bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–04–19
thirty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. PPARγ activation by leriglitazone counteracts neurodegeneration and neuroinflammation in a disease-relevant mouse model of COASY dysfunction.
  2. Uncovering mitochondrial defects in photoreceptors opens therapeutic opportunities for Stargardt disease.
  3. Diagnostic Criteria and Management of MELAS and Stroke-Like Episodes: Consensus-Based Statements.
  4. Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca2.
  5. Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease.
  6. A tRNA epitranscriptomic checkpoint coordinates sperm mitochondrial load with embryonic allophagic clearance.
  7. Systemic delivery of AAV-GFM1 corrects COXPD1 molecular alterations in Gfm1R671C/- mice.
  8. Clinical and genetic analysis of Chinese patients with Leigh syndrome caused by biallelic loss-of-function variants of the NDUFAF6 gene.
  9. Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
  10. Cell-type-targeted mitochondrial transplantation rescues cell degeneration.
  11. Reversible Metabolic and Liver Disease in Complex III Deficiency: Novel Variants Expand the Reported UQCRC2-Associated Phenotype.
  12. A ULK1-MTFR1L feedback loop links mitochondrial fission, mitophagy and apoptosis.
  13. Adenine Nucleotide Translocase: From Nucleotide Carrier to a Modulator of Mitochondrial Bioenergetics, Quality Control, and Cellular Communication.
  14. Comparative analysis of muscle pathologies and metabolic signaling in mouse models of mitochondrial dysfunction.
  15. The Caenorhabditis elegans Mitochondrial Electron Transport Chain: its role in Adaptation, Longevity, and Biotechnology.
  16. Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
  17. Beyond the genome: clinical challenges in diagnosing LONP1-related mitochondrial disorders.
  18. Scalable workflows for high-throughput respirometry.
  19. Therapeutic and mechanistic insights on mitochondrial transplantation in kidney disease.
  20. Therapeutic mitochondria transplants made more efficient with targeting tool.
  21. Mitochondrial homeostasis: the central hub governing the progression of atherosclerosis.
  22. Blockage of autophagy causes severe skeletal muscle disruption in a mouse model for myofibrillar myopathy 6.
  23. Mitochondrial translocation of MDM2 and TFAM reprograms metabolism in treatment-refractory cancers.
  24. Variants in the proteasome regulator PSMF1 cause a phenotypic spectrum from parkinsonism to perinatal lethality.
  25. Mitochondrial DNA regulation of hepatic ischemia-reperfusion injury and intervention strategies.
  26. ROMO1 and mitochondrial complex II/SDH are required for spare respiratory capacity and glucose homeostasis in mice.
  27. Mitochondrial transfer as a driver of immune microenvironment remodeling.
  28. Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.
  29. Rhesus macaques with an OPA1 mutation demonstrate features of autosomal dominant optic atrophy.
  30. Metabolic Control of Immunity and Inflammation: Mitochondrial Dynamics, Pharmacological Targets, and Therapeutic Opportunities.
  1. Pharmacol Res. 2026 Apr 13. pii: S1043-6618(26)00108-8. [Epub ahead of print]227 108193
    PPARγ activation by leriglitazone counteracts neurodegeneration and neuroinflammation in a disease-relevant mouse model of COASY dysfunction.
    Chiara Cavestro, Floriana Cascone, Andrea Legati, Rossella Izzo, Marcella Catania, Cristina Vergara, Laura Rodríguez-Pascau, Pilar Pizcueta, Valeria Tiranti, Ivano Di Meo.
      Coenzyme A (CoA) is a vital cofactor involved in energy metabolism, lipid biosynthesis, protein modification, and epigenetic regulation. Disruptions in CoA biosynthesis have been implicated in neurometabolic disorders such as pantothenate kinase-associated neurodegeneration (PKAN) and COASY protein-associated neurodegeneration (CoPAN), both within the heterogeneous spectrum of Neurodegeneration with Brain Iron Accumulation (NBIA). Specifically, CoPAN results from recessive variants in the COASY gene, encoding the bifunctional CoA synthase enzyme, leading to progressive neurodegeneration, motor impairment, and metabolic abnormalities. To investigate the neuronal impact of CoA deficiency, we developed an inducible, neuron-specific Coasy deleted mouse model. Unlike previous constitutive models, this system faithfully recapitulates key clinical and molecular features of CoPAN, including motor deficits, neurodegeneration, iron dyshomeostasis, and reduced survival. Strikingly, conditional neuronal Coasy ablation triggered extensive and progressive neuroinflammation, highlighting a neglected pathogenic component and potential therapeutic target. This model thus represents a robust platform to dissect disease mechanisms and evaluate candidate treatments. Given the established neuroprotective role of peroxisome proliferator-activated receptor gamma (PPARγ), we tested leriglitazone, a novel brain-penetrant full and selective PPARγ agonist effective in other rare neurodegenerative models. Leriglitazone treatment significantly improved motor performance, restored iron homeostasis, and attenuated both neuroinflammation and neurodegeneration. This study advances our understanding of the mechanism driving CoA-related neurodegeneration, highlights neuroinflammation as a pivotal pathogenic process, and demonstrates the therapeutic potential of PPARγ activation, underscoring leriglitazone as a promising candidate for CoPAN and potentially for the broader NBIA spectrum.
    Keywords:  Animal models; CoPAN; Coenzyme A; NBIA; Neuroinflammation; PPARγ
    DOI:  https://doi.org/10.1016/j.phrs.2026.108193
  2. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2504764123
    Uncovering mitochondrial defects in photoreceptors opens therapeutic opportunities for Stargardt disease.
    Simona Brillante, Mariagrazia Volpe, Anna Diana, Santiago Negueruela, Marta Molinari, Rosa Saurino, Eva Cipollaro, Elena Polishchuk, Erika Tenderini, Carla Damiano, Patrizia Tornabene, Roman Polishchuk, Giancarlo Parenti, Antonietta Tarallo, Sandro Banfi, Ivana Trapani, Sabrina Carrella, Alessia Indrieri.
      Stargardt disease type 1 (STGD1) is the most common hereditary macular degeneration. It is caused by mutations in ABCA4, which result in the progressive degeneration of the retinal pigment epithelium (RPE), ultimately leading to photoreceptor loss. Despite extensive efforts, STGD1 currently lacks effective treatments. Here, we first identified mitochondrial defects in the photoreceptors of Abca4-/- mice and STGD1 patient-derived retinal organoids. Specifically, we found reduced mitochondrial content, defective cristae morphology, and downregulation of OPA1, a critical regulator of mitochondrial integrity, demonstrating that photoreceptor defects in STGD1 also have a cell-autonomous origin, besides the RPE dysfunction. Importantly, we also demonstrated that correcting this pathological phenotype through the modulation of microRNAs 181a and b (miR-181a/b), key regulators of mitochondrial function, ameliorates the STGD1 phenotype. Indeed, genetic inactivation and adeno-associated viral vector-mediated silencing of miR-181a/b in STGD1 models restored OPA1 levels, improved mitochondrial phenotype, and reduced lipofuscin accumulation in the RPE. Our study demonstrates that mitochondrial dysfunction in photoreceptors is an important contributor to STGD1 pathology, opening promising therapeutic avenues for this disorder.
