recent advances in understanding of MPT regulatory mechanisms. Furthermore, this review highlights the functional roles of MPT in redox homeostasis and ferroptosis, a form of iron-dependent, lipid peroxidation-driven cell death. The PTP is a critical molecular switch, which can convert from a defender against mitochondrial redox stress and cell death processes, including specifically iron-dependent, lipid peroxidation-driven cell death, known as ferroptosis, into a ROS amplifier and cell death promoter depending on its open states. MOMP causes the uncoupling of the mitochondrial respiratory chain, and increases ROS production, leading to oxidative stress. The most recent work suggests that the interplay between MTCH2 and F-ATP synthase coordinates MOMP and the PTP opening to mediate the occurrence of MPT. This review provides insight on molecular switches that regulate MPT, determining redox state and cell death.
    Keywords:  ferroptosis; mitochondria; mitochondrial permeability transition; redox homeostasis; the permeability transition pore
    DOI:  https://doi.org/10.1016/j.jbc.2026.113244
  30. J Diabetes Metab Disord. 2026 Jun;25(1): 154
    Prevalence and treatment of mitochondrial diabetes in Southwest Finland.
    Nelli Rindell, Heidi Immonen, Mika H Martikainen.
       Purpose: Diabetes mellitus (DM) is a common manifestation of mitochondrial disease, typically associated with the mitochondrial DNA (mtDNA) variant m.3243A>G. We investigated the clinical features, treatment, and epidemiology of mitochondrial DM in the region of Southwest Finland.
    Methods: Electronic medical records at Turku University Hospital were searched for patients assigned ICD-10 codes E13.0-E13.9 during 2000-2022. Among 1004 screened individuals, nine patients with genetically confirmed mitochondrial diabetes were identified. Eight additional genetically confirmed patients were included from an ongoing mitochondrial disease research project, resulting in a cohort of 17 patients. The clinical characteristics and DM treatment of the patients were obtained from medical records.
    Results: We identified 17 patients with mitochondrial DM. Mean age at diagnosis of DM was 35 years (range 11 to 60 years). Most patients with mitochondrial DM had hearing impairment (14/17). Insulin treatment was typically initiated 3.5 years after the diagnosis of DM. Only six (35%) patients had HbA1c below 7.0% (53 mmol/mol). The prevalence of mitochondrial DM in the region of Southwest Finland in the end of 2022 was 2.7/100,000 and annual incidence during the study period 0.14/100,000.
    Conclusions: The onset of non-autoimmune diabetes in young adult age, particularly when associated with hearing impairment, suggests possible mitochondrial DM. Recognition of mitochondrial diabetes is essential for optimal management and complication prevention.
    Keywords:  Diabetes; Gene variant; Mitochondrial diabetes; Mitochondrial disease; Type 1 diabetes; Type 2 diabetes
    DOI:  https://doi.org/10.1007/s40200-026-01964-x
  31. Mitochondrion. 2026 Jun 06. pii: S1567-7249(26)00073-5. [Epub ahead of print]91 102183
    TTC19 and FMNL2 gene variants in a pediatric case of mitochondrial disorder with renal tubular acidosis.
    Prince Jacob, Sekar Deepha, Akhila Vasanth Hassan, Shilpa Rao, Rashmi Santhoshkumar, Kanika Vasudeva, Siddharth Kapahtia, Meenakshi Sharma, Bevinahalli Nanjegowda Nandeesh, Madhu Nagappa, Periyasamy Govindaraj.
      Mitochondrial complex III deficiency caused by pathogenic variants in TTC19 is a heterogeneous disorder typically presenting with progressive neurological involvement in late childhood. Early-onset of disease with predominant renal manifestations are uncommon and may complicate diagnosis. We report a child presenting with developmental delay, failure to thrive, lactic acidosis, and distal renal tubular acidosis (dRTA), raising suspicion of an underlying mitochondrial disorder. Whole exome sequencing (WES) analysis identified a homozygous intron-exon boundary deletion of 31 bp (c.463-19_474del) in TTC19 predicted to disrupt splicing, with functional evidence demonstrating aberrant transcript formation, reduced gene expression, and mitochondrial dysfunction in patient-derived fibroblasts. Based on the biochemical findings, re-analysis of exome data revealed a novel homozygous canonical splice-site variant (c.783-1G>A) in FMNL2. The splicing assay showed the skipping of exon 9, and reduced expression in the fibroblasts. This case expands the clinical spectrum of TTC19-related mitochondrial complex III deficiency with early-onset renal tubular acidosis. While TTC19 is the most plausible primary disease-causing gene, the functional disruption of FMNL2 suggests a potential contributory role or association with the renal phenotype. Hence, these findings highlight the importance of genomic re-analysis along with functional studies in resolving complex multisystem disorders.
    Keywords:  Complex III; FMNL2; Mitochondrial disorder; Renal tubular acidosis; TTC19
    DOI:  https://doi.org/10.1016/j.mito.2026.102183
  32. J Am Chem Soc. 2026 Jun 09.
    Tracking Gene Expression of Single Mitochondria in Live Neurons Using Nanotweezers.
    Annie Sahota, Binoy Paulose Nadappuram, Siân C Allerton, Flavie Lesept, Jack H Howden, Suzanne Claxton, Yaxian Liu, Francesco A Aprile, Josef T Kittler, Michael J Devine, Aleksandar P Ivanov, Joshua B Edel.
      Neurons are highly polarized cells that depend on mitochondria for energy and signaling homeostasis. Importantly, energy and signaling requirements vary considerably across individual neurons both spatially and temporally. Therefore, to fully understand neuronal mitochondria, methods are needed to analyze mitochondria in live cells over time. The nanotweezer, a minimally invasive single-cell sampling technique, enables precise extraction of individual mitochondria from defined subcellular locations. Here, we combine single-mitochondrial extraction from live neurons with targeted mitochondrial gene expression tracking and mtDNA profiling to develop a platform for live-cell single-mitochondrion tracking and analysis. By tracking the expression of specific mitochondrially encoded genes in the same neurons over time, we reveal preliminary data showing a downregulation of mitochondrial genes MT-ND1 and MT-ATP6 following exposure to α-synuclein aggregates, independent of the proximity of the aggregates to the sampled mitochondria. Our approach provides a proof-of-concept for precise, temporal measurements of mitochondrial composition and targeted gene expression in vitro at single-organelle resolution, opening opportunities for single-cell and single-organelle studies of neuronal mitochondrial heterogeneity and its perturbation in models of neurodegeneration.
    DOI:  https://doi.org/10.1021/jacs.6c02802
  33. bioRxiv. 2026 Jun 03. pii: 2026.05.30.724257. [Epub ahead of print]
    Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling.
    Iuliia Karavaeva, Astrid Linde Basse, Samuel A J Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F Havelund, Marie Sophie Isidor, Hannah J Richter, Sabina Chubanava, Yann Deleye, Zafir Kaiser, Yachen Shen, Ditte Neess, Frederike Sass, Fabian Finger, Lidia Argemi Muntadas, David Tandio, Tao Ma, Elahu Gosney Sustarsic, Hannes Embring, Cecilie Kynding Kristensen, Rebecca L McIntyre, Genesee J Martinez, Anna Sofie Husted, Matthew J Emmett, Zachary A Kipp, Mikkel Frost, Mark P Jedrychowski, Michel van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W McGarrah, Kaja Plucinska, Mohit K Midha, Andreas Prokesch, Paul Cohen, James G Granneman, Patrick Seale, Riekelt H Houtkooper, Jacob B Hansen, Steven P Gygi, Thue W Schwartz, Matthew Paul Gillum, Terry D Hinds, Raymond Edward Soccio, Phillip J White, Edmund R S Kunji, Thomas Moritz, Jonas T Treebak, Susanne Mandrup, Brice Emanuelli, Lawrence Kazak, Nils J Færgeman, Mitchell A Lazar, Zachary Gerhart-Hines.
      Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature. Yet how these diverse signals are molecularly integrated remains unknown. Here we show that clock, diet, and temperature cues converge on the orphan mitochondrial transporter, SLC25A34, to orchestrate thermogenic cycling of lipid synthesis and oxidation. During sleep, the clock suppresses Slc25a34 transcription through REV-ERBα. Waking, lipid-rich diets, or cold exposure abolish this repression, allowing lipolytic signals to stimulate Slc25a34 expression via PPARα. SLC25A34 then imports oxaloacetate into mitochondria to accelerate the export of substrates used for acetyl-CoA production in the cytosol. This feeds into cytosolic lipid synthesis and transcriptional induction of mitochondrial biogenesis, which collectively promote mitochondrial lipid oxidation. Thus, SLC25A34 confers circadian, dietary, and environmental control of thermogenic metabolism through interorganellar lipid cycling.
    DOI:  https://doi.org/10.64898/2026.05.30.724257
  34. Free Radic Biol Med. 2026 Jun 11. pii: S0891-5849(26)00877-4. [Epub ahead of print]
    Aberrant TIMM8B alternative splicing compromises mitochondrial respiratory chain integrity and redox homeostasis.
    Sang-Jin Lee, Sangsoo Lee, Kee K Kim, Jin-Young Lee.
      Mitochondrial redox homeostasis depends on respiratory chain integrity, but whether environmental stress alters this system through alternative splicing remains poorly understood. Here, we identify aberrant TIMM8B alternative splicing as a post-transcriptional mechanism that compromises mitochondrial respiratory chain function and redox homeostasis. Using perfluoroundecanoic acid (PFUnDA) as an environmental stressor, transcriptomic profiling of HaCaT cells revealed suppression of mitochondrial bioenergetic programs, including oxidative phosphorylation, the tricarboxylic acid cycle, mitochondrial central dogma, and protein import. Splicing analysis identified TIMM8B exon 1a inclusion as a prominent stress-associated event, which was validated by RT-PCR. The exon 1a-included isoform showed reduced transcript stability and markedly reduced detectable protein abundance. Functionally, PFUnDA impaired mitochondrial respiration in HaCaT and HDF cells. TIMM8B isoform-function analysis further showed that the exon 1a-included isoform failed to preserve ETC activity, mitochondrial membrane potential, and MitoSOX-associated redox signal, whereas the exon 1a-excluded isoform partially restored these mitochondrial readouts toward basal levels. In zebrafish, PFUnDA reduced mitochondrial fluorescence and induced NAC-sensitive oxidant accumulation. Collectively, these findings identify aberrant TIMM8B alternative splicing as a mechanism linking environmental stress to mitochondrial respiratory chain dysfunction and redox dysregulation.
    Keywords:  Alternative splicing; Electron transport chain; Mitochondrial redox homeostasis; PFAS; PFUnDA; TIMM8B; Zebrafish
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.022
  35. FASEB J. 2026 Jun 30. 40(12): e71972
    eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in Skeletal Muscle.
    Yingying Lin, Jianing Xia, Man Li, Junhao Zhang, Yonghao Mu, Lenian Ling, Minghao Lu, Jiahuan Wang, Kexin Liao, Yefeng Cai.
      Skeletal muscle adaptation to physiological and pathological stressors requires precise coordination of protein synthesis and mitochondrial function. While the roles of canonical translation regulators such as eIF2α and 4E-BP1 in exercise-induced protein synthesis modulation are well established, the contribution of eIF3, the largest eukaryotic initiation factor complex, to muscle stress responses remains poorly understood. Eukaryotic initiation factor 3 (eIF3) regulates mRNA translation and mitochondrial homeostasis, yet how individual eIF3 subunits respond to distinct modes of skeletal muscle stress remains unclear. Here, we systematically characterized eIF3 dynamics and mitochondrial function using two complementary mouse models: acute exhaustive training and dexamethasone (DEX)-induced atrophy. Integrated proteomic, transcriptional, and imaging analyses revealed a biphasic regulatory pattern: DEX treatment caused broad downregulation of eIF3a, eIF3b, eIF3c, eIF3g, and eIF3l, concurrent with comprehensive mitochondrial electron transport chain (ETC) impairment, while acute training selectively decreased eIF3d, eIF3e, eIF3g, and eIF3l but uniquely preserved eIF3f expression alongside adaptive ETC remodeling. This differential response pattern distinguishes eIF3 from other stress-responsive translation factors, as eIF2α phosphorylation typically causes global translation suppression whereas eIF3 dysregulation selectively impairs mitochondrial protein synthesis. Notably, eIF3f preservation under both conditions suggests a compensatory mechanism to maintain translational capacity. siRNA-mediated knockdown of eIF3e or eIF3f in C2C12 myotubes demonstrated their differential effects on mitochondrial protein expression and atrophy signaling, with eIF3f knockdown causing more severe mitochondrial protein suppression. Seahorse XF analysis confirmed that eIF3 subunit loss directly impairs mitochondrial oxygen consumption, while SUnSET assays demonstrated attenuated global protein synthesis upon eIF3e or eIF3f depletion. Furthermore, eIF3 knockdown suppressed mTORC1 signaling (p-mTOR, p-4EBP1, p-S6K, p-S6) and differentially modulated ubiquitin-proteasome activity without altering bulk autophagy. These findings establish eIF3 as a molecular integrator linking translational control to mitochondrial integrity in skeletal muscle physiology, positioning this complex as a potential therapeutic target for conditions ranging from exercise-induced adaptation to muscle wasting disorders.
    Keywords:  ETC complex; eIF3; mitochondria; muscle adaptation; skeletal muscle; translation regulation
    DOI:  https://doi.org/10.1096/fj.202600161R
  36. iScience. 2026 Jun 19. 29(6): 116092
    Sigma-1 receptor promotes glycolysis in neuronal systems by suppressing GRIM19.
    Simon Couly, Yuko Yasui, Ioannis Grammatikakis, Yuriko Kimura, Joshua J Hinkle, Juan L Gomez, Hsiang-En Wu, Ashish Lal, Michael Michaelides, Brandon K Harvey, Tsung-Ping Su.
      Sigma-1 receptor (S1R) is a Ca2+ sensitive, ligand-operated receptor chaperone protein present at the mitochondria-associated ER membrane. The relevance of S1R to glycolysis in neurons is not known. This study examines the impact of S1R on glycolysis, mitochondrial activity, and NAD+/NADH metabolism in wild-type and S1R knockout (S1R KO) Neuro2a (N2a) cells and mice. Both N2a cells and cortical neurons lacking S1R had reduced glycolytic activity, and increased mitochondria complex I protein GRIM19 (NDUFA13). Furthermore, we noted an increased NAD+/NADH ratio in S1R KO condition. PET-imaging revealed decreased [18F]fluorodeoxyglucose brain uptake in S1R KO mice. We observed that knocking-down GRIM19 rescued the glycolysis deficit in S1R KO condition. Altogether, these data show that S1R modulates glycolysis and NAD metabolism in neuronal systems. This insight into S1R function may expand the therapeutic potential of S1R ligands in conditions associated with impaired glycolysis and altered cellular NAD+/NADH ratios, such as aging and neurodegenerative diseases.
    Keywords:  molecular biology; neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.116092
  37. Neurobiol Dis. 2026 Jun 09. pii: S0969-9961(26)00222-6. [Epub ahead of print]227 107477
    Loss of astrocytic markers and impaired metabolic function in spinocerebellar ataxia type 7 patient-derived neural cultures.
    Linde F Bouwman, Ronald A M Buijsen, Linda M van der Graaf, Barry A Pepers, Bas J B Voesenek, Hailiang Mei, Bart P C van de Warrenburg, Willeke M C van Roon-Mom.
