bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–08–17
73 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Principles of cotranslational mitochondrial protein import.
  2. A Late-Onset and Mild Phenotype of Mitochondrial Complex I Deficiency Due to a Novel Reported Variant Within the ACAD9 Gene.
  3. Congenital-onset MLASA2 from a novel YARS2 variant: A literature review.
  4. Extraocular features of Leber hereditary optic neuropathy: A scoping review.
  5. Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
  6. Platelet mitochondrial complex I and IV activities are not reliable stratification biomarkers in Parkinson's disease.
  7. Zagociguat prevented stressor-induced neuromuscular dysfunction, improved mitochondrial physiology, and increased exercise capacity in diverse mitochondrial respiratory chain disease zebrafish models.
  8. How mitochondrial DNA complicates pre-implantation genetic screening and management.
  9. Severe clinical manifestation of mitochondrial disease due to the m.3243A>T variant: a case report of early-onset, multi-organ involvement and premature death.
  10. Mitochondrial stress orchestrates chromatin remodeling and longevity via phosphoregulation of the NuRD component LIN-40.
  11. Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.
  12. A novel mitochondrial regulon for ferroptosis during fungal pathogenesis.
  13. Elamipretide in the Management of Barth Syndrome: Current Evidence and a Case Report.
  14. Mitochondrial Trifunctional Protein Deficiency due to HADHA Variants Masquerading as Charcot-Marie-Tooth Disease.
  15. Peptide-mimetics derived from leucyl-tRNA synthetase are potential agents for the therapy of mt-tRNA related diseases.
  16. Mitochondrial Dysfunction in Aging and Age-related Disorders.
  17. Mitochondria protect against an intracellular pathogen by restricting access to folate.
  18. Technological advances in the diagnosis and management of inherited optic neuropathies.
  19. RePOWER: An International, Prospective, Non-Interventional Registry of Patients With Primary Mitochondrial Myopathy.
  20. A novel application of LC-MS/MS accurately quantifies the labile redox pools of cellular coenzymes Q9 and Q10.
  21. ROS-dependent localization of glycolytic enzymes to mitochondria.
  22. Mitochondrial dysfunction and lipid dysregulation in yeast lacking phosphatidylserine.
  23. The mitochondrial aspartate transporter Ucp4a regulates muscle aging and animal lifespan in Drosophila melanogaster.
  24. Loss of dynamin 1-like protein impairs mitochondrial function and self-renewal, and activates the integrated stress response in human embryonic stem cells.
  25. The Malate-Aspartate Shuttle supports thermogenic lipid mobilization in brown adipocytes.
  26. Predictors of powerhouse: a perspective of mitochondrial biomarkers in type 2 diabetes.
  27. McLeod syndrome mimicking mitochondrial myopathy due to a novel in-frame duplication in the XK gene.
  28. A Quinolinium-Functionalized Hemicyanine Dye for Ratiometric NAD(P)H Sensing in Live Cells, Kidney Tissues, and Drosophila melanogaster.
  29. Mitochondrial sirtuins, key regulators of aging.
  30. ndufs2 -/- zebrafish have impaired survival, neuromuscular activity, morphology, and one-carbon metabolism treatable with folic acid.
  31. Selective loss of ATP carriers in favour of SLC25A43 orthologues in metamonad mitochondria adapted to anaerobiosis.
  32. Redistribution of fragmented mitochondria ensures symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotes.
  33. Hexokinase regulates Mondo-mediated longevity via the PPP and organellar dynamics.
  34. Nigrostriatal dopaminergic vulnerability in Parkinson's disease: Neuroprotective strategies.
  35. RNA triggers chronic stress during neuronal aging.
  36. Complex II assembly drives metabolic adaptation to OXPHOS dysfunction.
  37. Reduced complex I activity in the retinal pigment epithelium, but not in rod photoreceptors, affects light signaling without impacting cell survival.
  38. Morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neurons.
  39. MacroD1 sustains mitochondrial integrity and oxidative metabolism.
  40. Resilience of the Mitochondrial Reticulum in Aging.
  41. ECHS1: pathogenic mechanisms, experimental models, and emerging therapeutic strategies.
  42. Brucella abortus induces dynamin-related protein 1 (DRP1)-dependent mitochondrial fission in infected macrophages via stress sensor IRE1α altering metabolic function.
  43. Mitochondrial clone tracing within spatially intact human tissues.
  44. Personalized Genome-Scale Modeling Reveals Metabolic Perturbations in Fibroblasts of Methylmalonic Aciduria Patients.
  45. LDS 698: A highly sensitive probe for tracking mitochondrial membrane potential in live cells.
  46. Children with rare genetic diseases get CRISPR Cures center.
  47. Estrogens protect bone mass by inhibiting NAD + metabolism in osteoclasts.
  48. The yeast Mkt1/Pbp1 complex promotes adaptive responses to respiratory growth.
  49. Immuhistochemically-confirmed mitochondrial cardiomyopathy presenting as a conduction system hamartoma: A case report.
  50. Glaucoma-associated Optineurin mutations increase transcellular degradation of mitochondria in a vertebrate optic nerve.
  51. Childhood POLG-related disorders: Focus on polyradiculoneuropathy.
  52. Distinct Mitochondrial DNA Deletion Profiles in Pediatric B- and T-ALL During Diagnosis, Remission, and Relapse.
  53. Mitochondrial Pyruvate Carrier Differentially Controls the Self-Renewal and Differentiation of Human Pluripotent Stem Cells.