    Keywords:  Stargardt disease; miR-181a/b; microRNA; mitochondria; photoreceptors
    DOI:  https://doi.org/10.1073/pnas.2504764123
  3. Eur J Neurol. 2026 Apr;33(4): e70588
    Diagnostic Criteria and Management of MELAS and Stroke-Like Episodes: Consensus-Based Statements.
    Michelangelo Mancuso, Marcello Bellusci, Valerio Carelli, Irenaeus de Coo, Daria Diodato, Felix Distelmaier, Omar Hikmat, Michio Hirano, Rita Horvath, Amel Karaa, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Chiara La Morgia, Piervito Lopriore, Mika Henrik Martikainen, Robert McFarland, Olimpia Musumeci, Robert D S Pitceathly, Guido Primiano, Shamima Rahman, Fernando Scaglia, Andrew Schaefer, Manuel Schiff, Luisa Semmler, Costanza Lamperti, Serenella Servidei.
       BACKGROUND AND PURPOSE: Mitochondrial Encephalomyopathy, Lactic acidosis and Stroke-like episodes (MELAS) is a rare multisystem mitochondrial disorder with clinical heterogeneity. Diagnostic criteria and management strategies for MELAS and mitochondrial stroke-like episodes (SLE) remain inconsistent. This work provides international consensus recommendations on the definition, diagnosis, and management of MELAS and SLE in pediatric and adult populations.
    METHODS: An international Delphi consensus process was conducted within the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD), in collaboration with the US Mitochondrial Medicine Society, the ERN for Hereditary Metabolic Disorders (MetabERN), and patient representatives. Following a systematic literature review, 54 statements addressing diagnostic definitions and management of MELAS were evaluated. Statements not reaching consensus were revised and re-evaluated during a face-to-face meeting.
    RESULTS: Consensus supported defining MELAS as a clinical syndrome characterized by one or more SLE in the context of mitochondrial dysfunction caused by a pathogenic mitochondrial DNA variant, particularly m.3243A>G in MT-TL1. The use of terms such as "MELAS-like" or "MELAS spectrum" was discouraged. The panel agreed that the efficacy of L-arginine, L-taurine, L-citrulline, coenzyme Q10, vitamins, and other supplements remains unproven and requires validation in clinical trials. Antiseizure medications should be initiated promptly when seizures are suspected during SLE, and intravenous corticosteroids may be beneficial acutely. Multidisciplinary management of neurological, neuropsychiatric, and systemic complications was endorsed.
    CONCLUSIONS: This international consensus provides updated definitions and practical guidance for the diagnosis and management of MELAS and SLE, aiming to harmonize clinical practice and inform future evidence-based research.
    Keywords:  MELAS; consensus; diagnostic criteria; management; primary mitochondrial diseases; recommendations
    DOI:  https://doi.org/10.1111/ene.70588
  4. Nat Commun. 2026 Apr 14.
    Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca2.
    Yingfan Zhang, Hailey A Parry, Laura Reyes, Alex Shamoun, Junhui Sun, Chengyu Liu, Danielle Springer, Audrey Noguchi, Sachiko Nakamori, Angel M Aponte, Jeeva Munasinghe, Raul Covian, Elizabeth Murphy, Brian Glancy.
      Transmembrane protein 65 (TMEM65) depletion in a patient caused severe mitochondrial encephalomyopathy, highlighting its clinical importance. Recent studies show TMEM65 acts as a mitochondrial Na+/Ca2+ exchanger in vitro. Here, we generated conditional Tmem65 knockout mice to define its role in neuromuscular tissues in vivo. Both whole-body and nervous system-specific Tmem65 knockouts exhibited severe growth retardation and seizure-associated sudden death at ~3 weeks, establishing TMEM65 as indispensable for neuronal function. Additionally, skeletal muscle-specific knockout produced adult-onset myopathy preceded by elevated mitochondrial Ca2+. Consistently, TMEM65 ablation caused loss of Na+-dependent mitochondrial Ca2+ export. Notably, blocking mitochondrial Ca2+ entry by mitochondrial calcium uniporter (MCU) knockout rescued the early lethality of whole-body Tmem65 ablation, extending lifespan from ~3 weeks to >1 year. These data reveal an essential physiological role for TMEM65 and suggest that modulating mitochondrial Ca2+ may offer therapeutic value for TMEM65 misexpression and other mitochondrial diseases associated with Ca2+ overload.
    DOI:  https://doi.org/10.1038/s41467-026-71761-w
  5. HGG Adv. 2026 Apr 13. pii: S2666-2477(26)00055-2. [Epub ahead of print] 100615
    Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease.
    Matthieu Mantecon, Cerina Chhuon, Kevin Roger, Ida Chiara Guerrera, Christine Bole, Patrick Nitschke, Claire-Marie Dufeu-Bérat, Margaret Ashcroft, Robert W Taylor, Nathalie Boddaert, Agnès Rötig.
      Mitochondrial disorders show remarkable clinical and genetic heterogeneity, and result from variants in either mitochondrial- or nuclear-encoded genes. CHCHD4 is a component of the mitochondrial import and assembly pathway that imports small cysteine-containing substrates. We report a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Western blot analysis showed decreased levels of CHCHD4 and diminished assembly of complexes I and IV in his fibroblasts. To demonstrate that CHCHD4 variants were responsible for the observed biochemical phenotype, we overexpressed wild-type CHCHD4 in control and subject fibroblasts, restoring levels of complex I and IV proteins and the associated assembly defects Proteomic studies pointed to electron transport and complex I biogenesis as the main dysregulated pathways and showed a severe loss of several complex I and IV proteins and/or assembly factors rescued by overexpression of wild-type CHCHD4. CHCHD4 has numerous targets and interacting factors and is involved in the export of iron-sulfur clusters synthesized inside mitochondria. Surprisingly, few of these interacting factors or non-mitochondrial functions were impacted by the observed CHCHD4 defect. In conclusion, our work establishes CHCHD4 deficiency as a cause of dysregulated mitochondrial protein import resulting in a severe neurological condition.
    DOI:  https://doi.org/10.1016/j.xhgg.2026.100615
  6. Autophagy. 2026 Apr 16. 1-3
    A tRNA epitranscriptomic checkpoint coordinates sperm mitochondrial load with embryonic allophagic clearance.
    Zhenhuan Luo, Qin-Li Wan, Dan Wu, Chenyang He, Tristan Argeo Rodriguez, Qinghua Zhou, Hao Wang.