      Spinocerebellar ataxia type 7 (SCA7) is a rare neurodegenerative disorder caused by a CAG repeat expansion in the ATXN7 gene. This repeat expansion results in an abnormally long polyglutamine (PolyQ) tract in the Ataxin-7 protein. This ultimately leads to the degeneration of most notably Purkinje cells and retinal cells. Because no treatment exist that can halt or slow disease progression, there is a critical need for patient-specific disease models to uncover new pathogenic mechanisms and enable therapeutic testing. In this study, induced human pluripotent stem cells (hiPSCs) derived from healthy controls and individuals with SCA7 were differentiated into a mixed neural cell population consisting of neurons and astrocytes. Although control and SCA7 neurons appeared morphologically similar, SCA7-derived astrocytes exhibited a pronounced loss of the astrocyte-specific markers GFAP and S100B. Transcriptome analysis revealed substantial alterations in genes related to glial differentiation, cellular metabolism and oxygen handling, protein homeostasis, and neuronal differentiation and neuronal signalling. Mitochondrial stress assays further confirmed a mitochondrial phenotype in SCA7 neural cells. Together, these findings demonstrate that hiPSC-derived neural cells provide a robust platform that can be used for studying disease mechanisms and testing potential therapies for SCA7.
    Keywords:  Astrocytes; Disease modeling; Human induced pluripotent stem cell-derived neural cultures; Metabolic profiling; Neurodegeneration; Neurons; Spinocerebellar ataxia type 7; Transcriptome analysis
    DOI:  https://doi.org/10.1016/j.nbd.2026.107477
  38. Am J Physiol Renal Physiol. 2026 Jun 11.
    Disruption of Polycystin-1 Cleavage Impairs Mitochondrial Bioenergetics and Calcium Uptake in a Substrate-Dependent Manner.
    Andressa G Amaral, Julian D C Serna, Camille C Caldeira da Silva, Eliene S Costa, Luiz F Onuchic, Alicia J Kowaltowski.
      Metabolic and mitochondrial alterations are central in the pathogenesis of Autosomal Dominant Polycystic Kidney Disease (ADPKD), since therapies targeting these alterations slow kidney disease progression in orthologous animal models. To investigate metabolic and mitochondrial defects in an animal model orthologous to ADPKD, we used male mice homozygous for a point variant in the GPS cleavage site of the polycystin-1 (Pkd1V/V) and evaluated oxygen consumption, Ca2+ uptake, and redox state in the mitochondrial fraction of Pkd1V/V kidneys and wild-type controls (WT). Our findings revealed mitochondrial heterogeneity in Pkd1V/V kidneys, with regions of preserved morphology alongside areas displaying swollen and disorganized mitochondria. Notably, preserved mitochondria were smaller, with either unchanged mitochondrial mass markers (TFAM, CYTC, mDNA/nDNA) or increased TOM20 levels compared to WT. Mitochondria isolated from Pkd1V/V kidneys showed reduction in oxygen consumption rates and calcium retention capacity in the presence of NADH-generating substrates, but not in the presence of succinate. Consistently, levels of specific proteins of complex I, III, and V were decreased, but not of complex II. Proteins involved in calcium homeostasis (VDAC1, MCU, MICU1, MICU2, and NCLX) were decreased in Pkd1V/V kidneys. No change in HRP-H2O2-mediated Amplex-red oxidation was observed in diseased mitochondria, and mitochondrial 4-HNE levels were unchanged, although increased in whole-kidney extracts. Together our results showed that cleaved PC1 plays a critical role in maintaining mitochondrial mass, integrity, and function. Given the orthologous nature of our animal model, the observed alterations may be applicable to human ADPKD.
    Keywords:  Autosomal Dominant Polycystic Kidney Disease; Calcium homeostasis; Mitochondrial bioenergetics; Oxidative stress; Polycystin-1 cleavage at GPS
    DOI:  https://doi.org/10.1152/ajprenal.00471.2025
  39. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2604082123
    Alpha-synuclein fibrils induce budding of mitochondrial-derived vesicles.
    Thomas Braun, Viviane Reber, Cinzia Tiberi, Andri Fränkl, Dhiman Ghosh, Roland Riek, Tetiana Serdiuk.
      α-synuclein (α-syn) aggregation is a hallmark of synucleinopathies, a class of neurodegenerative disorders such as Parkinson's disease (PD). Several lines of evidence indicate the involvement of mitochondria in the disease pathology. Despite extensive study, the link between α-syn aggregation and mechanisms of mitochondrial toxicity remains not fully understood. Using high-resolution imaging with electron microscopy, we examined SH-SY5Y cells exposed to α-syn fibrils vs control cells with a focus on mitochondria. We found that upon exposure to α-syn fibrils, mitochondria cristae structure gets defects, and mitochondria enhance the budding of mitochondrial-derived vesicles (MDVs). MDV formation reflects an evolutionarily conserved mechanism reminiscent of bacterial outer membrane vesicle biogenesis. Structural proteomics analysis by mass spectrometry corroborates this microscopy observation by identifying changes in multiple proteins that regulate cristae structure, MDV formation, and trafficking. Our results suggest that α-syn may promote MDV generation, and support an important link between α-syn and mitochondria which will be important for future mechanistic studies. The processes we detected could be of interest for diagnostics and potential therapeutic interventions.
    DOI:  https://doi.org/10.1073/pnas.2604082123
  40. J Neurol. 2026 Jun 06. pii: 374. [Epub ahead of print]273(7):
    Distinct age-related pattern of mitochondrial somatic mutations across multiple sclerosis phenotypes.
    Federica Esposito, Kaalindi Misra, Francesca Doyle, Ferdinando Clarelli, Antonio De Simone, Antonino Giordano, Giulia Visentin, Elisabetta Mascia, Maria Assunta Rocca, Massimo Filippi, Melissa Sorosina.
       BACKGROUND: Mitochondrial dysfunction has been proposed as a contributor to neurodegeneration in multiple sclerosis (MS). While the accumulation of somatic mitochondrial DNA (mtDNA) mutations with age is well documented in other neurodegenerative conditions, its role in MS progression remains largely unexplored. The aim of this study was to investigate the association between age and somatic mtDNA mutation burden in MS patients and evaluate whether any difference exists according to disease course.
    METHODS: A total of 404 MS patients were recruited. Whole mtDNA was sequenced from blood-derived DNA using long-range PCR and the Illumina® Nextera XT kit. Somatic mutations were defined based on heteroplasmy levels between 1-5%. Linear regression models were used to assess the association between age and mutation rate.
    RESULTS: We observed a significant age-dependent increase in low-frequency non-synonymous mtDNA mutations in MS. Analyses stratified by disease course revealed that this effect was substantially driven by PPMS patients (n = 238, P = 2.71 × 10-3), while no association was seen in RRMS (n = 155, P = 0.35), suggesting course-specific mitochondrial trajectories. Furthermore, fast-progressing patients showed a positive linear relationship between age and mtDNA mutation rate (P = 0.017), while slow-progressing ones showed an opposite trend (test for interaction P = 0.013).
    CONCLUSIONS: These findings support the existence of a differential age-related accumulation of somatic mtDNA mutations detected in blood across MS courses.
    Keywords:  Aging; Mitochondrial DNA; Multiple sclerosis; Somatic mutations
    DOI:  https://doi.org/10.1007/s00415-026-13926-7
  41. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00075-0. [Epub ahead of print]208 29-53
    Quantitative high-content profiling of mitochondrial morphology with automated statistical analysis and integrated data visualization.
    My-Anne Hong, Sophie Charrasse, Richard E Frye, Abdel Aouacheria.
      High-content screening (HCS) is a powerful approach for rapidly and efficiently assessing the harmfulness of numerous compounds across a wide range of cultured cell types. We recently developed a fully automated, miniaturized HCS wet-plus-dry pipeline (MITOMATICS) which leverages mitochondrial morphology as a sensitive and dynamic biomarker of cellular health or damage. Mitochondria are indeed not only vital for energy production and homeostasis, but also serve as critical gatekeepers of apoptotic cell death. MITOMATICS incorporates a proprietary software tool (MitoRadar) designed in-house to perform fast, comprehensive and cost-effective analysis of mitochondrial morphology in live cells. Together, the pipeline and its associated big data analytics software provide a valuable framework for early detection of acute mitotoxic effects of chemicals agents or physical stressors. To illustrate this, we present here a complete protocol for quantifying the impact of the pesticide chlorpyrifos-methyl on mitochondrial morphology of human lung epithelial BEAS-2B cells. Our results show that chlorpyrifos-methyl, even as a single compound, induces profound disruptions in mitochondrial subcellular structure. Beyond this case study, MitoRadar opens up promising avenues for investigating mitotoxicity across diverse cell types and environmental exposures, paving the way for a new generation of cellular diagnostics that could be of interest to the cell death community.
