bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–03–22
48 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. m.10010T>C Mitochondrial Disease: A Case Report With Hypoparathyroidism and Review of the Literature.
  2. Masked mitochondria slip into cells to treat disease in mice.
  3. Integrated molecular and clinical profiling of primary mitochondrial oxidative phosphorylation disorders in an Indian cohort: Insights from genetics, neuroimaging, and machine learning.
  4. Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.
  5. MitoTracker transfers from astrocytes to neurons independently of mitochondria.
  6. Transplantation of encapsulated mitochondria alleviates dysfunction in mitochondrial and Parkinson's disease models.
  7. Mitochondrial Precursor Overaccumulation Stress.
  8. Mobile Powerhouses: Mitochondria Transfer via Tunnelling Nanotubes in Brain Health and Neurodegenerative Diseases.
  9. Disturbed mitochondrial maturation in cardiolipin remodeling-deficient cardiomyocytes.
  10. Structures of respiratory supercomplexes and ATP synthase oligomers in mammalian mitochondrial inner membrane.
  11. Mitochondrial control of glycerolipid synthesis by a PEP shuttle.
  12. Deficient Cardiolipin Remodelling Alters Muscle Fibre Composition and Neuromuscular Connectivity in Barth Syndrome.
  13. Noncanonical role of MTP-18 in mitochondrial function and aging via electron transport chain interactions in Caenorhabditis elegans.
  14. Lifespan Predicts Mitochondrial Substitution Rates Across Vertebrates, but Methodology Matters.
  15. The regulation of mitochondrial ferritin on mitochondrial redox balance is essential to cell fate decision.
  16. Molecular mechanisms of mitochondrial uncoupling: focus on 2,4-dinitrophenol.
  17. Therapeutic Targeting of the Mitochondrial Dysfunction-PANoptosis Axis: Mechanistic Insights and Emerging Strategies.
  18. Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.
  19. Visual Loss from Leber's Optic Neuropathy Presenting in a 76-Year-Old Man with the 14484 Mutations.
  20. Impact of compound heterozygous SDHA variants on mitochondrial function in pediatric with neurological disease.
  21. Quantitative imaging of mitochondrial redox conditions at the single-organelle level.
  22. RHOT Proteins Link Mitochondrial Motility to Cardiomyocyte Sarcomere Maturation.
  23. TDP-43 impairs glycolysis by sequestering hexokinase 1 in amyotrophic lateral sclerosis.
  24. m6A deficiency induces dopaminergic neurodegeneration and progressive parkinsonism through a pathogenic loop with mitochondria.
  25. POLG-Related Parkinsonism with Good Response to Deep Brain Stimulation.
  26. MFF budding from mitochondria regulates melanosome size and maturation.
  27. Mitochondria "Shackled" by Mutant Huntingtin: Analysis of Morphological Alterations and Disruptions of Intracellular Transport.
  28. Pregnancy precipitates metabolic imbalance and accelerates death in an animal model of mitochondrial cardiomyopathy.
  29. The NAD-brain pharmacokinetic study of NAD augmentation in blood and brain using oral precursor supplementation.
  30. Non-muscle tropomyosins inhibit Myosin-19 and dynamically localize to mitochondrially-associated actin filaments.
  31. Aging Triggers an Intestinal Energy Crisis and HDL3 Deficiency Disrupting Gut-Liver Axis Homeostasis.
  32. Mitochondria acidify lysosomes through membrane contacts.
  33. SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.
  34. In vivo dynamic nuclear polarization magnetic resonance imaging reveals cardiac mitochondrial redox imbalance as an early indicator of heart failure.
  35. Progressive cognitive impairment and ventricular tachycardia in a boy with biallelic POLG variants and a de novo RYR2 variation.
  36. Human Endonuclease G Preferentially Cleaves Oxidatively Damaged DNA.
  37. ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.
  38. Cell-free mitochondrial DNA (cf-mtDNA) in human body fluids: molecular characteristics, release mechanisms, and clinical translation-an updated review.
  39. AARS2 R199C mutation induces lactylation-driven premature ovarian insufficiency phenotypes partially reversible by SIRT3.
  40. Parkinson's disease-associated PLA2G6 protects IP3R1 protein to control ER-mitochondria tethering and Ca2+ transfer.
  41. Features of Mitochondrial Dynamics Changes in Large Pyramidal Neurons of the Human Motor Cortex during Aging.
  42. Engineering Human Retinal Organoids and Eye-on-a-Chip Models for Degenerative Eye Disease.
  43. Gene therapy for Parkinson's disease: current landscape, translational challenges, and future directions.
  44. Autonomous Synthesis and Scrambling of Phospholipids, Linked to Recycling of Cofactors in Synthetic Cells.
  45. Skeletal muscle metabolism in health and disease: Mechanisms, interventions, and clinical perspectives.
  46. Decoding neurodegeneration one cell at a time.
  47. Identification of respiratory chain complex I deficiency due to NDUFA5 variants as a novel cause of infantile fatal disease.
  48. Angiotensin signaling is essential for stress erythropoiesis but causes retention of dysfunctional mitochondria in RBCs.
  1. Am J Med Genet A. 2026 Mar 19.
    m.10010T>C Mitochondrial Disease: A Case Report With Hypoparathyroidism and Review of the Literature.
    Jacob Mohr, Anja Lisbeth Frederiksen, Morten Duno, Anne Pernille Hermann, Trine Maxel Juul, Simone Rask Nielsen.
      Mitochondria are essential intracellular organelles that play a critical role in cellular metabolism, including the regulation of intracellular calcium signaling. Advances in genomic sequencing have facilitated the identification of rare pathogenic mitochondrial DNA (mtDNA) genetic variants in patients with unexplained endocrine disorders. We present a case report of a woman diagnosed with the rare mtDNA variant m.10010T>C. The case report includes a detailed clinical evaluation, heteroplasmy measurements across several tissues, and a review of previously published cases of patients heteroplasmic for the m.10010T>C variant. The patient developed myopathy and exercise-induced dyspnoea at 24 years of age. Nineteen years later, progressive muscle symptoms were accompanied by elevated blood lactate and hypoparathyroidism. Muscle biopsy revealed abnormal mitochondrial morphology with cytochrome C oxidase-negative fibers and deficiencies in respiratory chain Complexes I, II, and IV. Genetic analysis identified the m.10010T>C variant with 95% heteroplasmy in the muscle biopsy, 20% in urine, 4% in buccal mucosa, and undetectable in blood (< 1%). We report the first case of a m.10010T>C carrier with hypoparathyroidism, which is a rare and unexplained finding in mitochondrial disorders that may exacerbate myopathy.
    Keywords:  hypocalcemia; hypoparathyroidism; m.10010T>C; mitochondrial disease; myopathy
    DOI:  https://doi.org/10.1002/ajmg.a.70134
  2. Nature. 2026 Mar 19.
    Masked mitochondria slip into cells to treat disease in mice.
    Edward Chen.
      
    Keywords:  Cell biology; Gene therapy; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-00869-2
  3. Mitochondrion. 2026 Mar 16. pii: S1567-7249(26)00040-1. [Epub ahead of print] 102150
    Integrated molecular and clinical profiling of primary mitochondrial oxidative phosphorylation disorders in an Indian cohort: Insights from genetics, neuroimaging, and machine learning.
    Subhadeep Banerjee, Ritwick Mondal, Shramana Deb, Gourav Shome, Sharanya Chakraborty, Chinmay Saha, Alak Pandit, Gargi Sen, Sreela Bhattacharya, Purbita Sen, Nitai P Bhattacharya, Jayanta Roy, Anjan Chowdhury, Julián Benito-León.
      Primary mitochondrial disorders are clinically and genetically heterogeneous and remain underdiagnosed in resource-limited settings. We performed a retrospective observational study (March 2016-January 2024) at a tertiary neurology center in Eastern India to characterize the clinical, biochemical, neuroimaging, electrophysiological, and molecular features of suspected mitochondrial disease and to explore interpretable machine-learning approaches for syndromic stratification. Forty-eight patients from 42 unrelated families were classified as MELAS (n = 17), chronic progressive external ophthalmoplegia (CPEO; n = 14), Leber hereditary optic neuropathy (LHON; n = 10), or Leigh syndrome (n = 7). Mean age at presentation was 23.9 years (range: 9 months-60 years), with a slight male predominance. Neuroimaging was abnormal in 23/48 (47.9%) and showed syndrome-concordant patterns, including stroke-like cortical lesions in MELAS and symmetric basal ganglia involvement in Leigh syndrome; brain MRI was typically normal in CPEO. Elevated blood and/or cerebrospinal fluid lactate was common, and electroencephalographic abnormalities were concentrated in MELAS and Leigh syndrome. Targeted molecular testing in a subset identified pathogenic mtDNA variants consistent with phenotype, including MT-TL1 variants in MELAS, m.11778G>A in MT-ND4 in LHON, and m.8993T>G in MT-ATP6 in Leigh syndrome; no mtDNA deletions were detected in tested CPEO cases. Decision tree and random forest models highlighted clinically intuitive discriminators (e.g., visual loss, external ophthalmoplegia/ptosis, and seizure phenotype), supporting their potential role as transparent triage tools for targeted molecular evaluation. This cohort provides the first detailed characterization of mitochondrial syndromes in Eastern India and supports a pragmatic diagnostic framework integrating bedside phenotyping, targeted assays, and interpretable machine learning.
    Keywords:  Chronic progressive external ophthalmoplegia; Genetic diagnosis; Leber hereditary optic neuropathy; Leigh syndrome; MELAS; Machine learning; Mitochondrial disease; Neuroimaging; Oxidative phosphorylation; South Asia
    DOI:  https://doi.org/10.1016/j.mito.2026.102150
  4. Nat Commun. 2026 03 16. pii: 2532. [Epub ahead of print]17(1):
    Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.
    Yu-Hsin Hsieh, Pauline Kautz, Lena Nitsch, Ambre M Giguelay, Janet Liebold, Veronika Dimitrova, Stephania Contreras Castillo, Freya Jungen, Gabor Zsurka, Genevieve Trombly, Markus Schuelke, Wolfram S Kunz, Caleb A Lareau, Leif S Ludwig.
      Mitochondrial DNA (mtDNA) mutations occur more frequently than nuclear mutations and are associated with various diseases. While single-cell sequencing enables mtDNA variant heteroplasmy analysis, a holistic view of mtDNA mutational landscapes in individual cells has remained limited. Here, we leverage mitochondrial single-cell ATAC-seq and mtDNA-hypermutated POLGD274A knock-in HEK293 cell lines to introduce two metrics-single-cell mtDNA mutations per million base pairs (scmtMPM) and heteroplasmy-weighted mitochondrial local constraint scores (scwMSS)-to capture cellular mutational loads and somatic mosaicism. We demonstrate that individual POLGD274A cells exhibit complex mutational landscapes, with pathogenic mutations and truncating variants only present at subthreshold levels, indicative of their negative selection. In human healthy donors and mitochondriopathy patients, we identify constrained mutations in complex I, highlighting previously unrecognized mtDNA mutational landscape heterogeneity present on the single-cell level. Overall, scmtMPM and scwMSS provide a framework to investigate fundamental properties of mitochondrial genetics, disease, and somatic mosaicism.