      The strict maternal inheritance of mitochondrial DNA is enforced by the efficient elimination of paternal mitochondria, yet the role of epigenetic regulation in this process remains unclear. In our recent study, we identify the demethylase ALKB‑1 as an essential factor for paternal mitochondrial elimination (PME) in Caenorhabditis elegans (C. elegans), functioning through tRNA m1A demethylation. ALKB‑1 deficiency leads to tRNA hypermethylation, which disrupts mitochondrial proteostasis and increases ROS production, thereby activating SKN‑1-ATFS‑1 stress signaling. This cascade compromises mitochondrial reduction during spermatogenesis, resulting in an increased burden of paternal mitochondria transmitted to the embryo. Concurrently, ALKB‑1 is required in the embryo to sustain autophagic clearance, evidenced by impaired autophagic flux and delayed PME upon maternal loss. Thus, delayed clearance stems dually from an excessive mitochondrial load in sperm and a compromised autophagic degradation capacity in the embryo. Our work establishes ALKB‑1‑dependent tRNA demethylation as a dual‑germline epitranscriptomic checkpoint that ensures intergenerational mitochondrial quality control.
    Keywords:  Allophagy; Caenorhabditis elegans; demethylase ALKB‑1; paternal mitochondrial elimination; tRNA m1A
    DOI:  https://doi.org/10.1080/15548627.2026.2659294
  7. EMBO Mol Med. 2026 Apr 17.
    Systemic delivery of AAV-GFM1 corrects COXPD1 molecular alterations in Gfm1R671C/- mice.
    Miguel Molina-Berenguer, Diego Herrero-Martínez, Antoni Vallbona-Garcia, Ferran Vila-Julià, Yolanda Cámara, África Vales, Gloria González-Aseguinolaza, Javier Torres-Torronteras, Ramon Martí.
      Hepatoencephalopathy due to mutations in the nuclear gene GFM1, known as combined oxidative phosphorylation (OXPHOS) deficiency type I (COXPD1), is an autosomal recessive mitochondrial disease caused by defects or deficiency of the mitochondrial translation elongation factor G1 (EFG1), with no currently available cure. Patients with COXPD1 develop a severe encephalopathy, sometimes combined with liver failure, with neonatal onset and rapid progression that normally causes premature death. The Gfm1R671C/- mouse recapitulates the COXPD1 molecular phenotype in liver and brain, with drastic reduction of EFG1 levels, impaired mitochondrial translation, and OXPHOS deficiency. We conducted a gene therapy study using two different recombinant adeno-associated virus (rAAV) vectors targeting the liver or the brain to introduce the human GFM1 gene into 6-week-old Gfm1R671C/- mice. Successful transduction of the liver and the brain was observed after four weeks, entailing substantial recovery from mitochondrial EFG1 depletion and OXPHOS correction in both tissues, which demonstrates that transgenic human EFG1 is functional in mouse mitochondrial translation. Our study constitutes the first evidence supporting AAV-mediated gene therapy as a potential treatment for COXPD1.
    DOI:  https://doi.org/10.1038/s44321-026-00426-4
  8. Front Neurol. 2026 ;17 1778719
    Clinical and genetic analysis of Chinese patients with Leigh syndrome caused by biallelic loss-of-function variants of the NDUFAF6 gene.
    Qi Yang, Qiang Zhang, Xunzhao Zhou, Zailong Qin, Xuanjing Liang, Sheng Yi, Shujie Zhang, Weiliang Lu, Shang Yi, Jingsi Luo.
      Leigh syndrome (LS) is the most common pediatric mitochondrial disorder, typically presenting in infancy with developmental regression, neurological dysfunction, and characteristic brain MRI lesions. It is linked to over 110 genes affecting cellular energy production, making it highly genetically heterogeneous, with complex I deficiency being the most frequent cause. Biallelic mutations in NDUFAF6-a key assembly factor of complex I-cause autosomal recessive Leigh syndrome, specifically NDUFAF6-related Leigh syndrome, also designated as mitochondrial complex I deficiency, nuclear type 17 (MC1DN17; OMIM 618239). Herein, we describe two patients with biallelic loss-of-function variants in NDUFAF6. Patient 1 was homozygous for an in-frame duplication (c.362_364dupTGG; p. Val121dup), whereas patient 2 carried this duplication in trans with a novel frameshift variant (c.169_190dup; p. Leu64fs*2). Both patients manifested motor deterioration, dystonia, dysphagia, and elevated blood lactate levels during infancy, along with symmetrical basal ganglia necrosis on brain MRI. A retrospective analysis of all 24 MC1DN17 cases confirmed infantile/childhood onset, psychomotor regression, dystonia, bilateral striatal necrosis with additional features, and hyperlactataemia as universal characteristics. Mortality was low (1/24; 4%), with motor function maintained for longer than in some other LS-associated genetic subtypes. No clear genotype-phenotype correlation was identified, and disease progression remains difficult to predict. There are currently no disease-modifying treatments available; only supportive care can be provided. Our study expands the NDUFAF6 mutational spectrum and consolidates its distinct clinical profile, highlighting the need for long-term data to define natural history and guide therapy.
    Keywords:  Leigh syndrome; NDUFAF6 gene; complex I deficiency; novel variant; whole-exome sequencing
    DOI:  https://doi.org/10.3389/fneur.2026.1778719
  9. Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00193-0. [Epub ahead of print]86(8): 1511-1528.e12
    Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
    Lvxin Xie, Shuchao Ren, Li Zhang, Ziqing Wang, Tong Wu, Qing Dai, Shikun Xiang, Zhihua Qian, Yufan Xian, Shutong Xu, Xiao-Lin Chen, Chuan He, Yi Liu, Zhipeng Zhou.
      Mitochondria generate ATP through oxidative phosphorylation (OXPHOS), with core structural subunits encoded by mitochondrial DNA (mtDNA) and translated by mitochondrial ribosomes. However, how mitochondrial translation elongation influences OXPHOS biogenesis remains unclear. Here, we show that in Neurospora crassa, the mitochondrial ribosomal RNA (rRNA) methyltransferase 1 (MRM1) promotes OXPHOS biogenesis by repressing translation elongation independently of its catalytic activity. The N-terminal intrinsically disordered region (IDR) of MRM1 binds simultaneously to mitochondrial ribosomes and mRNAs. Disrupting either interaction accelerates elongation and enhances synthesis of mtDNA-encoded OXPHOS subunits but impairs their co-translational folding and membrane insertion. Pharmacological slowing of mitochondrial translation partially alleviates these defects. The MRM1 IDR is conserved in Ascomycete fungi and is essential for plant infection by Magnaporthe oryzae. Together, our findings identify translation elongation control as a mechanism coordinating mitochondrial protein synthesis and folding during OXPHOS biogenesis and MRM1 as a potential target for broad-spectrum antifungal strategies.
    Keywords:  Magnaporthe oryzae; Neurospora crassa; mitochondrial rRNA methyltransferase; mitochondrial translation; oxidative phosphorylation; protein folding; translation elongation
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.017
  10. Nature. 2026 Apr 15.
    Cell-type-targeted mitochondrial transplantation rescues cell degeneration.