    Keywords:  Automated morphometry; Computerized methods; Environmental toxicants; High-content screening; Image-based phenotyping; Live-cell imaging; Mitochondrial morphology; Mitotoxicity; Pesticides; Software
    DOI:  https://doi.org/10.1016/bs.mcb.2026.02.007
  42. JIMD Rep. 2026 Jul;67(4): e70103
    Heterozygous OGDH Variants Are Involved in Peripheral Neuropathy With Ataxia and Optical Atrophy.
    Liedewei Van de Vondel, Gyu S Lee, Jonathan De Winter, Satoshi Matsuzaki, Abigail Sandoval, Juan Felipe Ramirez, Alice Monticelli, Sukyeong Lee, Rita Horvath, Jan de Bleecker, Stephan Züchner, Kenneth M Humphries, Jonathan Baets, Wan Hee Yoon.
      2-oxyglutarate dehydrogenase (OGDH) encodes an E1 component of α-ketoglutarate dehydrogenase complex that plays a pivotal role in the Krebs cycle. Biallelic variants in OGDH have been reported to cause an early-onset neurodevelopmental and mitochondrial disorder. However, monoallelic OGDH variants have not been associated with human disease. Here, we identified de novo c.1909C>T (p.Arg637Trp) and heterozygous c.162T>G (p.Ser54Arg) variants in OGDH in unrelated individuals exhibiting late-onset neurological phenotypes, characterized by cerebellar ataxia, peripheral neuropathy and optic atrophy. In silico protein structure predictions suggest that the p.Arg637Trp mutation might influence protein function. To determine the functional effects of the OGDH variants in vivo, we generated Drosophila models harboring UAS-dOgdh (p.Arg639Trp) and UAS-dOgdh (p.Thr58Arg) mutations, homologous to the human variants. While the mutant OGDH expression did not lead to defects in development, it did lead to age-dependent locomotion defects. Further, we found that p.Arg639Trp mutant leads to defective OGDH activity, while p.Thr58Arg causes abnormal proteolytic cleavage and impaired mitochondrial import. These findings suggest that the variants act as dominant-negative and toxic gain-of-function mutations, respectively. Our data provide evidence that monoallelic OGDH variants are involved in late-onset neurological disease in humans.
    Keywords:  OGDH; ataxia; mitochondria; optical atrophy; peripheral neuropathy
    DOI:  https://doi.org/10.1002/jmd2.70103
  43. Nat Metab. 2026 Jun 11.
    Why machine learning fails at mass spectrometry for small molecules.
    Ling Min Serena Khoo, Regina Barzilay.
      
    DOI:  https://doi.org/10.1038/s42255-026-01544-6
  44. Stem Cell Reports. 2026 Jun 11. pii: S2213-6711(26)00162-1. [Epub ahead of print] 102951
    Electron transport chain complex I and mitochondrial fusion regulate ROS for differentiation in Drosophila neural stem cells.
    Rahul Kumar Verma, Atharva Bhingare, Dnyanesh Dubal, Richa Rikhy.
      Mitochondrial fusion and electron transport chain complex I are each essential for differentiation in Drosophila neuroblasts, but the mechanism by which they interact to mediate differentiation is unknown. We found that complex I subunit depletion did not affect type II neuroblast numbers but reduced their proliferation and decreased their lineage cells. Complex I depletion decreased the mitochondrial membrane potential and cristae numbers, increased fragmentation and ROS, and inhibited Notch signaling in lineage cells. Similarly, antioxidant enzyme depletion increased ROS and reduced lineage cells. Both complex I and antioxidant proteins promoted the G1/S transition and nuclear cyclin E levels. Additional mitochondrial fusion via Drp1 mutants restored ROS levels, proliferation, and differentiation defects in complex I and antioxidant protein-depleted neuroblasts. Overexpression of antioxidant proteins and an increase in Notch signaling alleviated ROS and the complex I depletion-driven defect in neuroblast proliferation and differentiation. Complex I and mitochondrial fusion together restrict ROS to support neuroblast proliferation and differentiation.
    Keywords:  Drosophila; Drp1; Notch; complex I; differentiation; mitochondria; mitochondrial fragmentation; mitochondrial fusion; neural stem cells; neuroblasts
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102951
  45. Neurosci Bull. 2026 Jun 09.
    Mitochondrial Transfer from Glia to Neurons: A Novel Protective Mechanism Against Peripheral Neuropathy.
    Xiao-Wen Meng, Yong-Jing Gao.
      
    DOI:  https://doi.org/10.1007/s12264-026-01659-6
  46. Front Synaptic Neurosci. 2026 ;18 1760254
    Synaptosomes isolated from cryopreserved MND motor cortex reveal altered calcium handling and reduced complex IV-linked respiration.
    Sean D Morrison, Lotten Ragnarsson, Sarah O Cook, Joseph A Rothnagel, Ernst Wolvetang, Bahaa Al-Mhanawi, Mohammed R Shaker, Thomas Robertson, Peter R Dodd, Peter G Noakes.
      Motor neuron disease (MND) is marked by progressive neurodegeneration in which presynaptic Ca2+-handling and mitochondrial metabolism are thought to be vulnerable, but direct functional studies in human brain are scarce because most material is frozen long-term. Here, we show that synaptosomes isolated from paired fresh and experimentally frozen mouse cortex, and from cryopreserved human motor cortex, retain recognisable synaptosome ultrastructural features, synaptic proteome enrichment, and depolarisation-evoked Ca2+-mobilisation. K+ and veratridine elicited robust, pharmacologically suppressible Ca2+ influx across preparations, and response amplitudes in human samples varied by region but did not correlate with donor age, post-mortem interval (PMI), or years in storage. Synaptosomes from neuropathologically confirmed MND motor cortex and hSOD1G93A mouse cortex showed significantly greater depolarisation-evoked Ca2+ entry than their respective controls, suggesting that increased presynaptic Ca2+ influx is shared across our human MND cohort and the hSOD1G93A mouse model. Using synaptosome preparations from MND and control motor cortices in Seahorse respiratory assays, we found that Complex IV-driven oxygen consumption (TMPD/ascorbate-evoked and azide-sensitive) was reduced in MND synaptosomes, whereas donor-matched free-mitochondrial fractions showed no group difference, supporting a Complex IV defect detectable in the synaptosome-enriched fraction within this cohort. By defining protein-to-OCR relationships for both fractions, we provide practical parameters for applying these assays to archived human cohorts. Together, these data suggest that archived cryopreserved human brain tissues can support informative synaptosome Ca2+ and bioenergetic readouts, and that synaptosome-enriched preparations may reveal disease-relevant presynaptic phenotypes in MND that are not evident in donor-matched bulk mitochondrial isolates.
    Keywords:  complex IV; human post-mortem brain; mitochondria; motor cortex; motor neuron disease; neurodegeneration; respiration; synaptosomes
    DOI:  https://doi.org/10.3389/fnsyn.2026.1760254
  47. Free Radic Biol Med. 2026 Jun 11. pii: S0891-5849(26)00876-2. [Epub ahead of print]
    SIRT3 regulates PRDX3 acetylation to support mitochondrial peroxide detoxification and limit oxidative stress-associated ferroptosis vulnerability.
    Tiange Wang, Jun Tu, Xiangyun Wei, Zi Liang, Rong Cai, Qiuju Fan, Jianli He, Tianshi Wang, Jinke Cheng.