    DOI:  https://doi.org/10.1038/s41467-026-70399-y
  5. Cell Rep Methods. 2026 Mar 13. pii: S2667-2375(26)00038-X. [Epub ahead of print] 101338
    MitoTracker transfers from astrocytes to neurons independently of mitochondria.
    Katriona L Hole, Rosalind Norkett, Emma Russell, Patrick Cottilli, Molly Strom, Jack H Howden, Nicola J Corbett, Janet Brownlees, Michael J Devine.
      The neuroprotective transfer of mitochondria from astrocytes to neurons has been primarily investigated by labeling astrocytic mitochondria with the dye MitoTracker. Here, we labeled astrocytic mitochondria with both a genetically encoded fluorophore (GFP) and MitoTracker dye and then imaged neurons immediately after co-culture with astrocytes or astrocyte-conditioned media (ACM). We report that MitoTracker transfers to neurons from both astrocytes and ACM, independently of mitochondrial transfer. Our observations provide an essential caveat to the use of this reagent and suggest that the investigation of astrocyte-neuron mitochondrial transfer, and other systems in which contact-independent transfer has been reported, requires the use of alternative labeling techniques.
    Keywords:  CP: cell biology; CP: neuroscience; MitoTracker; astrocyte; intercellular mitochondrial transfer; mitochondria; neuron
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101338
  6. Cell. 2026 Mar 18. pii: S0092-8674(26)00230-8. [Epub ahead of print]
    Transplantation of encapsulated mitochondria alleviates dysfunction in mitochondrial and Parkinson's disease models.
    Shiwei Du, Qi Long, Yanshuang Zhou, Jiangqin Fu, Hao Wu, Liang Yang, Yaohang Xie, Yingzhe Ding, Maolei Zhang, Jingyi Guo, Mengfei Wang, Jiajun Lin, Mingli Hu, Jian Zhang, Deyang Yao, Wei Li, Feixiang Bao, Ge Xiang, Yi Wu, Yile Huang, Haozhao Liang, Rui Wang, Heying Li, Baodan Chen, Chong Li, Junwei Wang, Jiwei Zhang, Dajiang Qin, Jianwei Sun, Yun Zhu, Fei Sun, Wuming Wang, Gang Lu, Wai-Yee Chan, Hui Zhao, Chenli Liu, Xingguo Liu.
      Mitochondrial transplantation holds significant potential for the treatment of mitochondrial diseases. However, how to efficiently deliver exogenous mitochondria to somatic cells or tissues remains unresolved. We present a mitochondrial transplantation approach to deliver mitochondria into the cells and tissues of mice and monkeys with high efficiency, based on encapsulating mitochondria with vesicles derived from the plasma membrane of erythrocytes. Treatment with encapsulated mitochondria complemented the loss, deletion, or mutation of mitochondrial DNA, thereby rescuing the associated bioenergetic and biochemical defects in patient-derived cells with mitochondrial disorders. Furthermore, mitochondrial capsules rescued the mitochondrial DNA depletion syndrome and Leigh syndrome in Dguok-/- and Ndufs4-/- mouse models, respectively. Moreover, in a mouse model of Parkinson's disease, mitochondrial capsules rescued neuron loss, improved motor skills, and restored mitochondrial function in the affected brain regions. Our study demonstrates the potential of this mitochondrial capsule as a treatment for mitochondrial disorders and proposes an "organelle therapy" strategy in regenerative medicine.
    Keywords:  Parkinson’s disease; degenerative disease; extracellular vesicle; mitochondria; mitochondrial diseases; mitochondrial transfer; mtDNA depletion syndrome; mtDNA mutation; organelle therapy
    DOI:  https://doi.org/10.1016/j.cell.2026.02.023
  7. Annu Rev Biochem. 2026 Mar 20.
    Mitochondrial Precursor Overaccumulation Stress.
    Liam P Coyne, Xin Jie Chen.
      Damage to mitochondria imparts multifaceted cellular stress that extends beyond bioenergetic deficit. One newly emerged example is mitochondrial precursor overaccumulation stress (mPOS). mPOS is marked by impaired mitochondrial protein import, causing the toxic accumulation and aggregation of unimported mitochondrial precursor proteins in the cytosol. Analogous to the well-studied endoplasmic reticulum stress, which blocks proteins from leaving the cell, mPOS can impose a drastic proteostatic burden in the cytosol and closely interconnects with cell signaling pathways. Here, we review how researchers discovered mPOS and discuss its central importance in several major mitochondria-induced stress signaling pathways. We then focus on the emerging field of mPOS in cell demise and human disease, and we present recent evidence that mPOS can affect cell fitness and survival independent of bioenergetics. Looking forward, mPOS may provide a complementary or alternative pathogenic mechanism to bioenergetic deficit for classic mitochondriopathy and many aging-associated degenerative diseases involving mitochondrial stress.
    DOI:  https://doi.org/10.1146/annurev-biochem-051424-061016
  8. Eur J Neurosci. 2026 Mar;63(6): e70463
    Mobile Powerhouses: Mitochondria Transfer via Tunnelling Nanotubes in Brain Health and Neurodegenerative Diseases.
    Anna Henrich, Hannah Scheiblich.
      Mitochondria are central regulators of cellular metabolism, calcium homeostasis and survival. Owing to the brain's exceptional energy demand, mitochondrial dysfunction is tightly linked to neurodegenerative and neuroinflammatory disorders. Recent evidence challenges the traditional view of mitochondria as strictly cell-autonomous organelles, revealing that they can be exchanged between cells via intercellular transfer by extracellular vesicles, gap junctions or tunnelling nanotubes (TNTs) as part of an adaptive mechanism of metabolic support and signalling. Among the pathways mediating this intercellular exchange, TNTs-thin, actin-rich cytoplasmic bridges-have emerged as key conduits for mitochondrial transfer in the nervous system. TNTs enable bidirectional exchange of mitochondria between neurons, glia and vascular cells, thereby promoting bioenergetic recovery after injury and modulating immune and inflammatory responses. This review summarizes current evidence for TNT-mediated mitochondrial transfer in the brain and highlights the underlying molecular mechanisms that coordinate mitochondrial movement, including cytoskeletal dynamics, mitochondrial trafficking machinery and stress-induced signalling cascades. While mitochondrial donation can restore metabolic balance and promote neuroprotection, it may also facilitate the spread of pathological proteins, contributing to disease progression. Understanding the underlying molecular mechanism of TNT-mediated mitochondrial transfer provides a new framework for exploring metabolic communication and cellular resilience in the brain. By emphasizing emerging conceptual and mechanistic insights, we outline how advancing this field could pave the way for the development of innovative therapeutic strategies for neurodegenerative and neuroinflammatory disorders.
    Keywords:  Miro1/2; actin dynamics; cell–cell connectivity; cytoskeletal remodelling; intercellular communication
    DOI:  https://doi.org/10.1111/ejn.70463
  9. iScience. 2026 Mar 20. 29(3): 115111
    Disturbed mitochondrial maturation in cardiolipin remodeling-deficient cardiomyocytes.
    Nanami Senoo, Macie S Sheridan, Yvonne Wohlfarter, Mackenzie T Primrose, Emmanouil Tampakakis, Markus A Keller, Steven M Claypool.
      Barth syndrome, a rare X-linked genetic disorder, features early-onset cardiomyopathy. The causal gene, TAFAZZIN, encodes a transacylase that mediates the acyl chain remodeling of cardiolipin, a critical phospholipid in the inner mitochondrial membrane. While Barth syndrome exhibits hallmark cardiolipin abnormalities, the precise mechanisms linking TAFAZZIN deficiency and disturbed cardiolipin metabolism to progressive cardiac dysfunction remain unclear. In this study, we modeled Barth syndrome cardiomyopathy in human induced pluripotent stem cell-derived cardiomyocytes with in vitro maturation treatments that simulate heart developmental stimuli. We found that cardiomyocyte maturation involves progressive cristae dynamics associated with protein and lipid alterations in the inner mitochondrial membrane. TAFAZZIN-deficient cardiomyocytes fail to adapt to the developmental stimuli, resulting in damaged cristae, compromised mitochondrial respiration, and cardiomyocyte dysfunction. These results demonstrate that TAFAZZIN deficiency perturbs functional and structural development of mitochondria, which may contribute to mitochondrial dysfunction and associated childhood progression to cardiomyopathy in Barth syndrome.
    Keywords:  Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115111
  10. Nat Commun. 2026 Mar 17.
    Structures of respiratory supercomplexes and ATP synthase oligomers in mammalian mitochondrial inner membrane.
    Atsuki Nakano, Takahiro Masuya, Shinsuke Akisada, Moe Ishikawa-Fukuda, Kaoru Mitsuoka, Hideto Miyoshi, Masatoshi Murai, Ken Yokoyama.
      Understanding the functional mechanisms of membrane protein complexes requires structural analysis within their native membrane environment. Here, we applied cryo-electron microscopy to determine the structures of FoF1 ATP synthase and respiratory supercomplexes (SCs) on sub-mitochondrial particles (SMPs) isolated from bovine heart mitochondria. Most FoF1 complexes were observed as dimers stabilized by the regulatory factor IF₁, and a tetrameric assembly comprising two FoF1-IF₁ dimers arranged linearly was also identified. This finding indicates that the tetrameric units of FoF1 are present in the mitochondrial inner membrane and contribute to shaping cristae tips in mammalian mitochondria. Fo domain maps resolve the e-subunit- c₈-ring interface and show no discrete density for a tightly bound lipid within the c₈-ring. In addition to the previously reported SCs compositions CI₁CIII₂CIV₁ and CI₁CIII₂CIV₂, our analysis identified an additional assembly with the composition CI₁CIII₂CIV₃, as well as a CI₂CIII₂CIV₆ mega-complex. This approach enables rapid structural determination of FoF1 ATP synthase and SCs from minimal membrane fractions, providing a foundation for elucidating the molecular basis of metabolic disorders and mitochondrial diseases at the level of higher-order architecture.
    DOI:  https://doi.org/10.1038/s41467-026-70578-x
  11. Cell. 2026 Mar 17. pii: S0092-8674(26)00224-2. [Epub ahead of print]
    Mitochondrial control of glycerolipid synthesis by a PEP shuttle.