    Temurkhan Ayupov, Verónica Moreno-Juan, Serena Curtoni, Alex Fratzl, Upnishad Sharma, Susana Posada-Céspedes, Ramona Ratiu, Rei Morikawa, Alexandra Graff Meyer, Margherita Pezzoli, Glenn Bantug, Morgan Chevalier, Yanyan Hou, Sarah A Nadeau, Álvaro Herrero-Navarro, Vikram Ayinampudi, Elizabeth Kastanaki, Natasha Whitehead, Rebecca A Siwicki, Mariana M Ribeiro, Ji Hoon Han, Annalisa Bucci, Christoph Hess, Simone Picelli, Magdalena Renner, Daniel J Müller, Cameron S Cowan, Simon Hansen, Botond Roska.
      A number of currently untreatable diseases, including neurodegenerative disorders, optic nerve atrophy and heart failure, are associated with mitochondrial dysfunction. Transplantation of healthy mitochondria has been proposed as a potential therapeutic strategy1-3. However, the lack of methods to target donor mitochondria to disease-affected cell types limits treatment specificity and efficacy. Here we developed MitoCatch as a system to deliver mitochondria to specific cell types using different types of protein binders. Donor mitochondria are captured by target cells by cell-surface-displayed monospecific binders, mitochondrion-displayed monospecific binders or bispecific binders linking mitochondria to target cells. Using MitoCatch, we show that donor mitochondria are efficiently internalized, exposed to the cytosol, move, and undergo fusion and fission inside target cells. By engineering binders with different affinities, we tune the efficiency of mitochondrial delivery. We demonstrate targeted mitochondrial transplantation to retinal cell types, neurons and cardiac, endothelial and immune cells in humans and mice. Transplanted mitochondria promoted the survival of damaged neurons from an individual with optic nerve atrophy in vitro and after neuronal injury in mice in vivo. MitoCatch is a potential strategy to target disease-affected cell types with mitochondria in organs affected by diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41586-026-10391-0
  11. Cells. 2026 Mar 27. pii: 596. [Epub ahead of print]15(7):
    Reversible Metabolic and Liver Disease in Complex III Deficiency: Novel Variants Expand the Reported UQCRC2-Associated Phenotype.
    Graeme Preston, Ibrahim Shammas, Filippo Pinto E Vairo, Anna Ligezka, Carlos Alberto de Moura Aschoff, Fabiano Poswar, Ida Vanessa D Schwartz, Tamas Kozicz, Eva Morava.
       INTRODUCTION: Ubiquinol-cytochrome c reductase core protein II (UQCRC2) encodes a core subunit of the mitochondrial electron transport chain (ETC) complex III (CIII). Biallelic pathogenic variants in UQCRC2 have been associated with mitochondrial disease characterized by lactic acidosis, developmental delay, hepatopathy, and episodic metabolic decompensation.
    METHODS: We reviewed the biochemical phenotypes of 14 individuals possessing UQCRC2 variants, including two novel cases. We performed biochemical studies of mitochondrial respiration and oxidative phosphorylation (OXPHOS) complex measurements in patient-derived fibroblasts.
    RESULTS: We report reduced CIII activity in a majority of individuals possessing variants in UQCRC2, as well as biochemical findings consistent with impaired mitochondrial energy metabolism, though impairments in mitochondrial respiration were variable. The two previously unreported, unrelated patients possessing the likely pathogenic missense variant c.361T>C, p.Tyr121His in UQCRC2 in trans with a 16p12.2 microdeletion encompassing UQCRC2 showed milder phenotypes, less severe metabolic decompensations, and no long-term neurological impairments. Both individuals display reduced CIII activity and mitochondrial respiratory dysfunction.
    DISCUSSION: These data expand the current understanding of genotypes associated with UQCRC2-associated mitochondrial disease to include the novel 16p12.2 microdeletion. These data also highlight the consistent biochemical phenotype associated with UQCRC2-associated mitochondrial disease, and the need for consistent biochemical and respiratory assessment of individuals possessing UQCRC2 variants to further our understanding of this phenotype.
    Keywords:  OXPHOS; Seahorse; complex III; hyperammonemia; microdeletion 16p12.2; mitochondrial
    DOI:  https://doi.org/10.3390/cells15070596
  12. J Cell Sci. 2026 Apr 13. pii: jcs.264577. [Epub ahead of print]
    A ULK1-MTFR1L feedback loop links mitochondrial fission, mitophagy and apoptosis.
    Riccardo Babic, Leon Lucya, Christoph Reiter, Franziska Kriegenburg, Ramón Castellanos-Martínez, David M Hollenstein, Florian Becker, Carola Hunte, Claudine Kraft.
      Mitophagy, the selective degradation of damaged mitochondria, preserves mitochondrial quality, yet how mitochondrial fission is coordinated with autophagy initiation remains unclear. Here we identify the mitochondrial outer membrane protein MTFR1L as a key component of mitophagy initiation hubs after using a synthetic FKBP-FRB system to tether ULK1 kinase to mitochondria independently of damage. We find that MTFR1L is enriched at ULK1 foci together with additional fission factors and constitutive mitochondrial targeting of MTFR1L shifts mitochondrial morphology towards fragmentation. MTFR1L depletion decreases respiratory capacity, elevates apoptosis, and impairs mitophagy flux. Upon mitophagy induction, MTFR1L is phosphorylated in a ULK1 kinase-dependent manner, and reciprocally modulates ULK1 activity, establishing a feedback loop. Moreover, MTFR1L is required for proper ATG13 stability. These findings position MTFR1L as a critical link between mitochondrial fission and the autophagy machinery, coordinating mitophagy initiation and cell survival.
    Keywords:  ATG13; Autophagy; MTFR1L; Mitophagy; ULK1
    DOI:  https://doi.org/10.1242/jcs.264577
  13. Cells. 2026 Apr 02. pii: 646. [Epub ahead of print]15(7):
    Adenine Nucleotide Translocase: From Nucleotide Carrier to a Modulator of Mitochondrial Bioenergetics, Quality Control, and Cellular Communication.
    Ursula Rauch-Kroehnert, Jacqueline Heger, Ulf Landmesser, Andrea Dörner.
      Adenine nucleotide translocase (ANT) has traditionally been defined as the ADP/ATP exchanger of the inner mitochondrial membrane. However, accumulating mechanistic evidence reveals a substantially broader functional spectrum that extends beyond nucleotide transport. In this review, we integrate these advances into a unified conceptual framework that positions ANT isoforms as modulators of mitochondrial bioenergetics, quality control, and cellular communication. Beyond its canonical exchange activity, ANT influences permeability transition thresholds and membrane potential stability, participates in regulated uncoupling and redox control, and contributes to inner membrane organization and cristae integrity. ANT further modulates TIMM23-dependent protein import and PINK1-Parkin-mediated mitophagy, thereby shaping mitochondrial quality control decisions. In addition, ANT regulates mitochondrial nucleic acid release and inflammasome activation, linking bioenergetic imbalance to innate immune signaling. Emerging evidence for alternative subcellular localizations suggests that ANT-dependent signaling extends mitochondrial state information to extracellular and intercellular contexts. Collectively, these findings support an expanded view of ANT as a multifunctional modulator linking mitochondrial energetic state to stress adaptation, inflammatory signaling, and tissue-level communication.