      Oxidative stress disrupts mitochondrial redox homeostasis and contributes to ferroptosis-associated vulnerability, yet the molecular link between impaired mitochondrial peroxide detoxification and ferroptosis-associated vulnerability remains incompletely defined. Here, we identify PRDX3 as a candidate SIRT3-regulated effector of mitochondrial peroxide control. In AML12 cells, oxidative stress reduced mitochondrial SENP1, increased SIRT3 SUMOylation and elevated mitochondrial protein acetylation. Mitochondrial acetylome profiling identified PRDX3 K92 as a SIRT3-responsive acetylation site. Genetic activation of SIRT3 reduced PRDX3 acetylation and was associated with enhanced PRDX3 dimerization, improved peroxide clearance and reduced mitochondrial H2O2, lipid peroxidation, iron accumulation and other ferroptosis-associated changes. Conversely, an acetylation-mimetic PRDX3 mutant impaired peroxide clearance and attenuated the protective phenotype associated with SIRT3 activation, whereas a deacetylation-mimetic mutant improved redox balance and cell viability under oxidative stress. In vivo, activation of the SIRT3-PRDX3 axis mitigated paraquat-induced liver injury. Collectively, these data support a model in which SIRT3-dependent regulation of PRDX3 acetylation helps sustain mitochondrial peroxide detoxification and limits oxidative injury during stress.
    Keywords:  PRDX3; SIRT3; ferroptosis; lysine acetylation; mitochondrial peroxide detoxification; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.021
  48. bioRxiv. 2026 Jun 06. pii: 2026.06.04.730191. [Epub ahead of print]
    Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.
    Thuraya M Mutawi, Shweta R Malvankar, Andrea Graziani, Udita Shah, Khanh Nguyen, David G Broadbent, Zachary Clark, Michaella J Rekowski, Susan M Lunte, Carlo Barnaba.
      Metformin is the most widely prescribed antidiabetic drug and an active candidate for repurposing in oncology. How it engages autophagy - a pathway central to both its metabolic and its anti-tumor effects - has remained unresolved, with reports of induction, suppression, and no effect. Here we show that metformin reroutes rather than induces or inhibits autophagy in human cancer cells: at therapeutic concentrations, it suppresses bulk cytosolic turnover by selectively blocking WIPI2-mediated phagophore tethering, while the ULK1 initiation complex relocates toward mitochondria and engages selective mitochondrial clearance. We trace this redirection to mitochondrial complex I inhibition, registered as a shift in the NAD + /NADH ratio before any change in the adenylate pool, and to a non-canonical reprogramming of the ULK1 complex that operates independently of mTORC1 and of the proposed PEN2-lysosomal route. AMPK is engaged in a subunit-specific manner that restrains ATG13 at initiation and enables WIPI2 displacement at maturation. The ULK1 complex is therefore the node at which metformin sets autophagic substrate selection, with direct implications for combination therapy in diabetes and cancer.
    DOI:  https://doi.org/10.64898/2026.06.04.730191
  49. Int J Mol Sci. 2026 Jun 05. pii: 5127. [Epub ahead of print]27(11):
    Evaluating a Coenzyme Q10-Based Food for Special Medical Purpose, for Mitochondrial Diseases Management: An Open-Label, Pilot Trial.
    Lucia Chico, Piervito Lopriore, Giulia Cecchi, Adriana Meli, Clara Bernardini, Linda Balestrini, Maico Polzella, Vincenzo Montano, Michelangelo Mancuso.
      Primary mitochondrial diseases (PMD) are rare disorders with limited therapeutic options. Coenzyme Q10 (CoQ10) supplementation is widely used, although formulation differences can affect absorption and efficacy. This open-label pilot feasibility trial evaluated a food for special medical purposes (FSMP) containing high-dose CoQ10 (250 mg per capsule) in patients with PMD. Ten patients (mean age: 55.5 ± 8.6 years) were enrolled. Serum/plasma biomarkers, including CoQ10, fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), ferric-reducing antioxidant power (FRAP), total sulfhydryl groups (t-SH), and advanced oxidation protein products (AOPP), were assessed at baseline (T0, after ≥30 days of conventional ubidecarenone) and after 30 days of FSMP administration (T1). Fatigue severity scale (FSS) and 5-times sit-to-stand test (5xSST) were evaluated at both timepoints. FSMP was administered at 250 or 500 mg/day. Twenty sex- and age-matched healthy controls were included for CoQ10 comparison. Absolute CoQ10 concentrations remained stable overall at T1, with all patients maintaining levels above 390 ng/mL (100% vs. 60% at T0), although concentrations remained lower than in healthy controls (p < 0.01). Dose-normalized CoQ10 exposure was significantly higher with FSMP versus conventional ubidecarenone (p < 0.001, Cohen's d = 7.31). FGF21, GDF15, AOPP, and t-SH remained unchanged, whereas FRAP increased at T1 (p < 0.01). No significant changes were observed in 5xSST and FSS. Exploratory analyses indicated inter-individual variability in functional responses. FSMP was associated with higher dose-normalized systemic CoQ10 exposure, more consistent circulating CoQ10, and increased FRAP levels. Its simplified dosing regimen may support long-term adherence. Larger studies are warranted to validate these preliminary findings.
    Keywords:  antioxidants; coenzyme Q10; food for special medical purposes; mitochondrial diseases
    DOI:  https://doi.org/10.3390/ijms27115127
  50. Parkinsonism Relat Disord. 2026 Jun 01. pii: S1353-8020(26)00198-7. [Epub ahead of print]149 108371
    Compound heterozygous PINK1 variants including a novel frameshift in a Chinese family with Parkinson's disease.
    Li Wang, Yu Zhan, Xiaoyang Lei, Lang Yang, Qianzhi Xu, Xingyou He, Dian He.
      
    Keywords:  Compound heterozygous mutation; PINK1; PINK1-associated Parkinson's disease; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.parkreldis.2026.108371
  51. bioRxiv. 2026 Jun 02. pii: 2026.05.29.728910. [Epub ahead of print]
    Reduced Myocardial Serine Synthesis Impairs Functional, Metabolic, and Redox Adaptations to Cardiac Stress.
    Malihe Rezaee, Mohammad Keykhaei, Navid Koleini, Tegbir Panesar, Simiao Li, Nalini Salvekar, David J Polhemus, Chengchen Hu, Mariam Meddeb, Liang Zhao, Kavita Sharma, Christopher Petucci, Nathaniel Snyder, Junichi Sadoshima, David A Kass.
       Background: Impaired myocardial metabolism is a defining feature of heart failure, but many defective pathways and mechanisms remain to be identified. Prior studies find phosphoglycerate kinase and its synthesized product 3-phospho-glycerate required for the serine synthetic pathway (SSP) are reduced in human HFpEF myocardium. As serine is also provided exogenously, the impact of SSP reduction is uncertain. Here, we tested if and how SSP decline coupled to phosphoglycerate dehydrogenase (PHGDH) impacts cardiomyocyte (CM) and whole heart metabolic remodeling and stress responses.
    Methods: Studies were performed in isolated CMs and mice with CM-selective knock-down of PHGDH. Using pharmacological inhibition or genetic silencing of PHGDH, we tested their impact on CM one-carbon metabolism pathways, cell hypertrophic responses, mitochondrial respiration, and in vivo functional, structural, and metabolic adaptations to pressure-overload stress.
    Results: In CMs, PHGDH inhibition caused dose-dependent serine depletion linearly coupled with cytotoxicity, accompanied by NAD/NADH and GSH/GSSG imbalance, reduced ATP, and disruption of one-carbon and nucleotide metabolites. Stable-isotope tracing revealed distinct metabolic fates of glucose-derived (SSP) versus exogenous serine. Exogenous serine did not rescue PHGDH-deficient CMs, whereas combined ribose and an anti-oxidant (DTT) attenuated injury and reduced nucleotide pools. PHGDH suppression reduced amino acid abundance, impaired nascent protein synthesis, and blunted endothelin-1-induced hypertrophic and mitochondrial respiration. In vivo , cardiomyocyte-specific PHGDH heterozygous mice (PHGDH +/- ) had no basal phenotype, but amplified chamber dilation, dysfunction, fibrosis, and mortality 4 weeks after transverse aortic constriction (TAC). Corresponding increases in amino acids, one-carbon metabolites, nucleotides, and TCA-cycle intermediates in wild-type TAC hearts were significantly blunted in PHGDH +/- hearts.