    Tadashi Yamamuro, Daisuke Katoh, Guilherme Martins Silva, Hiroshi Nishida, Satoshi Oikawa, Yusuke Higuchi, Dandan Wang, Masanori Fujimoto, Naofumi Yoshida, Mark Li, Jihoon Shin, Zezhou Zhao, Jin-Seon Yook, Lijun Sun, Shingo Kajimura.
      Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains a higher-energy phosphate bond than ATP and has diverse biological functions. However, how mitochondria-generated PEP is delivered to the cytosol and fulfills cell-specific requirements remains elusive. Here, we show that SLC25A35 regulates mitochondrial PEP efflux and glyceroneogenesis in lipogenic cells that utilize the pyruvate-to-PEP bypass. Reconstitution and structural studies demonstrated PEP transport by SLC25A35 in a pH gradient-dependent manner. Loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, thereby reducing glycerolipid synthesis. Significantly, hepatic inhibition of SLC25A35 in obese mice alleviated steatosis and improved systemic glucose homeostasis. Together, these results suggest that mitochondria facilitate glycerolipid synthesis by providing PEP via SLC25A35, offering lipogenic mitochondria as a target to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and type 2 diabetes.
    Keywords:  bioenergetics; diabetes; glyceroneogenesis; hepatic steatosis; mitochondria; obesity
    DOI:  https://doi.org/10.1016/j.cell.2026.02.017
  12. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70246
    Deficient Cardiolipin Remodelling Alters Muscle Fibre Composition and Neuromuscular Connectivity in Barth Syndrome.
    Catalina Matias, Paige L Snider, Elizabeth A Sierra Potchanant, Joshua R Huot, Rahul Raghav, Michael T Chin, Simon J Conway, Jeffrey J Brault.
       BACKGROUND: Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by mutations in the TAFAZZIN gene, which disrupts cardiolipin (CL) remodelling and mitochondrial function. While cardiac manifestations of BTHS are well characterized in male patients, the mechanisms underlying skeletal muscle weakness and fatigability are poorly understood.
    METHODS: We investigated neuromuscular and mitochondrial alterations in a novel murine model (TazPM) carrying a patient-derived D75H point mutation knocked into the Tafazzin locus. This mutation preserves protein abundance but abolishes enzymatic activity. Skeletal muscle function was assessed via weightlifting and hanging tests. Muscle fibre composition and neuromuscular junction (NMJ) integrity were evaluated using immunofluorescence, western blotting and in vivo electrophysiology. Mitochondrial morphology was examined by transmission electron microscopy, and bioenergetics were quantified using ultra-performance liquid chromatography. Stress signalling was assessed by western blotting.
    RESULTS: Male TazPM mice exhibited seven-fold elevated total monolysocardiolipin and five-fold reduced mature CL levels, confirming deficient transacylase activity. These mice exhibited lower muscle strength and endurance, 32% smaller muscle fibres of all types and a shift towards fast-twitch type 2B fibres, which are more susceptible to fatigue. Electrophysiological analysis revealed a 60% reduction in motor unit number and an increase in average single motor unit potential, indicating motor neuron remodelling. NMJ protein analysis showed decreased MUSK and DOK7 and increased CHRNA1, suggesting impaired NMJ integrity. Despite mitochondrial structural abnormalities and reduced expression of key mitochondrial proteins (NDUFB8, MCU, TMEM65), resting ATP, phosphocreatine and adenine nucleotide ratios were unchanged in both glycolytic and oxidative muscles. However, stress signalling pathways were markedly activated, including phosphorylation of eIF2α, increased CHOP, DELE1, p53 expression and altered Wnt/β-catenin signalling components.
    CONCLUSIONS: Whole-body deficiency of tafazzin enzymatic activity, as occurs in BTHS, is sufficient to result in widespread neuromuscular remodelling, including fibre size/type shifts, motor unit loss, NMJ dysregulation and stress pathway activation, without overt energetic failure at rest. These findings suggest that myopathy in BTHS arises not solely from mitochondrial ATP insufficiency but rather from cumulative structural and signalling adaptations.
    Keywords:  ATP; Barth syndrome; adenine nucleotides; cardiolipin; electrophysiology; integrated stress response; mitochondria; neuromuscular junction; skeletal muscle; tafazzin
    DOI:  https://doi.org/10.1002/jcsm.70246
  13. Biogerontology. 2026 Mar 15. pii: 71. [Epub ahead of print]27(2):
    Noncanonical role of MTP-18 in mitochondrial function and aging via electron transport chain interactions in Caenorhabditis elegans.
    Jyothi Priyanka Ghantasala, Timothy Wai, Writoban Basu Ball, Manjunatha Thondamal.
      Mitochondria provide energy and maintain homeostasis, and their dysfunction relates to aging. Disrupted structure and function of mitochondria are linked to age-related diseases, but the roles of many mitochondrial proteins in mitochondrial dynamics and aging remain unclear. We studied the role of the mitochondrial fission protein MTP-18 in mitochondrial dynamics and aging in C. elegans. Our data show that loss of mtp-18 increases longevity and stress resistance, alongside changes in key physiological processes. We tested whether mtp-18-mediated longevity is linked to the PI3K-dependent insulin/IGF-1 signaling (IIS) pathway. mtp-18-mediated longevity requires the Forkhead transcription factor DAF-16, a primary effector of the IIS pathway, but is not mediated by the canonical IIS cascade. We also observed unique interactions between mtp-18 and genes encoding components of the mobile electron carrier system in mitochondria, such as coenzyme Q and cytochrome c. Our study reveals that mtp-18 is an evolutionarily conserved, key aging regulator that maintains mitochondrial morphology. What sets this study apart from previous research is the identification of a novel mechanism by which MTP-18 affects these processes independently of the canonical IIS pathway, particularly through unique interactions with genes encoding components of the electron transport chain.
    Keywords:   C. elegans ; Electron transport chain; Insulin signlling pathway; Longevity; Mitochondrial fission; ROS
    DOI:  https://doi.org/10.1007/s10522-026-10415-2
  14. Genome Biol Evol. 2026 Mar 16. pii: evag067. [Epub ahead of print]
    Lifespan Predicts Mitochondrial Substitution Rates Across Vertebrates, but Methodology Matters.
    Jess E Sterling, Kendra D Zwonitzer, Justin C Havird.
      Why do some species live for mere months, while others persist for centuries? A leading explanation implicates mitochondria. The mitochondrial theory of aging predicts that mitochondrial efficiency diminishes with age due to the accumulation of mutations within mitochondrial DNA (mtDNA). While experimental evidence for this theory is mixed, evolutionary analyses offer an ideal opportunity to determine if mitochondrial substitution rates are linked to longevity. Here, we explored the relationship between mtDNA evolution and species' lifespans across four clades-Aves, Actinopterygii, Bivalvia, and Sebastidae-using five normalization strategies. Across most methods, long-lived vertebrates showed reduced synonymous and nonsynonymous substitution rates, suggesting lower mtDNA mutation. However, we found that the strength and direction of these relationships varied drastically depending on the normalization approach used (i.e., correcting for divergence, generation time, and phylogeny). We also analyzed mtDNA mutation spectra and found similar patterns in long- and short-lived species, suggesting decreased rates of mtDNA mutations in long-lived species are not due to suppression of specific mutation processes, as predicted from the free-radical theory of aging. We also find little evidence for a relationship between selection on mitochondrial protein-coding genes and lifespan. Our results align with the idea that decreased mutation rates may help preserve mitochondrial integrity in long-lived vertebrate species, but that these species have not been selected to have particularly efficient OXPHOS or protection against a specific mitochondrial mutation process. Together, these findings underscore the critical link between mitochondrial stability and lifespan, and highlight the power of natural systems in this field.
    Keywords:  Mitochondrial DNA; comparative genomics; generation time; longevity; phylogenetic comparative methods; substitution rates
    DOI:  https://doi.org/10.1093/gbe/evag067
  15. Redox Biol. 2026 Mar 11. pii: S2213-2317(26)00122-9. [Epub ahead of print]92 104124
    The regulation of mitochondrial ferritin on mitochondrial redox balance is essential to cell fate decision.
    Yuanyuan Liu, Yan-Zhong Chang.
      Mitochondrial ferritin (FtMt), first identified by Levi et al., is an iron-storage protein with high homology with cytoplasmic ferritin. It is mainly expressed in metabolically active tissues and exhibits distinct physiological and biochemical properties compared cytoplasmic ferritin. Over the past few decades, significant attention has been drawn to the unique structural and functional characteristics of FtMt that differentiates it from conventional ferritin. Mitochondrial ferritin specifically located on the mitochondrial exhibits unique advantages in mitochondrial redox balance through isolating iron within mitochondria, reducing oxidative stress and maintaining mitochondrial homeostasis. Moreover, it modulates the labile iron pool within mitochondria, facilitating the biosynthesis of iron-sulfur clusters and supporting cellular respiration. This review comprehensively discusses the pivotal function of FtMt in regulating mitochondrial redox homeostasis and its impact on cell fate decisions, specifically, its influence on apoptosis, ferroptosis through alterations in mitochondrial integrity. We also summarize recent advances in understanding the association between FtMt dysregulation and various diseases, emphasizing its implications in neurodegenerative diseases, cardiovascular disorders and cerebrovascular pathologies. By critically evaluating emerging evidence, this article aims to provide translational insights into targeting FtMt and mitochondrial redox homeostasis as therapeutic strategies for mitigating these clinically significant diseases.
    Keywords:  Cell death; Iron; Mitochondrial ferritin; Neurodegenerative disease; Redox
    DOI:  https://doi.org/10.1016/j.redox.2026.104124
  16. Eur Biophys J. 2026 Mar 16.
    Molecular mechanisms of mitochondrial uncoupling: focus on 2,4-dinitrophenol.
    Elena E Pohl, Olga Jovanović.
      
    Keywords:  Artificial uncoupler; Membrane proteins; Mitochondria; Patch clamp; SLC25; Uncoupling; Voltage clamp
    DOI:  https://doi.org/10.1007/s00249-026-01827-6
  17. Transl Res. 2026 Mar 14. pii: S1931-5244(26)00062-9. [Epub ahead of print]
    Therapeutic Targeting of the Mitochondrial Dysfunction-PANoptosis Axis: Mechanistic Insights and Emerging Strategies.
    Arpit Sharma, Shruti S Raut, Alok Shukla, Amit Singh, Abha Mishra.