    Keywords:  adenine nucleotide translocase; dsRNA transport; extracellular vesicles; immunometabolism; mitochondrial dynamics; mitochondrial permeability transition pore; mitochondrial signaling; mitochondrial uncoupling; mitophagy; mtDNA stability
    DOI:  https://doi.org/10.3390/cells15070646
  14. Sci Rep. 2026 Apr 16.
    Comparative analysis of muscle pathologies and metabolic signaling in mouse models of mitochondrial dysfunction.
    Hiroaki Tamashiro, Kaori Ishikawa, Kazuto Nakada.
      Mitochondria are vital organelles that produce ATP through oxidative phosphorylation, sustaining skeletal muscle, a tissue with high energy demand. When mitochondrial function is impaired, intracellular energy and nutrient balance are disrupted, activating metabolic signaling pathways. However, these responses vary across models, and the relationship between muscle pathology and signaling remains unclear. To address this, we compared soleus muscle pathology in Polgmut/mut mice, a premature aging model, and Mito-mice∆, a mitochondrial disease model. Both exhibited abnormal histochemical activity in mitochondrial respiration complex II and IV, yet differed in severity of mitochondrial accumulation and fiber-type-specific vulnerability. To explore the basis of these differences, we examined metabolic signaling pathways. Notably, phosphorylation levels of AMPK, a key sensor activated in response to altered AMP/ATP ratios, were significantly different between the two models. These findings suggest that muscle pathology induced by mitochondrial dysfunction is determined less by the extent of abnormalities in mitochondrial respiration complexes than by the specific metabolic signaling pathways engaged. This highlights the importance of signaling context in shaping disease mechanisms and underscores the need to consider pathway-specific responses when investigating mitochondrial dysfunction in skeletal muscle.
    Keywords:  Metaboloc signaling; Mitochondria; Mouse models; Muscle pathology
    DOI:  https://doi.org/10.1038/s41598-026-48532-0
  15. Exp Cell Res. 2026 Apr 13. pii: S0014-4827(26)00143-6. [Epub ahead of print] 115026
    The Caenorhabditis elegans Mitochondrial Electron Transport Chain: its role in Adaptation, Longevity, and Biotechnology.
    Estefani Yaquelin Hernández-Cruz, Salvador Uribe-Carvajal.
      In Caenorhabditis elegans (C. elegans) the mitochondrial electron transport chain (ETC) exhibits remarkable functional plasticity. This review summarizes the composition, regulation, and adaptive roles of complexes I-V. Depending on oxygen availability, the ETC uses either ubiquinone (UQ) or rhodoquinone (RQ), an ancestral strategy for hypoxia or high hydrogen sulfide (H2S) conditions. Mild ETC impairments can extend lifespan through redox signaling, mitohormesis, and activation of the mitochondrial unfolded protein response. These processes likely represent conserved mechanisms of bioenergetic adaptation and longevity. Moreover, C. elegans server as a translational model for human mitochondrial diseases and for screening mitochondrial or antiparasitic compounds.
    Keywords:  Caenorhabditis elegans; electron transport chain; longevity; mitochondria; rhodoquinone
    DOI:  https://doi.org/10.1016/j.yexcr.2026.115026
  16. Cell Metab. 2026 Apr 15. pii: S1550-4131(26)00106-3. [Epub ahead of print]
    Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
    Ignacio Heras-Murillo, Diego Mañanes, Josep Calafell-Segura, Adrián Belinchón García, Clara Borràs-Eroles, Pablo Munné, Annalaura Mastrangelo, Sarai Martínez-Cano, Pablo Hernansanz-Agustín, María A Zuriaga, José J Fuster, Marten Szibor, Ignacio Melero, José Antonio Enríquez, Navdeep S Chandel, Esteban Ballestar, Stefanie K Wculek, David Sancho.
      Activation of conventional dendritic cells (cDCs) favors increased glycolysis-driven lactic fermentation, while oxidative phosphorylation (OXPHOS) links to tolerance. Here, selective targeting of the mitochondrial electron transport chain (ETC) in cDCs uncovers a critical role for OXPHOS in regulating their immunogenicity. Disruption of ETC complex III dampens adjuvant-triggered primary human and mouse cDC1 activation and their capability to prime T cells for anti-cancer immunity, while it has a milder effect on cDC2s. Mechanistically, complex III impairment in cDC1s leads to a dysregulated redox and metabolite balance, altering DNA methylation of PU.1 and activator-protein-1 (AP-1) binding regions. These epigenetic changes hinder the rapid induction of immediate-early stimulus-induced genes in cDC1s upon stimulation. The reduced immunogenic responsiveness of ETC-impaired cDC1s can be rescued by ectopic expression of alternative oxidase and phenocopied by Tet2 deficiency. Our findings reveal that electron flow through the ETC maintains a poised activation state in cDC1s, essential for effective anti-tumor immunity.
    Keywords:  DNA methylation; dendritic cells; electron transport chain; immunity; metabolites; mitochondria; redox balance
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.012
  17. Front Cell Dev Biol. 2026 ;14 1779332
    Beyond the genome: clinical challenges in diagnosing LONP1-related mitochondrial disorders.
    Qianni Jiang, Jing Duan, Chao Liu, Yuanyuan Zhu, Qi Zeng, Yuhui Hu, Zhiqiang Luo, Dezhi Cao, Jianxiang Liao, Li Chen.
       Background: LONP1 encodes an ATP-dependent protease essential for maintaining mitochondrial homeostasis. LONP1 variants have been associated with cerebral-ocular-dental-auricular-skeletal anomalies syndrome, pediatric cataract, congenital diaphragmatic hernia, and neurodevelopmental disorders; moreover, these variants can be inherited in both autosomal recessive and autosomal dominant modes.
    Methods: We conducted a retrospective analysis of the clinical data and genetic test results of a Chinese boy diagnosed as having mitochondrial encephalopathy. Subsequently, we evaluated the pathogenicity of candidate variants and conducted a literature review encompassing 47 cases of LONP1 variants.
    Result: The proband was a 4.5-year-old boy who had experienced focal epilepsy seizures since birth. He presented with recurrent seizures and did not respond to anti-seizure medications. He showed global developmental delay, microcephaly, pachygyria, and hyperlactatemia. Initial genetic testing through single and trio whole-exome sequencing before 6 months of age yielded no conclusive results. Recurrent seizures and elevated lactic acid levels at 18 months of age prompted reanalysis with trio whole-exome sequencing, leading to the identification of a likely pathogenic variant in LONP1: c.901C>T (p.Arg301Trp). By 10 months of age, the patient had already developed primary adrenal insufficiency and experienced multiple adrenal crises triggered by respiratory infections, necessitating admission to the intensive care unit. The crises were effectively managed with hydrocortisone. However, despite intensive medical interventions, the patient succumbed to a metabolic crisis triggered by a severe respiratory infection at the age of 4.5 years.