    Conclusions: Cardiomyocyte SSP is a critical regulator of redox balance, one-carbon metabolism, purine synthesis, amino acid homeostasis, and growth-related pathways required for cardiac adaptation to pressure overload. It is non-redundant with exogenous serine by providing distinct influences on key metabolic pathways and is a potential therapeutic target.
    DOI:  https://doi.org/10.64898/2026.05.29.728910
  52. Free Radic Biol Med. 2026 Jun 07. pii: S0891-5849(26)00870-1. [Epub ahead of print]
    PARS2 deficiency impairs mitochondrial homeostasis and activates ferroptotic to drive developmental and epileptic encephalopathy.
    Ziheng Li, Zhao Xu, Genfu Zhang, Ang Ma, Zongpu Zhou, Jiong Qin, Zhixian Yang.
      PARS2 , encodes a mitochondrial aminoacyl-tRNA synthetase associated with developmental and epileptic encephalopathy (DEE), a severe neurological disorder characterized by refractory epilepsy and intellectual disability. While genetic associations between PARS2 and DEE have been established, the underlying molecular mechanisms remain poorly understood. This study integrates genetic analyses of clinical cases of infantile epileptic spasms syndrome (IESS) with functional assessments in PARS2-deficient animal models and cell models to elucidate these mechanisms. Our findings indicate that PARS2 deficiency disrupts mitochondrial integrity and impairs oxidative phosphorylation, resulting in elevated intracellular calcium levels. This calcium overload activates CaMKK2-AMPK-Drp1 signaling, promoting excessive mitochondrial fission and PINK1-Parkin-mediated mitophagy, ultimately leading to degradation of GPX4 and subsequent ferroptosis. Notably, pharmacological inhibition of Drp1 using Mdivi-1 successfully rescued mitochondrial fragmentation and mitigated ferroptosis. These results unveil a novel calcium-mitophagy-ferroptosis pathway as a crucial mechanism in PARS2-related DEE and propose a potential therapeutic strategy for DEE.
    Keywords:  ( Developmental and epileptic encephalopathy; PARS2; ferroptosis); mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.019
  53. Stem Cell Reports. 2026 Jun 11. pii: S2213-6711(26)00169-4. [Epub ahead of print] 102958
    Scalable hypothalamic neuron differentiation from human pluripotent stem cells suitable for modeling metabolic disorders.
    Vukasin M Jovanovic, Narisu Narisu, Lori L Bonnycastle, David Castellano, Seungmi Ryu, Ravi Tharakan, Kendall T Mesch, Qiang Chen, Fahrünisa Meryem Betül Erol, Hannah J Glover, Tingfen Yan, Neelam Sinha, Chaitali Sen, Shu Yang, Dvir Blivis, Daniel F Bennett, Giovanni Rosales-Soto, Jason Inman, Pinar Ormanoglu, Christopher A LeClair, Natalie D Shaw, Menghang Xia, Martin Schneider, Erick O Hernandez-Ochoa, Michael R Erdos, Anton Simeonov, Shuibing Chen, Francis S Collins, Claudia A Doege, Carlos A Tristan.
      The hypothalamus, composed of multiple nuclei, is essential for maintaining the body's homeostasis. Within the mediobasal hypothalamus, the arcuate nucleus (ARC) contains key neuronal populations, including appetite-suppressing pro-opiomelanocortin (POMC) neurons that regulate energy and glucose balance. Here, we present a chemically defined, scalable method for differentiating human pluripotent stem cells (hPSCs) into hypothalamic neurons enriched for POMC cells, compatible with robotic cell culture platforms for high-throughput use. Neuronal identity was validated by MERFISH single-cell transcriptomics, RNA-Seq, ATAC-Seq, and comparison to human hypothalamus. The method is robust across multiple hPSC lines, showing consistent induction of ventral diencephalon and hypothalamic markers. Derived neurons display metabolic disease-relevant features, including body mass index (BMI)-associated gene enrichment, and ATAC-Seq identifies potential candidate regulatory regions linked to hypothalamic development and metabolic traits. Functional assays reveal neuronal responses to insulin and the GLP-1 receptor agonist Exendin-4, and transcriptional responses to altered glucose conditions. This platform delivers a physiologically relevant model of human hypothalamic neurons that enables deeper mechanistic and therapeutic studies of metabolic disease.
    Keywords:  GLP1R agonist; GnRH neurons; POMC neurons; automated biomanufacturing; human hypothalamus; iPSC; insulin; metabolic disease modeling; obesity; pluripotent stem cells; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102958
  54. J Clin Med. 2026 Jun 05. pii: 4370. [Epub ahead of print]15(11):
    Stem Cell Therapy for Parkinson's Disease: A Mechanistically Distinct Role for Muse Cells.
    Michael H Mesches, Ann-Charlotte Granholm, Daniel Paredes, Karin Mesches, Yo Oguma, Mari Dezawa.
      Cell replacement therapy is a promising investigational approach for Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra. Although current PD therapies provide symptomatic relief, none halt or reverse disease progression. Early transplantation studies using fetal dopaminergic neurons provided proof of concept for PD cell replacement, with recent efforts focusing on pluripotent stem cell-derived dopaminergic progenitors that are now entering clinical testing. These strategies face challenges, however, including immune compatibility, tumorigenic risk, and the need for controlled differentiation and functional integration. Multi-lineage differentiating stress-enduring (Muse) cells are endogenous, non-tumorigenic pluripotent-like stem cells that home to sites of tissue injury and differentiate in response to the host microenvironment. A targeted literature search of PubMed and Scopus, however, did not identify prior reviews specifically addressing Muse cells in the context of PD, highlighting a gap in the literature. Here, we examine current limitations of established cell-replacement approaches and consider whether Muse cells may represent a mechanistically distinct cell source. Early clinical studies of Muse cell therapy in stroke and amyotrophic lateral sclerosis suggest an encouraging safety profile and preliminary signals of potential therapeutic benefit, although these findings are based on small, early-stage trials and require confirmation. The evidence supporting Muse cell therapy in PD is currently limited to a single preclinical animal study, supported by mechanistic in vitro findings and indirect evidence from other neurologic disease models; therefore, its relevance to PD remains to be established, and current evidence is insufficient to support conclusions regarding clinical efficacy. Together, these observations provide a rationale for further targeted preclinical investigation and support the systematic evaluation of Muse cells as a mechanistically distinct candidate for regenerative therapy in PD.
    Keywords:  Muse cells; Parkinson’s disease; cell replacement therapy; pluripotent cells; stem cells
    DOI:  https://doi.org/10.3390/jcm15114370
  55. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2511427123
    Drp1-driven fragmentation of scleral mitochondria promotes myopia development.
    Zhenqi Guan, Wenting Li, Shengcong Liu, Xingxing Yang, Yuejia Peng, Long Ye, Luyao Wang, Yuan Lu, Sisi Dong, Huihui Liu, Jian Yuan, Jianzhong Su, Jia Qu, Xianqun Fan, Fei Zhao, Miaozhen Pan, Xiangtian Zhou.
      The global epidemic of myopia constitutes a growing public health concern worldwide. Myopia development is characterized by pathological scleral remodeling through fibroblast-myofibroblast transdifferentiation (FMT) and extracellular matrix (ECM) degradation. Since myopia is progressive, the development of sustainable and safe preventive interventions is imperative. While mitochondrial dynamics critically regulate fibrotic processes in other organs, their role in scleral homeostasis has remained unexplored. Here, we identify pathological mitochondrial fragmentation, caused by increased mitochondrial fission, as a key driver of myopia progression. Using two mammalian animal models, we demonstrate that both genetic and pharmacological enhancement of mitochondrial fission (inducing mitochondrial fragmentation) exacerbates collagen loss and accelerates axial elongation, whereas genetic and pharmacological inhibition of mitochondrial fission prevents collagen degradation and attenuates myopia progression. Hypoxia-induced FMT in cultured human scleral fibroblasts (HSFs) requires activation of mitochondrial fission, revealing overproduction of reactive oxygen species (ROS) as the downstream effector on HSFs and in both animal models. Our multilevel analyses identify the mitochondrial fission-ROS axis as a key pathway linking scleral hypoxia to ECM remodeling. Lycopene, a naturally occurring carotenoid antioxidant, significantly attenuated scleral ROS levels and was found suitable for long-term application, highlighting its potential as a therapeutic agent for myopia control. Collectively, these findings have identified a therapeutic target and agent for controlling myopia progression.