      Mitochondria are fundamental organelles that regulate cellular homeostasis through energy production, metabolic integration, and signaling cascades. Beyond their bioenergetic role, mitochondrial dysfunction is increasingly recognized as a pivotal instigator of PANoptosis, a novel, coordinated inflammatory cell death pathway that amalgamates key features of pyroptosis, apoptosis, and necroptosis. This integrated cell death is executed by multiprotein complexes termed PANoptosomes, which are nucleated by specific sensors like ZBP1, AIM2, and NLRC5. Central to this process is the release of mitochondrial danger signals, including reactive oxygen species (ROS) and mitochondrial DNA (mtDNA), which act as potent upstream triggers. For instance, ROS can directly oxidize and activate necroptotic mediators like RIPK1, while cytosolic mtDNA engages innate immune sensors such as cGAS-STING and inflammasomes, thereby initiating PANoptosome assembly. Concurrently, defects in core mitochondrial processes including impaired oxidative phosphorylation, disrupted dynamics (fission/fusion), and faulty mitophagy exacerbate these inflammatory signals, creating a permissive environment for PANoptosis. This mitochondrial-PANoptosis axis is implicated in the pathogenesis of a broad spectrum of diseases. Consequently, therapeutic strategies targeting mitochondrial integrity or specific PANoptotic components hold significant promise for mitigating pathological inflammation and cell loss. This review focuses on the molecular mechanisms linking mitochondrial dysfunction to PANoptosis and explores the translational potential of this interplay to reshape therapeutic approaches in diseases.
    Keywords:  & Mitochondrial dysfunction; Cell death; Immune; PANoptosis; Therapeutics
    DOI:  https://doi.org/10.1016/j.trsl.2026.03.004
  18. FEBS J. 2026 Mar 19.
    Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.
    Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.
      The stress-inducible protein Sestrin2 (SESN2) has recently emerged as an orchestrator of mitochondrial signaling. The regulation of mitochondria-related pathways, such as aerobic respiration, is thought to be mediated by SESN2, but the underlying mechanisms are not fully understood. Here, we characterized mitochondria in Sesn2-knockdown myoblasts under physiological conditions using oxygen consumption rate measurements, fluorescence microscopy, and protein content analysis. We discovered that SESN2 is essential for sustaining oxidative phosphorylation and maintaining the mitochondrial network organization. SESN2 loss diminished ATP production, decreased the levels of nuclear- and mitochondrial-encoded complex IV subunits, and increased superoxide generation. Moreover, the assessment of mitochondrial distribution in Sesn2-knockdown cells revealed a more fragmented network. This was associated with an increased ratio of short to long optic atrophy 1 (OPA1) forms. Remarkably, disruption of mitochondrial signaling suppressed cellular proliferation and altered both cell and nuclear morphology. In summary, our findings suggest that SESN2 plays an important role in maintaining cellular homeostasis, partly through its impact on mitochondrial function.
    Keywords:  SESN2; mitochondria; mitochondrial dynamics; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/febs.70497
  19. Neuroophthalmology. 2026 ;50(2): 159-166
    Visual Loss from Leber's Optic Neuropathy Presenting in a 76-Year-Old Man with the 14484 Mutations.
    Laura Goldfarb Cyrino, Bianca Jimena Saldaña Lagos, Pedro Henrique Varalta Martins, Julia F Bonato Cavalcanti, Leonardo E Ariello, Mario Luiz Ribeiro Monteiro.
      Leber's Hereditary Optic Neuropathy (LHON) is an important hereditary optic neuropathy that typically causes bilateral visual loss, predominantly in male patients. While it usually manifests in young adults, it can uncommonly present in older individuals without a family history, potentially leading to diagnostic confusion. The mechanisms underlying why some individuals with these mutations develop optic neuropathy while others remain asymptomatic are still under investigation. Factors such as heteroplasmy, epigenetic modifications, and environmental triggers, including alcohol consumption, are thought to contribute. However, the exact triggers that convert carriers into symptomatic individuals remain poorly understood, with cigarette smoking and alcohol intake being potential contributors. The purpose of this paper is to describe a 76-year-old patient who experienced, painless bilateral visual loss progressing over 4 weeks. Despite extensive evaluation, including imaging, blood tests, and genetic testing, a mitochondrial mutation (T14484C) associated with LHON was identified. Although LHON is rare, especially in the elderly, and usually presents in younger males, this case highlights the need for clinicians to consider LHON as a potential diagnosis in older patients presenting with unexplained visual loss.
    Keywords:  Leber’s hereditary optic neuropathy; ganglion cells; mitochondrial mutation; mtDNA; optic neuropathy
    DOI:  https://doi.org/10.1080/01658107.2025.2487842
  20. Mitochondrion. 2026 Mar 13. pii: S1567-7249(26)00039-5. [Epub ahead of print] 102149
    Impact of compound heterozygous SDHA variants on mitochondrial function in pediatric with neurological disease.
    Rocío Garrido-Moraga, Pablo Serrano-Lorenzo, María J Esteban-Amo, Marcello Bellusci, Miguel Á de la Fuente, Joaquín Arenas, Adrián González-Quintana, Cristina Ugalde, María Simarro, Miguel A Martín.
      This study examines two rare compound heterozygous missense variants in the SDHA gene, c.1535G > A (p.R512Q) and c.1753C > T (p.R585W), identified in a pediatric patient presenting with neurological manifestations, including epilepsy, developmental delay, and optic atrophy. The SDHA gene encodes a key component of succinate dehydrogenase (SDH), an essential enzyme complex at the intersection of two fundamental metabolic pathways: the Krebs cycle, and the mitochondrial respiratory chain (MRC). Patient-derived fibroblasts were used to evaluate the impact of the mutations on SDH activity and MRC assembly and function. The analysis revealed significant decreases in SDH activity and subunit levels, as well as impaired assembly. Additionally, complex I (CI) activity and CI-containing supercomplexes formation were also impaired, indicating more widespread mitochondrial dysfunction. Unexpectedly, basal and maximal respiration rates remained unchanged, though spare respiratory capacity was significantly reduced. These findings demonstrate the deleterious effects of the c.1535G > A and c.1753C > T variants, which had previously been associated with primary mitochondrial disorder (PMD) and tumors but had not been functionally validated until now.
    Keywords:  Compound heterozygous mutations; Mitochondrial dysfunction; Neurological disorders; SDHA gene
    DOI:  https://doi.org/10.1016/j.mito.2026.102149
  21. Mitochondrion. 2026 Mar 13. pii: S1567-7249(26)00037-1. [Epub ahead of print]89 102147
    Quantitative imaging of mitochondrial redox conditions at the single-organelle level.
    Steffen Pöschel, Michael Müller.
      Mitochondria are morphologically and functionally heterogeneous and dynamically adapt to the current metabolic status of their hosting cell. Moreover, they are prominent sources but also sensitive targets of redox modulation and oxidative stress. Such subcellular ROS/redox signals are considered pivotal aspects in health and disease. Yet, their deciphering requires advanced optical tools. Here we took advantage of transgenic redox-indicator mice expressing a mitochondria-targeted reduction/oxidation-sensitive green fluorescent protein (roGFPm) in excitatory projection neurons. By excitation-ratiometric two-photon microscopy we quantified in acute brain slices the redox conditions of individual mitochondria. After developing adequate redox sensor calibrations and solving laser-mediated bleaching issues, we finally chose caudoputamen, which showed the most promising mitochondrial arrangement for our imaging approach. Confirming the reliability of single-mitochondria redox imaging, we characterized the interplay of redox state and mitochondrial morphology. In general, roGFPm was more oxidized in spherical than in filamentous mitochondria. Acute hypoxia reverted mitochondria to a more roundish shape and evoked a reducing shift. Furthermore, the fraction of spherical mitochondria increased with aging. Around postnatal day (pd)350, a significantly higher fraction of roundish mitochondria was present in females than in males. In addition, from pd150 on, female mice showed lower degrees of roGFPm oxidation than males. Both findings might be linked to estrogen levels, which decrease in female mice with reproductive senescence around pd350. In view of the pivotal role of mitochondria for cellular wellbeing and their involvement in various neuropathologies, the established single-organelle redox-imaging approach will foster further detailed studies.
    Keywords:  2-photon microscopy; Aging; Hypoxia; Mitochondria; Reactive oxygen species; Redox imaging; roGFP
    DOI:  https://doi.org/10.1016/j.mito.2026.102147
  22. Circ Res. 2026 Mar 16.
    RHOT Proteins Link Mitochondrial Motility to Cardiomyocyte Sarcomere Maturation.
    Natali Froese, Ivanna Shymotiuk, Alexander Froese, Felix Polten, Jonas Jablinski, Tim Scholz, Mortimer Korf-Klingebiel, Christopher Werlein, Paolo Galuppo, Anna Gigina, Katharina Wihler, Johanna Schneider, Sergej Erschow, Maren Heimerl, Malgorzata Szaroszyk, Jan Hegermann, Christoph Wrede, Theresa Schweitzer, Andreas Pich, Robert Geffers, Melanie Ricke-Hoch, Mark P Kühnel, Danny D Jonigk, Adam R Wende, E Dale Abel, Viacheslav O Nikolaev, Kai C Wollert, Johann Bauersachs, Christian Riehle.
       BACKGROUND: Cardiomyocyte mitochondria align with sarcomeres during heart development. Mitochondrial motility is controlled by RHOT (ras homolog family member T) 1 and RHOT2. RHOT1 and RHOT2 are atypical Rho-like small GTPases that are anchored to the outer mitochondrial membrane and couple mitochondria to kinesin and dynein motors. We hypothesized that RHOT protein expression and mitochondrial motility are required for mitochondrial positioning during cardiomyocyte development.
    METHODS: We generated mice with cardiomyocyte-selective deletion of Rhot1 and Rhot2 during embryogenesis (cRhot1/2-KO [constitutive and embryonic cardiomyocyte-selective Rhot1/2 knockout]) or tamoxifen-inducible deletion in the adult heart (iRhot1/2-KO [inducible cardiomyocyte-selective Rhot1/2 knockout mice]) to assess the importance of mitochondrial motility during and after cardiomyocyte maturation. Mitochondrial motility was determined by a motor protein-driven single mitochondria motility assay. Respiratory capacity was measured in isolated mitochondria. Intracellular mitochondrial localization and ATP production in isolated cardiomyocytes were assessed by confocal microscopy and after adenoviral expression of the fluorescence resonance energy transfer-based ATP biosensor ATeam. Cardiac ultrastructure was assessed by electron micrographs; mass spectrometry was used for proteome analysis.
    RESULTS: cRhot1/2-KO mice developed fatal cardiomyopathy associated with sarcomere disarray and perinuclear accumulation of mitochondria and ATP production. Mitochondria isolated from cRhot1/2-KO hearts exhibited impaired motility but preserved respiratory capacity. Mechanistically, proteome analysis identified that RHOT proteins bind mitochondria to contractile muscle fiber proteins. In contrast, inducible deletion of Rhot1 and Rhot2 in adult iRhot1/2-KO mice did not result in heart failure. Despite impaired motility of isolated mitochondria, intracellular mitochondrial localization, local ATP production, and sarcomere structure were preserved in adult iRhot1/2-KO hearts after cardiomyocyte maturation.