    Conclusion: In this study, we discuss the clinical manifestations and genetic features of a pediatric patient with mitochondrial encephalopathy resulting from a rare LONP1 variant, emphasizing the diagnostic and therapeutic challenges of mitochondrial disorders. Furthermore, our findings enhance the understanding of LONP1-related diseases and offer additional evidence supporting the autosomal dominant inheritance pattern of LONP1.
    Keywords:  CODAS syndrome; LONP1; adrenal crises; autosomal dominant; mitochondrial encephalopathy
    DOI:  https://doi.org/10.3389/fcell.2026.1779332
  18. Life Sci Alliance. 2026 Jun;pii: e202503446. [Epub ahead of print]9(6):
    Scalable workflows for high-throughput respirometry.
    Corey A Osto, Eugene V Mosharov, Ayelet M Rosenberg, Martin Picard, Linsey Stiles, Orian Shirihai.
      Mitochondrial respirometry, the measurement of oxygen consumption rate (OCR) by the electron transport chain (ETC), is a cornerstone of mitochondrial biology and the gold standard for measurements of mitochondrial function. However, existing respirometry methodologies are poorly suited for large-scale studies and high-throughput applications, ultimately limiting the applicability of these methods. This limitation necessitates new methodologies, which are more easily scaled as mitochondrial studies become more complex and diverse. In this study, we detail a respirometry approach we have developed for high-throughput applications including optimized plate layouts, volume-based sample normalization, robust control selection, and automated data processing and quality control. Furthermore, we validate these methodologies across a respirometry study running 703 human brain samples, totaling more than 10,000 data points, which underwent our automated data processing and quality control techniques. Our workflow streamlines assay preparation, execution, and analysis to make respirometry scalable, while reducing operator burden and preserving data integrity. With this study, we provide a transferable blueprint for high-throughput respirometry as the mitochondrial biology field and the studies within it continue to expand in scale.
    DOI:  https://doi.org/10.26508/lsa.202503446
  19. Nat Rev Nephrol. 2026 Apr 14.
    Therapeutic and mechanistic insights on mitochondrial transplantation in kidney disease.
    James D McCully, Aybuke Celik, Amish Asthana, Giuseppe Orlando.
      Acute kidney injury (AKI) and chronic kidney disease (CKD) are major contributors to global morbidity and mortality, with limited treatment options beyond supportive care. Mitochondrial dysfunction is a shared feature of both conditions, driving impaired energy production, oxidative stress and cell death. Owing to its reliance on oxidative phosphorylation, the kidney is especially vulnerable to ischaemia-reperfusion injury, a leading cause of AKI and a risk factor for long-term loss of kidney function. Persistent mitochondrial damage contributes to the transition from AKI to CKD, and strategies aimed at restoring mitochondrial health, therefore, have therapeutic potential. Here, we focus on mitochondrial transplantation, a therapeutic approach that delivers viable, respiratory-competent mitochondria to injured tissue to support recovery. Mitochondria for transplantation can be isolated from a variety of sources (autologous or allogeneic) without triggering an immune, autoimmune or inflammatory response, or a reaction to damage-associated molecular patterns. Isolated mitochondria can be delivered by intra-arterial injection, and, once in the target organ, they are rapidly integrated into the cells through endocytosis. Mitochondrial transplantation supports the restoration of mitochondrial function and associated signalling pathways, promoting enhanced organ function and cellular viability. Several preclinical studies have demonstrated improved kidney function, reduced inflammation and preserved mitochondrial structure following mitochondrial therapy in models of ischaemia.
    DOI:  https://doi.org/10.1038/s41581-026-01072-2
  20. Nature. 2026 Apr 15.
    Therapeutic mitochondria transplants made more efficient with targeting tool.
    Samantha J Krysa, Jonathan R Brestoff.
      
    Keywords:  Biotechnology; Cell biology; Diseases
    DOI:  https://doi.org/10.1038/d41586-026-00910-4
  21. Precis Clin Med. 2026 Jun;9(2): pbag010
    Mitochondrial homeostasis: the central hub governing the progression of atherosclerosis.
    Hao Liu, Shuaiyong Zhao, Huiqin Gao, Yue Wang, Junyan Gao, Ping Guo, Yiting Yang, Wenrui Cui, Shuanglin Zhang, Yaping Shi, Guanxing Xie, Yutong Han, Junya Zhou, Qingqi Zhang, Yunzeng Zou.
      Atherosclerosis is a disease centered on chronic inflammation, in which mitochondrial damage plays a key role in its initiation and progression. Traditionally, atherosclerosis is thought to be triggered by cholesterol accumulation, but recent studies have revealed that mitochondrial dysfunction has emerged as an important driving factor by inducing innate immune imbalance. In atherosclerosis, mitochondria undergo changes in membrane permeability, metabolic disorders, and dynamic imbalance due to oxidative stress and other factors, releasing mitochondrial damage-associated molecular patterns (mt-DAMPs). These mt-DAMPs activate innate immune pathways, promote the production of type I interferons and the release of pro-inflammatory factors such as interleukin 1β, and accelerate plaque progression. Mitophagy exerts a protective effect by eliminating damaged mitochondria. Specifically, the PINK1-Parkin pathway labels damaged mitochondria through ubiquitination; mitophagy receptors (such as NIX, FUNDC1, and BNIP3) directly bind to LC3 to initiate ubiquitination-independent mitophagy; and mitochondrial-derived vesicles selectively encapsulate damaged components and target them to lysosomes for degradation. All these processes can reduce mt-DAMP-induced damage and inhibit excessive immune activation. In this review, we summarize that innate immune imbalance caused by mitochondrial damage is a key mechanism for atherosclerosis progression. Mitochondrial quality control clears damaged mitochondria through multiple pathways, alleviates inflammatory responses and plaque burden, and provides potential targets for atherosclerosis treatment. Its precise regulatory mechanisms and drug development are future research directions.
    Keywords:  atherosclerosis; immunometabolism; mitochondrial DNA (mtDNA); mitochondrial homeostasis; mitochondrial quality control; mt-DAMPs
    DOI:  https://doi.org/10.1093/pcmedi/pbag010
  22. Nat Commun. 2026 Apr 11. pii: 3436. [Epub ahead of print]17(1):
    Blockage of autophagy causes severe skeletal muscle disruption in a mouse model for myofibrillar myopathy 6.
    Kerstin Filippi, Kathrin Graf-Riesen, Maithreyan Kuppusamy, Andreas Unger, Kenichi Kimura, Martin Matijass, Henrique Baeta, Magdalena Podlacha, Daniel Haertter, Alexei P Kudin, Martin Wiemann, Grzegorz Węgrzyn, Cornelia Kornblum, Jens Reimann, Wolfgang A Linke, Pitter F Huesgen, Wolfram S Kunz, Bernd K Fleischmann, Michael Hesse.