    Keywords:  Drp1; ROS; mitochondria; myopia; sclera
    DOI:  https://doi.org/10.1073/pnas.2511427123
  56. Int J Mol Sci. 2026 May 29. pii: 4948. [Epub ahead of print]27(11):
    Molecular Hydrogen as a Regulator of Mitochondrial Quality Control and Metabolic Reprogramming.
    Fangfang Li, Yue Jing, Chao Xia, Ruping Zhao, Mengyu Liu, Pengxiang Zhao, Xuemei Ma, Fei Xie.
      The biological effects of molecular hydrogen are moving beyond the traditional explanatory framework of "selective antioxidation." This article systematically integrates the basic, preclinical, and preliminary clinical evidence for hydrogen in metabolic diseases, neurodegenerative disorders, and cancer, centering on the two major themes of mitochondrial quality control and metabolic reprogramming. Current studies indicate that hydrogen can reshape redox homeostasis, coordinate mitochondrial biogenesis, dynamic balance, and mitophagy, and modulate key signaling axes such as AMPK/Sirtuins, PGC-1α, and PPARα, aimed at optimizing mitochondrial function, thereby influencing adaptive glucose and lipid metabolism as well as cellular bioenergetic homeostasis. Although its upstream initiating events and context dependency remain to be clarified, existing evidence supports the view that hydrogen is an important network regulator linking redox regulation, mitochondrial homeostasis, and metabolic adaptation.
    Keywords:  mitochondrial quality control; molecular hydrogen; redox homeostasis
    DOI:  https://doi.org/10.3390/ijms27114948
  57. Metab Eng. 2026 Jun 12. pii: S1096-7176(26)00083-2. [Epub ahead of print] 102488
    Development of a Noncanonical Redox Cofactor Platform in Saccharomyces cerevisiae.
    William B Black, Kristina McKee, Kelly N Richardson, Samer Saleh, Mikhail Gednov, Austin Si, Han Li.
      Saccharomyces cerevisiae is a keystone host for biomanufacturing, yet its metabolic engineering is often complicated by the crosstalk between heterologous pathways and native metabolism. In particular, allocating and balancing the universal reducing equivalents nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) typically requires laborious genetic modifications. To address this challenge, we established an orthogonal redox cofactor infrastructure in S. cerevisiae based on nicotinamide mononucleotide (NMN(H)), which is decoupled from the host's NAD(P)H-based metabolism because NMN(H)-dependent pathway networks comprise only a small number of user-defined reactions, their optimization is substantially simplified. First, by rewiring glycolysis to eliminate NAD(P)H generation from glucose, we repurposed glucose as a dedicated electron source for NMNH reducing power. We then demonstrated that NMN(H) selectively drives the reduction of citral to citronellal, both unstable aldehydes, while suppressing the rapid over-reduction to alcohols observed with native cofactors without identifying or disrupting the numerous endogenous alcohol dehydrogenases in resting S. cerevisiae cells. Finally, we engineer S. cerevisiae to accumulate an intracellular NMN+ pool of ∼2.9 mM, comparable to NAD+ intracellular levels, enabling the first self-sustained, new-to-nature redox cofactor system in eukaryotic organism. This work establishes NMN(H) as a functional third nicotinamide-based redox cofactor in yeast and provides a generalizable eukaryotic platform for orthogonal redox biocatalysis.
    Keywords:  Metabolic Engineering; Nicotinamide Mononucleotide; Noncanonical Redox Cofactor; Saccharomyces cerevisiae; Synthetic Biology
    DOI:  https://doi.org/10.1016/j.ymben.2026.102488
  58. Nat Commun. 2026 Jun 12.
    Nitrate-Sialin2 axis couples ER-mitochondrial calcium signaling with fatty acid metabolism to drive white adipose browning.
    Ou Jiang, Zichen Cao, Sihan Kong, Qibing Wu, Tianyi Zhang, Xinyue Chen, Bo Zhou, Yao Feng, Songyue Wu, Jinsong Wang, Mo Chen, Xiaoyu Li, Songlin Wang.
      White adipose browning is a promising route to restore energy balance; however, how inorganic anion signals engage intracellular organelle networks to drive this process remains unclear. Here, we identify Sialin2 as a nitrate sensor that converts dietary nitrate into a spatially confined thermogenic program by coupling ER-mitochondria Ca2+ transfer with lipid routing into mitochondrial oxidation. Sialin2 localizes to mitochondria and the endoplasmic reticulum (ER), where it strengthens ER-mitochondria contacts and engages the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter 1 (MCU1) conduit to enhance inducible mitochondrial Ca2+ uptake. In parallel, Sialin2 associates with lysosomal acid lipase (LIPA), acyl-CoA synthetase long-chain family member 3 (ACSL3), and carnitine palmitoyltransferase 1 A (CPT1A) to channel lipid-droplet-derived fatty acids into β-oxidation, thereby fueling the tricarboxylic acid cycle and uncoupling protein 1 (UCP1)-dependent respiration. Loss of Slc17a5 abolishes nitrate-evoked browning and metabolic benefits, whereas nitrate supplementation improves adipose thermogenesis and systemic metabolic indices in male mice with diet-induced obesity without adrenergic stimulation. Together, these findings identify an organelle-specific nitrate-sensing mechanism that couples inorganic anion signalling to substrate routing in adipocytes and establish a non-hormonal pathway for restoring metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-74256-w
  59. Redox Biol. 2026 May 22. pii: S2213-2317(26)00229-6. [Epub ahead of print]95 104231
    Fasting requires Peroxiredoxin 2 and Peroxiredoxin 6 to coordinate redox dependent mitochondrial and lipid remodelling in Caenorhabditis elegans.
    Penglin Li, Yating Zheng, Jose C Casas-Martinez, Qin Xia, Antonio Miranda-Vizuete, Katarzyna Goljanek-Whysall, Brian McDonagh.
      Fasting induces conserved metabolic and redox adaptations that promote stress resistance and longevity. However, the molecular mechanisms linking transient redox changes and altered metabolism to downstream signalling events remain incompletely understood. Using Caenorhabditis elegans, the roles of peroxiredoxins in coordinating redox-dependent responses to fasting and refeeding were determined. A 4-hr fasting protocol over 5 days extended lifespan, improved late-life physiological activity, reduced age-related lipofuscin and lipid accumulation. The fasting protocol generated a transient increase in mitochondrial ROS, promoted mitochondrial turnover, and attenuated age-related mitochondrial fragmentation. These adaptive responses required the activation and nuclear localisation of the stress-responsive transcription factors DAF-16/FOXO and SKN-1/Nrf2. However, these adaptive responses were abolished in prdx-2 and prdx-6 mutant strains, which exhibited persistent redox imbalance, mitochondrial fragmentation, altered stress resistance, and disrupted DAF-16 and SKN-1 signalling. Mechanistically, loss of 2-Cys PRDX-2 impaired activation of the p38 MAPK PMK-1 pathway, resulting in defective SKN-1 activation. In contrast, loss of 1-Cys PRDX-6 disrupted lipid metabolic signalling, preventing induction of NHR-80 and downstream fatty acid desaturases required for metabolic adaptations. Despite distinct initial signalling pathways, both peroxiredoxins converged on the regulation of DAF-16 and SKN-1. Together, these findings identify PRDX-2 and PRDX-6 as redox sensors that translate a fasting-induced transient ROS signature into mitochondrial and lipid remodelling pathways to promote healthy ageing.