    CONCLUSIONS: RHOT proteins bind mitochondria to contractile muscle fiber proteins and are required for mitochondrial positioning in cardiomyocytes during development. Our study links mitochondrial motility and local ATP production to structural and functional maturation of the heart.
    Keywords:  heart failure; mitochondria; myocytes, cardiac; proteome; sarcomere
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327297
  23. Acta Neuropathol. 2026 Mar 16. pii: 26. [Epub ahead of print]151(1):
    TDP-43 impairs glycolysis by sequestering hexokinase 1 in amyotrophic lateral sclerosis.
    Cassandra Barone, Rihua Wang, Sarah Cooke, Hang Pong Ng, Rodolfo S Ferreira, Helen C Miranda, Xin Qi.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and cytoplasmic mislocalization of TDP-43. While metabolic dysfunction is increasingly recognized in ALS, the mechanistic link between impaired energy metabolism and TDP-43 pathology remains unknown. Here, we show that cytoplasmic TDP-43 directly disrupts glycolysis by targeting hexokinase 1 (HK1), the first rate-limiting enzyme of the pathway. In cells expressing a TDP-43 variant lacking its nuclear localization signal and in patient-derived iPSC motor neurons, TDP-43 accumulation in the cytoplasm reduces glycolytic capacity, indicating a neuron-intrinsic metabolic defect. Across cellular models including patient-derived neurons, TDP-43 mutant mice, and postmortem spinal cord tissue from ALS patients, we observe consistent decreases in HK1 protein level, mitochondrial association, and enzymatic activity, despite unchanged transcript levels. Mechanistically, cytoplasmic TDP-43 directly binds to HK1, disassociating it from mitochondria and promoting its sequestration into insoluble aggregates. This mislocalization impairs glycolysis and increases neuronal vulnerability. Notably, compensation for HK1 loss reduces cytoplasmic TDP-43 and ubiquitin accumulation, improves motor performance, and prolongs survival in TDP-43-associated ALS models. Together, these findings identify a previously unrecognized mechanism by which TDP-43 impairs glycolysis through HK1 misregulation and highlight glycolytic restoration as a potential therapeutic strategy in ALS.
    Keywords:  Glucose; Metabolism; Motor neuron; Spinal cord
    DOI:  https://doi.org/10.1007/s00401-026-02996-6
  24. J Clin Invest. 2026 Mar 17. pii: e197183. [Epub ahead of print]
    m6A deficiency induces dopaminergic neurodegeneration and progressive parkinsonism through a pathogenic loop with mitochondria.
    Sun Liu, Qihuan Ren, Guiling Mo, Zengguang Li, Huili Huang, Yuhao Zhou, Ziteng Miao, Xin Cao, Bilian Wu, Zhuoyu Xiao, Shihui Yu, Guangjin Wu, Linjian Xia, Jinru Cui, Junyuan Mo, Yuan Li, Laixin Xia, Juan Shen, Shan Xiao.
      Despite substantial progress in understanding the molecular pathology of Parkinson's disease (PD), the underlying drivers of PD in many cases remain unknown. Here we investigate the role of RNA modification in PD, following observations of selective m6A hypomethylation in the substantia nigra (SN) of mouse PD models and dysregulated METTL3 and ALKBH5 expression in dopaminergic (DA) neurons from PD patients. We find preferential m6A deposition on transcripts of PD risk genes and a previously unreported heterozygous METTL3 p.K480R mutation in PD patients. Mettl3K480R/+ mice exhibit progressive METTL3 reduction and m6A hypomethylation in the SN, leading to progressive DA neuron loss, phospho-α-synuclein increase, and levodopa-responsive motor and non-motor deficits, mimicking PD progression. Dopamine transporter-specific METTL3 knockout mice recapitulate m6A hypomethylation, neurodegeneration and levodopa-responsive parkinsonism. Mechanistically, m6A deficiency disrupts mitochondrial biogenesis and function through regulating Tfam expression, while mitochondrial dysfunction reciprocally impairs m6A deposition, creating a pathogenic loop. Importantly, supplementation with S-adenosylmethionine (SAMe) enhances m6A modification, disrupts the pathogenic loop and alleviates parkinsonism in mouse models. Our findings reveal m6A dysregulation as an important contributor to PD pathogenesis, provide a valuable preclinical mouse model for PD progression, and highlight RNA methylation-targeted therapies as a promising strategy for PD intervention.
    Keywords:  Genetics; Mitochondria; Neuroscience; Parkinson disease; RNA processing
    DOI:  https://doi.org/10.1172/JCI197183
  25. Mov Disord Clin Pract. 2026 Mar 18.
    POLG-Related Parkinsonism with Good Response to Deep Brain Stimulation.
    Evdokia Efthymiou, Fabian Büchele, Sujitha Mahendran, Lennart Stieglitz, Bettina Balint.
      
    Keywords:  POLG mutation; deep brain stimulation; mitochondrial disorder; subthalamic nucleus; young‐onset Parkinson's disease
    DOI:  https://doi.org/10.1002/mdc3.70588
  26. Nat Commun. 2026 Mar 14.
    MFF budding from mitochondria regulates melanosome size and maturation.
    Ana Paula Magalhães Rebelo, Aurora Maracani, Samuele Greco, Federica Dal Bello, Lucia Santorelli, Marco Gerdol, Alberto Pallavicini, Tomas Knedlik, Sara Schiavon, Luca Scorrano, Philip S Goff, Christian Frezza, Elena V Sviderskaya, Paolo Grumati, Marta Giacomello.
      Melanosomes are lysosome-related organelles that produce and accumulate melanin. Their maturation is regulated through interactions with mitochondria and involves the export and recycling of proteins via tubular transport and fission events whose mechanisms are unknown. Here, we demonstrate that the mitochondrial fission factor protein (MFF) is involved in melanosome fission. MFF is trafficked between mitochondria and melanosomes and locates at melanosome fission events. Upon downregulation of MFF, but not of dynamin-related protein 1 (DRP1), melanosomes enlarge, intracellular melanin accumulates, and melanosomal lumenal catabolism increases, indicating that MFF-dependent melanosome fission is required for their maturation. We show that MFF interacts with regulators of the ARP2/3 complex, which drives F-actin nucleation. Actin filaments accumulate between melanosomes at MFF-enriched membrane constriction sites, and silencing of ARP2/3 subunits mimics the increase in melanosome size. MFF regulates actin-dependent fission of melanosomes via the ARP2/3 complex, indicating an extramitochondrial function for MFF in the regulation of melanosome homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-70572-3
  27. Biochemistry (Mosc). 2026 Feb;91(2): 253-273
    Mitochondria "Shackled" by Mutant Huntingtin: Analysis of Morphological Alterations and Disruptions of Intracellular Transport.
    Vyacheslav I Pasko, Aleksandra S Churkina, Lilia D Belikova, Anton S Shakhov, Svetlana V Lavrushkina, Anton V Burakov, Alexandra N Bogomazova, Maria A Lagarkova, Irina B Alieva.
      Mitochondria are semi-autonomous, multifunctional organelles that supply cells with energy. They are highly dynamic structures, capable of moving, fusing, dividing, and forming branched networks. The number, density, and complexity of mitochondrial network are unique to each cell type and reflect cellular demands for ATP and other mitochondria-dependent metabolites. Mitochondrial dysfunction is a hallmark of many neurodegenerative diseases; however, the relationships between neurodegeneration and mitochondrial morphogenesis, intracellular localization, and dynamics remain incompletely understood. Interpretation and comparison of published data are complicated by the diversity of analytical approaches used to study mitochondrial behavior. In this research, we investigated the effects of a pathogenic mutation in the huntingtin protein (HTT), which causes Huntington's disease (HD), on mitochondrial morphology and motility, with particular emphasis on associated disruptions in the cytoskeletal organization. We performed a systematic evaluation of automated mitochondrial analysis tools and selected MiNA, TrackMate, and JACoP as the optimal platforms for quantitative assessment of the effects of mutant HTT (mHTT) on the mitochondrial morphology, motility, and interaction with cytoskeletal components and identification of specific disruptions directly related to HD pathogenesis. Our analysis revealed that mitochondria in mHTT-expressing cells are significantly shorter, more branched, and less motile than in control cells. Moreover, their interactions with microtubules and vimentin intermediate filaments are markedly altered. Together, these findings establish a link between HD and specific defects in the mitochondrial network, thus contributing to understanding cellular mechanisms of HD development, and suggest that mHTT disrupts the interaction of mitochondria with cytoskeletal components responsible for their movement and distribution in the cell, thereby negatively affecting mitochondrial motility and morphology.
    Keywords:  Huntington’s disease; huntingtin; mitochondrial dynamics; neurodegenerative diseases
    DOI:  https://doi.org/10.1134/S0006297925602850
  28. Mol Metab. 2026 Mar 16. pii: S2212-8778(26)00036-0. [Epub ahead of print] 102352
    Pregnancy precipitates metabolic imbalance and accelerates death in an animal model of mitochondrial cardiomyopathy.
    Nicole M Sayles, Gabriella Casalena, Dazhi Zhao, Ryan W Dellinger, Holly E Holmes, Onorina Manzo, Alexander Galkin, Annarita Di Lorenzo, Giovanni Manfredi.
      During pregnancy, the heart undergoes major physiological and metabolic changes to increase cardiac workload and the demand for energy production is especially elevated during the trial of labor. Normally, cardiac structure and metabolism revert to the pre-pregnancy state shortly after delivery. However, in some cases peripartum/postpartum cardiomyopathy (PPCM) occurs, which increases a person's risk of major cardiac events following pregnancy. The molecular mechanisms underlying PPCM remain poorly understood. In this study, we investigate the transcriptional, metabolic, and bioenergetic profiles of postpartum (PP) hearts in a mouse model of cardiomyopathy caused by the pathogenic p.S55L mutation in the mitochondrial protein coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10). Heterozygote p.S55L mutant CHCHD10 mice develop acute heart failure during the immediate PP period. We observe cardiac remodeling, mitochondrial stress, and profound metabolic rewiring in PP mutant CHCHD10 hearts. Metabolic rewiring results decreased levels of heme and the depletion of key cofactors of energy metabolism, including NAD(H) and ADP. These findings suggest that mutant CHCHD10 hearts fail to meet the increased energy demands associated with the trial of labor due to the insufficient turnover rate of NAD+/NADH and ADP/ATP. We propose that this metabolic insufficiency drives PP mortality in mutant CHCHD10 mice. In support of this hypothesis, dietary supplementation with nicotinamide riboside and pterostilbene, a naturally derived polyphenol, increased PP survival and cardiac energy metabolites in mutant CHCHD10 mice. Our work provides novel insights into the molecular mechanisms of PP cardiomyopathy associated with mitochondrial stress and suggests potential beneficiary effects of dietary NAD(H) supplementation.