      Myofibrillar myopathy 6 is a rare, autosomal-dominant neuromuscular disorder caused by an amino acid exchange Pro209Leu in the co-chaperone BAG3, which disrupts muscle protein turnover and causes severe muscle weakness and shortened lifespan. We generated transgenic mice overexpressing the human mutant BAG3P209L-GFP, which rapidly develop skeletal muscle weakness unlike controls expressing BAG3WT-GFP. Here we show that mutant mice exhibit sarcomere breakdown, inflammation, protein aggregates, centralized nuclei and mitochondrial defects in their skeletal muscles, thereby reducing contraction force by ~90%. Omics profiling uncovered impaired protein synthesis, blocked autophagy, impaired mitophagy and loss of sarcomere proteins. Pathway modulation in vitro and in vivo showed autophagy dysfunction as the primary driver for the pathology, while BAG3 knockdown gene therapy markedly restored muscle function in vivo. In summary, this model recapitulates core disease features, revealing how BAG3 aggregates and loss of BAG3 function impair autophagy to drive muscle degeneration.
    DOI:  https://doi.org/10.1038/s41467-026-71749-6
  23. NPJ Precis Oncol. 2026 Apr 16.
    Mitochondrial translocation of MDM2 and TFAM reprograms metabolism in treatment-refractory cancers.
    Jie Qing Eu, Nur Afiqah Binte Mohamed Salleh, Jayshree Hirpara, Naoto Ohi, Emiri Omori Takaki, Tuan Zea Tan, Ju Ee Seet, Susan Swee-Shan Hue, Shu Jun Chan, Dorothy Xi Yue Lim, Lingzhi Wang, Regina Tong Xin Wong, Azhar Ali, Yaw Chyn Lim, Boon-Cher Goh, Li Ren Kong, Shazib Pervaiz, Andrea LA Wong.
      Tyrosine kinase inhibitors (TKI) are frontline therapies for oncogene-addicted cancers, yet metabolic rewiring frequently drives acquired resistance. Here, we identify a mitochondrial trafficking mechanism that regulates oxidative phosphorylation (OXPHOS) dependence in TKI-resistant tumours. Using resistant cell models and patient-derived materials, we demonstrate that OXPHOS activation is regulated by an AKT-driven, competitive interaction between mitochondrial MDM2 and the mitochondrial transcription factor TFAM at mitochondrial DNA (mtDNA). Mechanistically, adaptive AKT activation promotes cytosolic redistribution of MDM2 with reciprocal accumulation of TFAM in mitochondrial, enhancing mtDNA transcription and OXPHOS activity. To validate this mitochondrial-cytosolic exchange, we develop a quantitative, high-resolution imaging approach to map MDM2 and TFAM localization. In a TKI-resistant clinical cohort (n = 76), we revealed a positive correlation between AKT activation, MDM2 phosphorylation and TFAM mitochondrial trafficking, defining a spatial, subcellular biomarker signature of metabolically reprogrammed TKI resistance. Pharmacologic disruption of the AKT-MDM2-TFAM signaling axis reverse TKI resistance, linking mitochondrial genome regulation to therapy resistance and suggesting a metabolic vulnerability for combinatorial targeting.
    DOI:  https://doi.org/10.1038/s41698-025-01257-1
  24. Nat Commun. 2026 Apr 15.
    Variants in the proteasome regulator PSMF1 cause a phenotypic spectrum from parkinsonism to perinatal lethality.
    PSMF1 Study Group
      Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here we identify PSMF1 as a gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal lethality with neurological manifestations across 18 pedigrees with 25 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/hPI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants may affect proteasomal abundance and assembly, and are associated with alterations of mitochondrial membrane potential, respiration, dynamics and mitophagy in patient-derived fibroblasts. Furthermore, Drosophila and mouse models of PI31 loss of function exhibit age-dependent motor impairment, as well as brain-wide mitochondrial membrane depolarization and dopaminergic neurodegeneration in aged flies, and diffuse gliosis in mice. Collectively, our findings unequivocally link defective PSMF1/hPI31 to early-onset parkinsonism and neurodegeneration, and suggest proteasomal and mitochondrial dysfunction as pathogenic contributors.
    DOI:  https://doi.org/10.1038/s41467-026-71351-w
  25. J Transl Med. 2026 Apr 17.
    Mitochondrial DNA regulation of hepatic ischemia-reperfusion injury and intervention strategies.
    Ruotong Shen, Peng An, Mengwei Chen, Ping Lu, Jingjing Yang, Longlong Wu, Rong Wang.
      
    Keywords:  Immune responses and inflammatory damage; Ischemia-reperfusion injury; Mitochondrial DNA; Mitochondrial quality control; Programmed cell death
    DOI:  https://doi.org/10.1186/s12967-026-08155-5
  26. Diabetologia. 2026 Apr 17.
    ROMO1 and mitochondrial complex II/SDH are required for spare respiratory capacity and glucose homeostasis in mice.
    Lisa Wells, Qian Yang, Caterina Iorio, Mithusha Peragerasingam, Zurie Campbell, Andy Cheuk-Him Ng, Courtney Reeks, Siu-Pok Yee, Robert A Screaton.
       AIMS/HYPOTHESIS: Reactive oxygen species modulator 1 (ROMO1) is a highly conserved inner mitochondrial membrane protein that senses reactive oxygen species and regulates mitochondrial dynamics. ROMO1 is required for mitochondrial fusion in vitro, and silencing ROMO1 increases sensitivity to cell death stimuli. The physiological role of ROMO1 remains unclear.
    METHODS: To determine the role of Romo1 in vivo, we used gene targeting in mice to ablate Romo1 in the whole mouse and to conditionally knock out Romo1 in the pancreatic beta cell. Mitochondrial functional analyses were performed on isolated mouse and human islets lacking Romo1/ROMO1.
    RESULTS: We show that ROMO1 is essential for embryonic development, as Romo1 null mice die before embryonic day 8.5, earlier than GTPases OPA1 or MFN1/2 which catalyse mitochondrial inner and outer membrane fusion. Knockout of Romo1 in adult pancreatic beta cells results in impaired glucose homeostasis in young male mice (4 months) due to an insulin secretion defect. Isolated islets from male, but not female, mice showed impaired glucose-stimulated insulin secretion. While mitochondria from female mice were morphologically normal, mitochondria in Romo1 adult beta cell knockout (RABKO) cells from male mice were swollen and fragmented, with a reduction in mtDNA content. Knockout of Romo1 did not affect basal respiration in males or females, but deletion of Romo1 in both sexes in mice and of ROMO1 in isolated human islets reduced spare respiratory capacity, which involved the specific loss of respiratory activity at complex II/succinate dehydrogenase. Ageing of female RABKO mice resulted in loss of spare respiratory capacity and glucose intolerance.
    CONCLUSIONS/INTERPRETATION: Our data demonstrate that ROMO1 is a key regulator of mitochondrial bioenergetics and spare respiratory capacity and is required for effective nutrient coupling to insulin secretion in the beta cell. These observations point to a critical role for spare respiratory capacity in the maintenance of euglycaemia and to the potential for targeting ROMO1/complex II to promote glucose coupling in settings of insulin insufficiency.