    Keywords:  Ageing; Fasting; Lipid remodelling; Mitochondrial dynamics; Oleic acid; Peroxiredoxin
    DOI:  https://doi.org/10.1016/j.redox.2026.104231
  60. medRxiv. 2026 Jun 05. pii: 2026.05.28.26354198. [Epub ahead of print]
    DHDDS-related juvenile parkinsonism is caused by impaired lipid metabolism, glycosylation, and mitochondrial dysfunction, which can be rescued by NAD⁺ treatment.
    I J J Muffels, K A Kantautas, G MacDonald, K Garapati, R R Pasupuleti, R J Tinker, R Shah, M A Thevandavakkam, J Donnelly, R Hrstka, D Smith, J Van Klinken, F Vaz, A Pandey, E O Perlstein, T Kozicz, E Morava.
       Background: Mono-allelic Dehydrodolichyl Diphosphate Synthase ( DHDDS) variants are associated with juvenile Parkinsonism, developmental delay and seizures. Symptoms are progressive, and various mechanisms, such as defective glycosylation, lysosomal dysfunction and cholesterol accumulation have been hypothesized to underlie disease symptoms. There is no treatment for DHDDS-related disease.
    Methods: Patient-derived cortical forebrain organoids were created to elucidate disease mechanisms and evaluate potential treatments. In these neuronal models, glycosylation, lipidomics, proteomics, cholesterol/ganglioside accumulation, mitochondrial function and electrophysiological activity were assessed. Finally, we investigated the effects of nicotinamide mononucleotide (NMN), identified through a yeast-based drug screen, in neuronal cell models and in six patients in an off-label, N-of-1, observational series.
    Results: DHDDS-patient derived organoids showed visual signs of degeneration after four months of culturing. This was accompanied by significant cholesterol accumulation in astrocytes, decreased mitochondrial respiration and loss of deep-layer neurons. In addition, we identified glycosylation abnormalities, showing for the first time that glycosylation in human tissue is affected by monoallelic DHDDS variants. Proteomic analysis revealed altered protein expression of proteins involved in lipid metabolism, cytoskeletal organization and neuronal development. We found that oral Nicotinamide Mononucleotide supplementation led to significant improvement in mitochondrial respiration and electrophysiological parameters in organoids, concurring with clinical improvements in all of the treated patients, particularly regarding their ataxia and tremor.
    Conclusion: Our findings reveal a progressive phenotype in DHDDS-patient-derived brain organoids, with mitochondrial dysfunction and astrocyte-specific metabolic alterations contributing to disease pathology. Notably, NMN treatment led to clinical improvements in patients with heterozygous DHDDS variants, highlighting its potential as a therapeutic strategy.
    DOI:  https://doi.org/10.64898/2026.05.28.26354198
  61. EMBO Rep. 2026 Jun 06.
    The Legionella effector RidL binds the large fission GTPase Drp1 to promote mitochondrial fragmentation.
    Ana Katic, Elizabeth Teresa Vittori, Stefanie Halter, Kevin Steiner, A Leoni Swart, Milad Radiom, Francisco Javier García-Rodríguez, Tobias Jäggi, Xiaodan Li, Jason A Mears, Carmen Buchrieser, Pedro Escoll, Vikram Govind Panse, Hubert Hilbi.
      Intracellular pathogens such as Legionella pneumophila secrete effector proteins that manipulate host cell processes to promote bacterial survival. One such effector, RidL, is known to inhibit retrograde trafficking by interacting with the retromer complex via its N-terminal domain. Here, we identify a second function of RidL mediated by its C-terminal domain, which directly binds to the mitochondrial fission GTPase dynamin-related protein 1 (Drp1) and related large GTPases. In vitro, RidL reduces Drp1 GTPase activity and disrupts its oligomerization. During infection, RidL localizes to mitochondria, enhances the accumulation of Drp1 and the outer membrane protein Tom20, and impairs mitochondrial dynamics and function. Moreover, in L. pneumophila-infected cells, RidL promotes phosphorylation of Drp1 at Ser616, leading to Drp1 activation and mitochondrial fragmentation. These findings establish RidL as a bifunctional effector that targets both the retromer complex and Drp1 through distinct domains. By interfering with host mitochondrial dynamics, RidL enables L. pneumophila to remodel host organelles and optimize conditions for intracellular replication.
    DOI:  https://doi.org/10.1038/s44319-026-00823-3
  62. J Muscle Res Cell Motil. 2026 Jun 06. pii: 15. [Epub ahead of print]47(3):
    The pseudokinase domain PK1 of UNC-89/obscurin is required for mitochondrial morphology and function in C. elegans.
    Yohei Matsunaga, Nasab Ghazal, Andreas Heim, Till Dorendorf, Hiroshi Qadota, Yuchu Wang, Thomas U Mayer, Olga Mayans, Jennifer Q Kwong, Guy M Benian.
      UNC-89 is a giant modular protein located at the sarcomeric M-line of C. elegans striated muscle and is required for sarcomere organization and function. UNC-89 contains two protein kinase domains, PK1 and PK2, separated by 850 residues, that includes a 645-residue long intrinsically disordered sequence that acts like an elastic spring. Bioinformatic analysis suggests that PK2 is an active kinase whereas PK1 is a pseudokinase. We recently reported that a genome-edited worm, unc-89(sf22), that expresses UNC-89 carrying a kinase-inactivating point mutation in PK2 has an unusual phenotype with normally organized sarcomeres and SR, normal muscle function and yet fragmented mitochondria, increased ATP levels, increased glycolysis and alterations in electron transport chain complexes and respiration. Here, we show that a genome-edited worm unc-89(sf23), that expresses UNC-89 with an in-frame deletion of the C-lobe of PK1 has approximately the same phenotype as the PK2 catalytically dead mutant. The fact that mutations in two different regions of UNC-89 result in a mitochondrial phenotype is further evidence of communication between the sarcomere and mitochondria. We further demonstrate that in vitro PK2 interacts with full length PK1 and the C-lobe of PK1. The protein kinase domains of giant sarcomeric proteins are autoinhibited by parts of their own sequence, and this is also likely for PK2, but the mechanism by which PK2 would be activated is unknown. Our data is compatible with a model in which PK1 interacts with PK2 and thereby stimulates PK2 kinase activity.
    Keywords:   C. elegans ; Kinase domain; Mitochondria; Striated muscle; UNC-89/obscurin
    DOI:  https://doi.org/10.1007/s10974-026-09733-2
  63. Nature. 2026 Jun 10.
    Mitochondria directly interact with the nuclear pore complex.
    Ivan Menendez-Montes, Consuelo Marin-Vicente, Shibani Mukherjee, Mahmoud Salama Ahmed, Manuel Jose Gomez, Chukwuemeka George Anene-Nzelu, Chang Jie Mick Lee, Svenja Koslowski, Ashley Solmonson, Tara Tassin, Shah R Ali, Pedro Pessoa, Abdallah Elnwasany, Nicholas T Lam, Suwannee Thet, Enrique Calvo, Alisson C Cardoso, Ana Helena M Pereira, Feng Xiao, Ping Wang, Asim Mohamed, Hamed El-Feky, Ahmed Elghamry, Gonzalo Gancedo-Alonso, Ngoc Uyen Nhi Nguyen, Ching-Cheng Hsu, Aundrea K Westfall, Ralph DeBerardinis, Roger Sik-Yin Foo, Michael Kinter, Steve Pressé, Chao Xing, Luke Szweda, Asaithamby Aroumougame, Fatima Sanchez-Cabo, Jose Antonio Enriquez, Miguel Torres, Jesus Vazquez, Hesham A Sadek.
      Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes1, which control pathways including redox and calcium homeostasis2,3. Recent studies have also reported direct mitochondria-nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling4,5. Here we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knockout, RANBP2 truncation or site-directed mutagenesis of RANBP2-VDAC1 interacting amino acids resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in the levels of the nuclear phosphoproteome and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. Moreover, deletion of the RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the nuclear pore complex, a phenomenon critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interaction remain to be revealed.
    DOI:  https://doi.org/10.1038/s41586-026-10588-3
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒14 at 12:55.