    Keywords:  CHCHD10; NAD(H); cardiomyopathy; metabolism; mitochondria; postpartum
    DOI:  https://doi.org/10.1016/j.molmet.2026.102352
  29. iScience. 2026 Mar 20. 29(3): 114764
    The NAD-brain pharmacokinetic study of NAD augmentation in blood and brain using oral precursor supplementation.
    Haakon Berven, Magnus Svensen, Heidi Eikeland, Nora Tvedten, Erika V Sheard, Solveig Amdahl Af Geijerstam, Mona Søgnen, Adrian McCann, Lena Arnsten, Ove Årseth, Vivian Skjeie, Arve Hjellbrekke, Geir-Olve Skeie, Yamila N Torres Cleuren, Gonzalo S Nido, Kristoffer Haugarvoll, Frank Riemer, Charalampos Tzoulis, Christian Dölle.
      Nicotinamide adenine dinucleotide (NAD) augmentation therapy (NAD-AT) is increasingly explored in clinical trials across multiple indications, especially neurological diseases, yet its human pharmacokinetic profile remains incompletely defined. We report findings from a phase I pharmacokinetic trial assessing systemic and cerebral responses to oral NAD precursors in healthy individuals (n = 6) and persons with Parkinson's disease (n = 6) receiving 1,200 mg/day nicotinamide riboside or nicotinamide mononucleotide. Blood NAD increased slowly, plateauing after approximately two weeks of treatment, and declined with similarly slow kinetics following treatment discontinuation. Cerebral NAD levels increased measurably after four weeks of treatment. NAD-related metabolites showed faster increase and washout dynamics compared to NAD itself. Collectively, these data suggest that effective NAD-AT requires sustained oral administration over at least 2-4 weeks and that once-daily dosing is sufficient to maintain stable NAD levels. NAD responses exhibited considerable interindividual variability, but were not influenced by disease status or sex, indicating broad applicability.
    Keywords:  Biopharmaceuticals; Health sciences; Pharmaceutical compounds formulation; Pharmaceutical preparation; Pharmaceutical science
    DOI:  https://doi.org/10.1016/j.isci.2026.114764
  30. J Biol Chem. 2026 Mar 17. pii: S0021-9258(26)00247-4. [Epub ahead of print] 111377
    Non-muscle tropomyosins inhibit Myosin-19 and dynamically localize to mitochondrially-associated actin filaments.
    Cameron P Thompson, Luther W Pollard, Mengqi Xu, Erika L F Holzbaur, E Michael Ostap.
      Myosin-19 (Myo19) is a mitochondrially localized actin-based motor important for regulating mitochondrial homeostasis, including the stabilization of mitochondrial-endoplasmic reticulum (mitoER) contact sites. Thus, proper regulation of Myo19 is likely required to maintain mitochondrial health and function, but little is known about regulatory mechanisms. Non-muscle tropomyosins are known to differentially regulate members of the myosin superfamily, leading us to hypothesize that tropomyosins may regulate Myo19-actin filament interactions. Here, we show that the interaction of Myo19 with actin filaments is inhibited by the association of Tropomyosin 3.1 (Tpm3.1) and 1.7 (Tpm1.7) with F-actin. This inhibition is highly cooperative, as both Tpm isoforms induce an all-or-none stalling of Myo19-driven filaments in in vitro gliding assays. In HeLa cells, Tpm3.1 is associated with actin filaments in close proximity to mitochondria. This localization is dynamic, as Tpm3.1 interacts with the mitochondrially-associated actin wave in interphase cells. These findings point toward a tropomyosin-based regulatory mechanism that spatially regulates Myo19 activity in a dynamic manner.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111377
  31. Aging Cell. 2026 Mar;25(3): e70445
    Aging Triggers an Intestinal Energy Crisis and HDL3 Deficiency Disrupting Gut-Liver Axis Homeostasis.
    Yumeng Li, Tongtong Bao, Lumin Gao, Xutong Tian, Junyu Xue, Caike Jin, Shujin Wang, Xin Wu.
      During aging, decreased intestinal barrier function and its ability to synthesize metabolites are closely associated with various age-related diseases. However, the mechanism by which impaired intestinal synthesis contributes to gut-liver axis aging remains unclear. This study reveals that aging induces a mitochondrial energy crisis and defective membrane localization of ABCA1, significantly inhibiting the biosynthesis of high-density lipoprotein 3 (HDL3) in the intestine. Exogenous supplementation with β-nicotinamide mononucleotide (NMN) restores intestinal NAD+ homeostasis, enhances oxidative phosphorylation efficiency, and promotes ATP-dependent lipid transport, thereby rejuvenating the production of gut-derived HDL3. Further investigations demonstrate that gut-originated HDL3 neutralizes lipopolysaccharide (LPS) in the liver and attenuates TLR4-mediated inflammatory cascades, ultimately ameliorating age-related liver injury. These findings elucidate a novel mechanism whereby NMN modulates the NAD+-mitochondria-ABCA1-HDL3 axis to preserve gut-liver axis function, offering a promising therapeutic strategy for mitigating aging-related pathologies in this metabolic cross-talk.
    Keywords:  NAD+; NMN; aging; gut‐derived HDL3; gut–liver axis; mitochondrial function
    DOI:  https://doi.org/10.1111/acel.70445
  32. Cell Rep. 2026 Mar 15. pii: S2211-1247(26)00190-7. [Epub ahead of print]45(3): 117112
    Mitochondria acidify lysosomes through membrane contacts.
    Zhiqi Tian, Rui Chen, Guiqian Fang, Kangqiang Qiu, Weijun Wu, Xintian Shao, Daili Liu, Huilin Que, Xueqian Wang, Ji Gao, Jianyu Zhang, Bidyut Kundu, Qixin Chen, Jun-Lin Guan, Yueguang Rong, Ben Zhong Tang, Kai Li, Yujie Sun, Jiajie Diao.
      The acidic environment within the lysosome lumen is essential for its digestive function. However, the source of protons responsible for acidification has remained elusive. Here, using a molecular probe to monitor lysosomal digestion, we discovered enhanced lysosome content degradation at mitochondria-lysosome contact (MLC) sites, which was caused by lysosomal acidification. Using a mitochondrial probe, we observed a proton flux from mitochondria to lysosomes at these MLC sites. Furthermore, we found that physically bringing mitochondria and lysosomes into close proximity can increase lysosome acidification to enhance content digestion under disease conditions. These findings unveil a crucial physiological role of MLCs in cellular functions.
    Keywords:  CP: cell biology; lysosome acidification; mitochondria-lysosome contact; proton flux
    DOI:  https://doi.org/10.1016/j.celrep.2026.117112
  33. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2529914123
    SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.
    Xinxin Chen, Siwen Wang, Mauricio Torres, Sijie Hao, Shengyi Sun, Ling Qi.
      Mitochondrial integrity is central to energy homeostasis, particularly in brown adipose tissue where dynamic remodeling fuels thermogenesis. Two major proteostatic systems, the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy, have been shown to intersect in vitro, but their physiological coordination in metabolically active tissues remains unclear. Here, we demonstrate that ERAD and autophagy act in synergy to safeguard mitochondrial integrity in brown adipocytes. Using various adipocyte-specific knockout (KO) mouse models and high-resolution ultrastructural 2D and 3D imaging, we show that simultaneous deletion of Sel1L and Atg7 (double KO, DKO) causes striking mitochondrial abnormalities under room temperature, absent in single KO or Sel1L-Ire1a double knockout mice. DKO adipocytes accumulate hyperfused megamitochondria extensively penetrated by ER tubules, accompanied by ER expansion, excessive ER-mitochondrial contacts, and impaired thermogenesis. These findings reveal that SEL1L-HRD1 ERAD and autophagy cooperate, rather than act redundantly, to maintain mitochondrial integrity in brown fat, uncovering a previously unrecognized mitochondrial surveillance mechanism based on ERAD-autophagy crosstalk.
    Keywords:  3D FIB-SEM; ER–mitochondrial contacts; brown adipocytes; megamitochondria; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2529914123
  34. Redox Biol. 2026 Mar 11. pii: S2213-2317(26)00118-7. [Epub ahead of print]92 104120
    In vivo dynamic nuclear polarization magnetic resonance imaging reveals cardiac mitochondrial redox imbalance as an early indicator of heart failure.
    Koki Ichihashi, Fuminori Hyodo, Abdelazim Elsayed Elhelaly, Hiroyuki Tomita, Shoya Shiromizu, Keita Fujimoto, Hirohiko Imai, Yoshifumi Noda, Hiroki Kato, Akira Hara, Masayuki Matsuo.
      Heart failure is a major cause of mortality worldwide. Accumulating evidence indicates that mitochondrial dysfunction, particularly excessive generation of reactive oxygen species (ROS) from the mitochondrial electron transport chain (ETC), plays a vital role in the onset and progression of heart failure. Importantly, mitochondrial dysfunction is believed to emerge at an early stage of heart failure development. However, due to the lack of noninvasive techniques to directly evaluate cardiac mitochondrial function in vivo, the timing and dynamics of mitochondrial functional alterations during the early phase of heart failure development remain unclear. Carbamoyl-PROXYL (CmP) is a membrane-permeable nitroxyl probe that mediates redox reactions within the mitochondrial ETC in the presence of reduced nicotinamide adenine dinucleotide, thereby sensitively indicating mitochondrial electron transfer dynamics. We applied in vivo dynamic nuclear polarization magnetic resonance imaging (DNP-MRI) to a mouse model of doxorubicin (DOX)-induced heart failure to validate its utility. In DOX-treated mice, the CmP reduction rate was significantly accelerated as early as 30 min after drug administration. However, no significant change was detected in epirubicin-treated mice compared with control animals. Considering that DOX induces ROS production through redox cycling at mitochondrial ETC complex I, these results demonstrate that in vivo DNP-MRI enables noninvasive visualization of ETC-associated mitochondrial redox imbalance in the living heart immediately after the onset of cardiotoxic stress, even when ROS generation has just begun and conventional functional changes are unapparent. Therefore, in vivo DNP-MRI represents a powerful noninvasive modality for the early diagnosis of heart failure.
    Keywords:  Heart failure; Histopathology; In vivo DNP-MRI; Mitochondria; Redox imbalance
    DOI:  https://doi.org/10.1016/j.redox.2026.104120
  35. Sci Rep. 2026 Mar 20.
    Progressive cognitive impairment and ventricular tachycardia in a boy with biallelic POLG variants and a de novo RYR2 variation.
    Valentina Fumini, Alexandru Ionut Gilea, Elena Tacchetto, Leonardo Salviati, Enrico Baruffini, Mara Doimo.