    Keywords:  Islet; Mitochondria; Pancreatic beta cell; RNA interference; ROMO1; Spare respiratory capacity; Type 2 diabetes
    DOI:  https://doi.org/10.1007/s00125-026-06728-z
  27. Front Immunol. 2026 ;17 1743261
    Mitochondrial transfer as a driver of immune microenvironment remodeling.
    Xiaoya Zhang, Danmei Zhang, Jin Guo, Chunxia Shi, Zuojiong Gong.
      Mitochondria are central regulators of immunometabolism, and emerging evidence identifies intercellular mitochondrial transfer as a key driver of immune microenvironment remodeling. Beyond energy production, transferred mitochondria reshape immune niches by reprogramming metabolic fitness, redox balance, inflammatory tone, and immune cell interactions. Through multiple transfer routes, including tunneling nanotubes, extracellular vesicles, and gap junctions, mitochondrial exchange modulates immune activation, immunosuppression, and tolerance across diverse physiological and pathological contexts. In this review, we summarize current mechanisms of mitochondrial transfer and highlight how this process directionally remodels the immune microenvironment in inflammation, cancer, and autoimmune diseases. We further discuss therapeutic strategies aimed at modulating mitochondrial transfer to reprogram immune responses, providing new perspectives for immunomodulation and disease intervention.
    Keywords:  cancer; immune cell; immune microenvironment; inflammation; mitochondria transfer
    DOI:  https://doi.org/10.3389/fimmu.2026.1743261
  28. Trends Biochem Sci. 2026 Apr 16. pii: S0968-0004(26)00061-7. [Epub ahead of print]
    Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.
    Andrew N Bayne, Jean-François Trempe.
      PINK1/Parkin-mediated mitophagy and other related mitochondrial quality control pathways are critical to maintaining cellular homeostasis and neuronal health, and indeed, mutations in PINK1 and PRKN that disrupt this pathway cause early-onset Parkinson's disease. While PINK1-dependent Parkin recruitment to damaged mitochondria has been established for over a decade, recent structural and biochemical advances have illuminated the mechanisms governing their allosteric activation and integration into broader cellular signaling networks. This review synthesizes these insights, focusing on the molecular determinants of PINK1/Parkin activation and the regulatory crosstalk that integrates mitophagy with other cellular stress responses. These mechanistic advances position the PINK1/Parkin pathway as a promising, tractable therapeutic target for Parkinson's disease and related pathologies.
    Keywords:  PINK1; Parkin; Parkinson’s disease; mitochondrial quality control (MQC); mitophagy; stress response; therapeutic development
    DOI:  https://doi.org/10.1016/j.tibs.2026.02.014
  29. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2509165123
    Rhesus macaques with an OPA1 mutation demonstrate features of autosomal dominant optic atrophy.
    Tracy N Jaggers, Ana Ripolles-Garcia, Ala Moshiri, Brett D Story, Jun Wang, Rui Chen, Lucy G Moore, Leandro B C Teixeira, Jaeho Shim, Ana C Raposo, Maria Isabel Casanova, Sophie M Le, Sangwan Park, Laura J Young, Soohyun Kim, Karolina P Roszak, Vanessa Ureno, Paige M Karpinen, Nayeli Echeverria, Monica Ardon, Brian C Leonard, Marguerite Knipe, Eliza Bliss-Moreau, Brad Fortune, J Timothy Stout, Jeffrey Rogers, Nicholas Marsh-Armstrong, Sara M Thomasy.
      Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy primarily caused by mutations in OPA1. We identified and defined a spontaneous nonhuman primate (NHP) model of ADOA using rhesus macaques heterozygous for a missense mutation (OPA1A8S). With ocular examinations, ophthalmic imaging, electroretinography, histopathology, immunohistochemistry, and transmission electron microscopy (TEM), we documented retinal nerve fiber layer (RNFL) thinning, retinal ganglion cell (RGC) loss and dysfunction, OPA1 mislocalization, and reduced axonal mitochondrial density in affected macaques. Our investigation revealed substantial phenotypic variability among affected macaques, shedding light on the pathogenesis of ADOA. The retinas were evaluated using techniques such as spectral-domain optical coherence tomography and fundus photography facilitating observation of structural changes in the retina and optic nerve. Thinning of the RNFL and optic nerve head degeneration, hallmark features of ADOA, were observed in affected macaques. Decreased RGC function in the OPA1 heterozygotes was demonstrated with pattern electroretinography. Histopathological analysis and immunohistochemical staining of postmortem retinal tissue suggested RGC loss in the papillomacular bundle, with reduced OPA1 and mitochondria in the RGC axons, indicating dysfunctional mitochondrial dynamics and reduced function consistent with ADOA. Ultrastructural changes were evident with TEM including dysmorphic mitochondria, axonal loss, myelin disruption, and hypertrophic astrocytic processes. The observed similar pattern of RGC loss and dysfunction coupled with phenotypic heterogeneity in our NHP model reflects the clinical variability observed in human ADOA patients indicating that therapeutic interventions in this foveate model will likely translate to the human condition.
    Keywords:  OPA1; autosomal dominant optic atrophy; nonhuman primate; optic neuropathy; retinal ganglion cell
    DOI:  https://doi.org/10.1073/pnas.2509165123
  30. Pharmacol Res. 2026 Apr 15. pii: S1043-6618(26)00109-X. [Epub ahead of print] 108194
    Metabolic Control of Immunity and Inflammation: Mitochondrial Dynamics, Pharmacological Targets, and Therapeutic Opportunities.
    Chunling Wang, Wangzheqi Zhang, Yue Shu, Lizhou Song, Yiwen Wan, Haoling Zhang, Lulong Bo, Yadong Guo.
      Immune responses and inflammation are not stand-alone processes linearly regulated by the canonical signaling pathways but complex systems biology events, which are deeply rooted in the metabolic state of cells and dynamically modulated. However, immunometabolic studies have identified that programmed alterations of metabolic circuits also occur during activation of immune cells, effector function maintenance and the induction of tolerance. Mitochondria represent a unique point of convergence between energetics, inflammation and immunity, particularly as they are key orchestrators of immune responses. In addition to their classical roles in oxidative phosphorylation (OXPHOS) and metabolic intermediate synthesis, mitochondria are involved in innate immune perception of inflammatory signals and the amplification of these responses by generating reactive oxygen species (ROS), bioenergetic signaling intermediates, and mitochondrial DNA. Crucially, mitochondria are not stable entities but are tightly regulated by dynamic events such as fusion, fission, trafficking and selective degradation. These structural alterations dynamically influence the metabolic commitment, inflammatory response potency and fate choices of immune cells. Mitochondrial dynamics should not be regarded as a mere auxiliary regulatory layer of immunometabolism; instead, they represent the central organizing principles between metabolic states, inflammatory cues, and immune cell fate determination, thereby defining a new hierarchical organization of immune and inflammatory regulation.
    Keywords:  Immunometabolism; immune cell fate; inflammatory responses; mitochondrial dynamics; pharmacological targets; therapeutic opportunities
    DOI:  https://doi.org/10.1016/j.phrs.2026.108194
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