      Routine use of next-generation sequencing has shown that most common phenotypes are genetically heterogeneous and that in many cases, mutations in the same gene may cause markedly different phenotypes. Furthermore, complex clinical presentations are often due to multiple coexisting genetic defects. Here, we describe a patient with a complex clinical phenotype: a childhood-onset neurodevelopmental disorder with progressive intellectual disability, and supraventricular tachyarrhythmias that led to cardiac arrest in early teens. The complex phenotype is paralleled by a complex genotype. The neurological manifestations were likely due to biallelic POLG variants. POLG encodes the catalytic subunit of mitochondrial polymerase gamma. Pathogenic POLG variants cause both autosomal and recessive diseases, with a wide variety of clinical presentations. This heterogeneity makes validating novel substitutions challenging. One of the patient's variants, p.(W113R), was novel, and to assess its pathogenicity, we employed a functional yeast-based assay. The cardiac phenotype was likely due to a de novo pathogenic variant in the RYR2 gene, which encodes a calcium release channel that plays an essential role in heart excitation-contraction coupling. The yeast assay was essential to establish the pathogenicity of the novel POLG variant and to correctly characterize this complex genotype.
    Keywords:   POLG ; POLG-related disorder; RYR2 ; Neurodevelopmental disorder; supraventricular tachyarrhythmias; yeast model
    DOI:  https://doi.org/10.1038/s41598-026-44913-7
  36. Biochemistry. 2026 Mar 19.
    Human Endonuclease G Preferentially Cleaves Oxidatively Damaged DNA.
    Wen-Ting Lu, Yi-Ping Chen, Wei-Zen Yang, Hanna S Yuan, Jason L J Lin.
      Endonuclease G (EndoG) is a conserved endonuclease implicated in mitochondrial DNA (mtDNA) replication, maintenance of mtDNA integrity under oxidative stress, and the removal of nuclear and paternal mtDNA during apoptosis and early embryogenesis. Despite its biological significance, the substrates targeted by EndoG and its cleavage preferences remain unclear. Here, we characterize human EndoG (hEndoG) across diverse nucleic acid substrates, including single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), nicked and gapped dsDNA, modified dsDNA containing 8-oxoguanine (oxoG-DNA) and hydroxymethylated cytosine (5hmC-DNA), single-stranded RNA (ssRNA), and RNA/DNA hybrids. We show that hEndoG binds most of these substrates with only modest differences in affinity (∼10-fold), yet displays a particularly strong preference for cleaving oxidatively damaged DNA, including nicked and gapped dsDNA, and oxoG-DNA. Notably, hEndoG preferentially cleaves the strand opposite the gapped or nicked site, and it targets the complementary strand to the modified base in oxoG-DNA and 5hmC-DNA. Our structural modeling of hEndoG bound to ssDNA and dsDNA indicates that ssDNA is a favored substrate because its flexibility allows kinked conformations that position the scissile phosphate near the catalytic Mg2+ in the His-Me finger motif. Together, these findings support a critical role for hEndoG in preserving mitochondrial genome integrity under conditions of oxidative stress by selectively targeting and removing oxidatively damaged DNA.
    DOI:  https://doi.org/10.1021/acs.biochem.5c00669
  37. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2534066123
    ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.
    Ziqi Zou, Jiajie Zhou, Yanhua Lu, Yuting Huang, Linru Zhou, Xiaoyu Wang, Jiahui Chen, Hengrui Tian, Xinnuo Ge, Chenyao Guo, Weiran Yao, Xiaosheng Zheng, Jia He, Yue Du, Yiting Zhou, Yinjing Song, Wei Luo, Qingqing Wang, Jun-Ping Liu, Meng Xia.
      Neuro-immune crosstalk is increasingly recognized in Parkinson's disease (PD), and ATP13A2 is well known for its neuroprotective role. However, it remains unclear whether ATP13A2 mutations carried by PD patients contribute to immune dysfunction that exacerbates disease progression. Here, we systematically demonstrate that many ATP13A2 mutations result in a loss-of-expression phenotype. ATP13A2 is highly expressed in macrophages. Myeloid ATP13A2 deficiency causes uncontrolled NLRP3 inflammasome activation driven by lysosomal alkalization and subsequent disrupted mitochondrial homeostasis, rendering mice susceptible to a PD-like phenotype. PD-linked ATP13A2 loss-of-expression mutants fail to restore the ATP13A2 levels required to suppress NLRP3 hyperactivation in ATP13A2-depleted human THP-1 monocytes. Macrophages from a PD patient carrying the ATP13A2 loss-of-expression L927P mutation exhibit excessive NLRP3 activation due to lysosomal-mitochondrial dysfunction. Our findings provide insight into PD pathogenesis, emphasizing genetic factor-driven dysregulated macrophage NLRP3 activation, particularly in ATP13A2 loss-of-expression mutation cases.
    Keywords:  ATP13A2 mutation; NLRP3 inflammasome; Parkinson’s disease; macrophage; neuroinflammation
    DOI:  https://doi.org/10.1073/pnas.2534066123
  38. Front Mol Biosci. 2026 ;13 1774015
    Cell-free mitochondrial DNA (cf-mtDNA) in human body fluids: molecular characteristics, release mechanisms, and clinical translation-an updated review.
    Yu Liu, Xixiang Ma, Qingmei Guan, Shunchang Zhou.
      Since its discovery, cell-free mitochondrial DNA (cf-mtDNA) has emerged as a promising non-invasive molecular marker for disease diagnosis and prognosis. However, the biological origins of cf-mtDNA remain incompletely understood, which limits its clinical applications. This review comprehensively summarizes the molecular characteristics, release mechanisms, and diagnostic applications of cf-mtDNA. By discussing standardization of cf-mtDNA detection methods, this review aims to provide theoretical foundations for clinical translation of this emerging biomarker.
    Keywords:  body fluids; cf-mtDNA; molecular features; molecular markers; release mechanism
    DOI:  https://doi.org/10.3389/fmolb.2026.1774015
  39. Reproduction. 2026 Mar 14. pii: xaag035. [Epub ahead of print]
    AARS2 R199C mutation induces lactylation-driven premature ovarian insufficiency phenotypes partially reversible by SIRT3.
    Hai-Hui Zhang, Zhi-Ling Zhang, Wei Xu.
      Premature ovarian insufficiency (POI) often arises from genetic causes, yet the pathogenic consequences of many variants remain undefined. The AARS2 R199C mutation has been repeatedly reported in patients, but its physiological effects were unknown. Here, we generated the first homozygous Aars2 R194C knock-in mouse to model this variant in vivo. Female knock-in mice showed irregular estrous cycles, reduced fecundity, altered endocrine profiles, and accelerated depletion of the primordial follicle pool, reproducing core features of POI. Mutant ovaries exhibited increased lysine lactylation of the metabolic enzymes pyruvate dehydrogenase alpha 1(PDHA1) and carnitine palmitoyltransferase 2(CPT2), accompanied by reduced activity and impaired mitochondrial respiration in granulosa cells. These metabolic defects were associated with sustained activation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and premature follicle activation. Loss of the mitochondrial de-lactylase Sirtuin-3 mitigated these abnormalities, whereas pharmacological inhibition of pyruvate dehydrogenase and carnitine palmitoyltransferase in wild-type mice phenocopied key knock-in features. Together, these findings demonstrate that the Aars2 R194C/R199C mutation alone is sufficient to induce POI and establish a lactylation-driven metabolic mechanism underlying early follicle activation.
    Keywords:  AARS2; granulosa cells; lactylation; mitochondrial metabolism; premature ovarian insufficiency; primordial follicles
    DOI:  https://doi.org/10.1093/reprod/xaag035
  40. Nat Commun. 2026 Mar 19.
    Parkinson's disease-associated PLA2G6 protects IP3R1 protein to control ER-mitochondria tethering and Ca2+ transfer.
    Zhi-Hao Lin, Nai-Jia Xue, Yi Liu, Feng Zhang, Xiao-Li Si, Ran Zheng, Lu-Yan Gu, Yao-Lin Li, Yi Fan, Jun Tian, Wolfgang H Oertel, Hyemyung Seo, Jia-Li Pu, Bao-Rong Zhang.
      Mutations in the phospholipase A2 group VI (PLA2G6) gene have been linked to autosomal recessive Parkinson's disease (PD), yet the molecular mechanisms remain poorly understood. This study provides the in vitro and in vivo evidence, specifically in dopaminergic neurons derived from patients with PD, that PLA2G6 loss-of-function disrupts the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), a critical regulator of Ca2+ transfer and energy homeostasis. This study demonstrates that the PLA2G6 protein localizes to the MAM and physically associates with the IP3R1-GRP75-VDAC1 complex. PLA2G6 deficiency destabilizes this complex, accelerating IP3R1 degradation, which in turn reduces ER-mitochondria contacts and impairs Ca2+ transfer. Notably, introducing a MAM linker restores the phenotypes caused by PLA2G6 loss. In iPSCs-derived dopaminergic neurons from patients with PD harboring PLA2G6 mutations, the structural and functional disruption of the MAM is further confirmed, underscoring its role in PD pathogenesis. These findings uncover the pivotal function of PLA2G6 within the MAM and suggest that modulating inter-organelle contacts could be a therapeutic strategy for correcting PD's ion channel dysfunction and energy imbalances.
    DOI:  https://doi.org/10.1038/s41467-026-70752-1
  41. Biochemistry (Mosc). 2026 Feb;91(2): 380-387
    Features of Mitochondrial Dynamics Changes in Large Pyramidal Neurons of the Human Motor Cortex during Aging.
    Tatiana I Baranich, Dmitry N Voronkov, Kseniia M Okulova, Ekaterina V Shcherbak, Anna V Egorova, Olga V Velts, Maria S Ryabova, Kristina A Skvortsova, Zainab M Omarova, Dmitry A Kharlamov, Valeria V Glinkina, Vladimir S Sukhorukov.
      Brain aging is a physiological process characterized by various neurodegenerative manifestations, largely driven by mitochondrial dysfunctions, including changes in mitochondrial metabolism and dynamics. Conflicting reports in the literature regarding mitochondrial fusion and fission in the human cerebral cortex during aging underscore the need to elucidate the mechanisms of this dysfunction. The aim of this study was to assess features of mitochondrial dynamics in the large pyramidal neurons of the human motor cortex during aging. The study was conducted on autopsy material from the motor cortex of individuals aged 75 years and older. The control group consisted of similar material from individuals aged 35-44 years who died from sudden cardiac death. Intensity of immunohistochemical staining for TOMM20, Drp1, Mfn1, Mfn2, and Opa1 proteins in the large pyramidal neurons of the human motor cortex was evaluated. Decrease in the staining intensity of TOMM20 and Opa1 markers and increase in the staining intensity of the Drp1 marker were observed, indicating enhanced mitochondrial fragmentation in the pyramidal neurons of layer V of the motor cortex, possibly associated with reduction in the mitochondrial pool volume due to dysfunction in the mitochondrial fusion process, which impedes organelle growth.
    Keywords:  adaptation; aging; brain; fission; fusion; mitochondrial dynamics; motor cortex; neurodegeneration
    DOI:  https://doi.org/10.1134/S0006297925604447
  42. ACS Biomater Sci Eng. 2026 Mar 16.
    Engineering Human Retinal Organoids and Eye-on-a-Chip Models for Degenerative Eye Disease.
    Jiansen Wang, Yang Yang, Zichen Hong, Yantao Xing, Mingxia Gu, Tasneem P Sharma, Jason S Meyer, Feng Guo.
      Degenerative eye diseases are major causes of irreversible vision loss worldwide, but effective treatments remain limited, partly due to the lack of effective human models. Retinal organoids derived from stem cells can recapitulate key structural and physiological features of the human retina, offering powerful tools to study disease mechanisms and develop new therapies. Here, we review recent progress in engineering retinal organoids and eye-on-a-chip models for modeling degenerative eye diseases, with a focus on engineering innovations. We first describe conventional methods for organoid differentiation and characterization along with current outstanding challenges. To better engineer retinal organoids, new strategies that leverage microfluidics and biomaterials have emerged to regulate dynamic and physiologically relevant environments for organoid differentiation. Moreover, the integration of artificial intelligence, multimodal sensing, and data analytics improves the monitoring and prediction of retinal function and therapeutic outcomes. Finally, we discuss future directions in innovating next-generation retinal organoid and eye-on-a-chip models for disease modeling, drug discovery, and vision restoration, highlighting their potential for precision ophthalmology.
    Keywords:  AI; Eye disease; Eye-on-a-chip; Retinal organoids; Vision technology
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c02202
  43. Expert Rev Neurother. 2026 Mar 16.
    Gene therapy for Parkinson's disease: current landscape, translational challenges, and future directions.
    Vito Evola, Mayur S Parmar.
       INTRODUCTION: Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic neuronal loss. Gene therapy has emerged as a disease-modifying strategy capable of targeting these mechanisms through dopamine restoration, neurotrophic support, and correction or silencing of pathogenic mutations, which collectively contribute to neuronal vulnerability and α-Synuclein - driven degeneration.
    AREAS COVERED: Herein, the authors synthesize contemporary viral and non‑viral platforms designed to restore dopamine biosynthesis, deliver neurotrophic factors, and correct pathogenic mutations (GBA1, LRRK2, PINK1). The authors summarize clinical translation with emphasis on trials targeting dopamine synthesis (AAV2 AADC, ProSavin/AXO Lenti PD), neurotrophic factors (AAV2 GDNF, AAV2 NRTN), pathogenic variants (AAV9 GBA1/PR001; LRRK2 RNAi; emerging CRISPR/PINK1 strategies), and circuit modulation (AAV GAD), correlating mechanistic ration. They also examine translational challenges including vector biodistribution and immune responses.
    EXPERT OPINION: Gene therapy for PD is transitioning from symptomatic modulation toward targeted molecular correction. Clinical trials have validated durable, neuron specific expression using AAV and lentiviral vectors and demonstrated target engagement across dopamine synthesis, trophic support, and genetic mutation - specific strategies. Persistent challenges include limited vector biodistribution, reduced retrograde transport in advanced disease, immune variability, and surgical infrastructure requirements. Overcoming these via engineered capsids, delivery optimization, and validated biomarkers will enable precision, stage‑specific interventions.
    Keywords:  Adeno-associated virus; clinical trials; dopaminergic neurons; neurodegeneration; viral vectors; α-synuclein
    DOI:  https://doi.org/10.1080/14737175.2026.2647033
  44. ACS Synth Biol. 2026 Mar 18.
    Autonomous Synthesis and Scrambling of Phospholipids, Linked to Recycling of Cofactors in Synthetic Cells.
    Jelmer Coenradij, Eleonora Bailoni, Marco Lupacchini, Wessel F Groenhof, Mart Venekamp, Dirk J Slotboom, Arnold J M Driessen, Marten Exterkate, Bert Poolman.
      Compartmentalization of reactions is essential for life and allows nonequilibrium conditions to be maintained within cells. For cell growth, the membranes need to expand through lipid synthesis and a continuous supply of ATP and building blocks. Here, we build a minimal system in vesicles that integrates ATP supply, CTP and CMP recycling, and glycerol-3-phosphate synthesis with the conversion of phosphatidic acid to phosphatidylglycerol. We use four transmembrane proteins and three soluble enzymes to enable autonomous phospholipid synthesis in both the outer and inner leaflets of the membrane. The system displays biphasic lipid synthesis kinetics: a rapid phase with phosphatidylglycerol production in the cis leaflet of the membrane and a slower phase dependent on lipid scrambling. We present previously unreported scramblase activity of two integral membrane proteins: phosphatidylglycerophosphatase A and the mitochondrial ATP/ADP carrier. This work lays the foundation for autonomous lipid biosynthesis in synthetic cells and enables the exploration of emergent properties in compartmentalized systems.
    Keywords:  bottom-up synthetic biology; lipid scrambling; lipid synthesis; lipid translocation; membrane reconstitution; recycling of cofactors
    DOI:  https://doi.org/10.1021/acssynbio.5c00973
  45. iScience. 2026 Mar 20. 29(3): 115024
    Skeletal muscle metabolism in health and disease: Mechanisms, interventions, and clinical perspectives.
    Donghai Lin, Linglin Zhang, Caihua Huang, Wei Shao.
      Skeletal muscle is a vital metabolic organ that regulates systemic energy homeostasis by coordinating glucose uptake, fatty acid oxidation, and amino acid metabolism. Its remarkable capacity for dynamic adaptation, termed metabolic flexibility, underpins physical performance and protects against metabolic diseases such as obesity, type 2 diabetes, and sarcopenia. This review provides an integrative synthesis of the molecular and signaling networks that orchestrate skeletal muscle metabolism, focusing on key regulators including insulin, AMPK, mTOR, and PGC-1α. We also examine how disruptions in these pathways lead to mitochondrial dysfunction, lipid dysregulation, and muscle wasting. We explore the therapeutic landscape across pharmacological, exercise-based, and nutritional interventions, emphasizing mitochondrial-targeted strategies and myokine-mediated communication as emerging modalities for restoring metabolic resilience. Additionally, we emphasize the growing importance of multi-omics technologies and inter-tissue communication in improving mechanistic understanding and advancing precision medicine. This review integrates mechanistic, translational, and clinical perspectives to underscore the importance of a systems-level approach to skeletal muscle metabolism. This approach is essential for developing targeted, multidimensional therapies aimed at enhancing metabolic health and extending healthspan.
    Keywords:  endocrinology; health sciences; medical specialty; medicine
    DOI:  https://doi.org/10.1016/j.isci.2026.115024
  46. J Clin Invest. 2026 Mar 16. pii: e199841. [Epub ahead of print]136(6):
    Decoding neurodegeneration one cell at a time.
    Olivia Gautier, Thao P Nguyen, Aaron D Gitler.
      Neurodegenerative diseases are characterized by protein misfolding and the selective vulnerability of specific neuronal subtypes. This selective vulnerability presents a paradox; most neurodegenerative disease genes are expressed broadly throughout the brain, and some ubiquitously, but only certain types of neurons are lost while others are resistant. The molecular basis for selective neuronal vulnerability has remained a mystery, but recent genomics technological innovations are starting to provide mechanistic insights. Here, we review how single-cell genomics techniques - single-cell transcriptomics, single-cell epigenomics, and spatial transcriptomics - advance our molecular understanding of selective vulnerability and neurodegeneration across Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington disease. Together, these approaches reveal the cell types affected in disease, define disease-associated molecular states, nominate candidate determinants of vulnerability and degeneration, and situate degenerating neurons within their local tissue context. Continued development and application of these techniques, including single-cell perturbation screens, will expand descriptive atlases of relevant cell types in health and disease and identify causal mechanisms, revealing the molecular basis of vulnerability and degeneration and informing therapeutic development.
    DOI:  https://doi.org/10.1172/JCI199841
  47. Genes Dis. 2026 Jul;13(4): 101920
    Identification of respiratory chain complex I deficiency due to NDUFA5 variants as a novel cause of infantile fatal disease.
    Yang Wang, Xi Yang, Xue Yan, Yumin Zhu, Xue Xia, Ting Li, Yi Liao, Bingkun Lei, Jingmin Yang, Deyuan Li.
      
    DOI:  https://doi.org/10.1016/j.gendis.2025.101920
  48. JCI Insight. 2026 Mar 12. pii: e200722. [Epub ahead of print]
    Angiotensin signaling is essential for stress erythropoiesis but causes retention of dysfunctional mitochondria in RBCs.
    Parul Rai, Swarnava Roy, Paritha Arumugam, Diamantis G Konstantinidis, Sithara Raju Ponny, Marthe-Sandrine Eiymo Mwa Mpollo, Archana Shrestha, Theodosia A Kalfa, Punam Malik.
      We previously reported that excessive angiotensin-II (AT)->AT receptor-1 (ATR1) signaling results in sickle cell anemia (SCA)-associated nephropathy. Herein, we showed hyperangiotensinemia in SCA results from high erythroid cell-generated reactive oxygen species (ROS), which oxidized angiotensinogen (ATGN) and favored its rapid conversion to AT. Increased AT->ATR1 signaling in SCA erythroid cells generated ROS and created a positive feedback loop of ROS->oxidized ATGN->AT->ATR1-> ROS, perpetuating the hyperangiotensinemia. ATR1-blocker, losartan, reduced erythrocyte ROS, oxidized-AGTN, and AT levels. The ROS->AT->ATR1->ROS loop was driven by sickle erythropoiesis as it was reproduced when WT mice were transplanted with SCA hematopoiesis. Using SCA and WT mice with germline- and erythroid-specific ATR1-deficiency, we found that stress-erythropoiesis, but not steady-state-erythropoiesis, was critically dependent on erythroid AT->ATR1 signaling, which acted in harmony with increased erythropoietin signaling. Further, instead of the canonical AT->ATR1-> NADPH-oxidase->ROS signaling in steady-state erythropoiesis, AT->ATR1 signaling in stress-erythroid cells increased mitochondrial mass and dysfunctional mitochondria, which thereby increased ROS. SCA mice with erythroid-specific ATR1 deficiency had decreased RBC accumulation of dysfunctional mitochondria and decreased ROS, which reduced SCA-associated nephropathy. Overall, we demonstrated that AT->ATR1 signaling was essential for stress-erythropoiesis but led to increased dysfunctional mitochondria retention in mature RBCs, which generated ROS and perpetuated hyperangiotensinemia, resulting in end-organ damage.
    Keywords:  Cell biology; Cell stress; Hematology; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.200722
This page is being maintained by Thomas Krichel. It was last updated on 2026‒03‒22 at 13:26.