  54. Global profiling of N-terminal cysteine-dependent degradation mechanisms.
  55. Defective Ribosome Recycling: A Bridge Between Translation Fidelity, Organelle Dysfunction, and Diseases: Exploring How Flawed Ribosome Recycling Factors Impact Ribosome Metabolism and Organelle Homeostasis, Leading to Human Diseases.
  56. Targeted delivery of diverse biomolecules with engineered bacterial nanosyringes.
  57. Biallelic Variants in the DARS2 Gene as a Novel Cause of Axonal Charcot-Marie-Tooth Disease.
  58. Mitochondria hoard folate to starve a parasite.
  59. Protocol for the spatiotemporal profiling of RNA within nuclear compartments in human cell lines using SLAM-RT&Tag.
  60. α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons.
  61. Mitochondrial Quality Control: Insights into Intracerebral Hemorrhage.
  62. Oxytocin Enhances Demethylation Through TET Enzyme Expression in Neurons of Aged Mice: Oxytocin as a Potential Antiaging Peptide.
  63. How to kill the 'zombie' cells that make you age.
  64. Methylation Data Analysis and Interpretation.
  65. Mitochondrial dysfunction and oxidative stress in Parkinson's disease: mechanisms, biomarkers, and therapeutic strategies.
  66. Advancing precision medicine therapeutics for Parkinson's utilizing a shared quantitative systems pharmacology model and framework.
  67. Potentiation of mitochondrial function by mitoDREADD-Gs reverses pharmacological and neurodegenerative cognitive impairment in mice.
  68. High-fidelity and differential nonsense suppression in live cells and a frontotemporal dementia allele with human transfer RNAs.
  69. Design considerations for C9orf72 disease prevention trials.
  70. REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate.
  71. Clinical and variant spectrum of patients harboring ATAD3A variants.
  72. Glutamatergic synaptic resilience to overexpressed human alpha-synuclein.
  73. Systemic mitochondrial involvement in mitochondrial myopathy with episodic hyper-creatine kinase-emia: insights from an autopsy case.
  1. Cell. 2025 Aug 07. pii: S0092-8674(25)00811-6. [Epub ahead of print]
    Principles of cotranslational mitochondrial protein import.
    Zikun Zhu, Saurav Mallik, Taylor A Stevens, Riming Huang, Emmanuel D Levy, Shu-Ou Shan.
      Nearly all mitochondrial proteins are translated on cytosolic ribosomes. How these proteins are subsequently delivered to mitochondria remains poorly understood. Using selective ribosome profiling, we show that nearly 20% of mitochondrial proteins can be imported cotranslationally in human cells. Cotranslational import requires an N-terminal presequence on the nascent protein and contributes to localized translation at the mitochondrial surface. This pathway does not favor membrane proteins but instead prioritizes large, multi-domain, topologically complex proteins, whose import efficiency is enhanced when targeted cotranslationally. In contrast to the early onset of cotranslational protein targeting to the endoplasmic reticulum (ER), the presequence on mitochondrial proteins is inhibited from initiating targeting early during translation until a large globular domain emerges from the ribosome. Our findings reveal a multi-layered protein sorting strategy that controls the timing and specificity of mitochondrial protein targeting.
    Keywords:  NAC; TOM complex; cotranslational protein import; localized translation; mitochondria; mitochondrial targeting sequence; nascent polypeptide-associated complex; protein folding; protein targeting; ribosome profiling
    DOI:  https://doi.org/10.1016/j.cell.2025.07.021
  2. Int J Mol Sci. 2025 Jul 24. pii: 7128. [Epub ahead of print]26(15):
    A Late-Onset and Mild Phenotype of Mitochondrial Complex I Deficiency Due to a Novel Reported Variant Within the ACAD9 Gene.
    Anna Gaelle Giguet-Valard, Samira Ait-El-Mkadem Saadi, Sophie Duclos, Didier Lacombe, Rémi Bellance, Nadège Bellance.
      Acyl-CoA dehydrogenase 9 deficiency is considered as a rare neuromuscular syndrome with an autosomal recessive transmission. The ACAD9 protein presents two essential functions, i.e., the limiting step enzyme of the fatty acid β-oxidation pathway and one of the complex's compounds involved in the respiratory chain complex I assembly. Thus, loss-of-function mutations are known to convey mitochondrial cytopathologies. A patient with a mild and late-onset phenotype, suffering from exercise intolerance and hypertrophic cardiomyopathy, was diagnosed as a compound heterozygote of the ACAD9 gene. The first c.1240C> T p.Arg414Cys variant has been previously reported and is known to be responsible for ACAD9 deficiency. However, the second c.1636G> A p.Val546Met variant has never been described. The goal was to investigate the eventual pathogenicity of this new genetic variant. For this purpose, molecular cloning was generated to express the ACAD9 gene with the V546M variant in a cell line (ACAD9mut) and compared to cells expressing the wild-type ACAD9. Then, the mitochondrial respiration, ATP production, the mitochondrial network, and the oxidative phosphorylation's composition were investigated to reveal the effects of the V546M variant. While avoiding to affect the amount of the respiratory chain's complexes, the new ACAD9 variant was entirely responsible for reducing over 50% of the mitochondrial complex I activity.
    Keywords:  complex I; mitochondrial cytopathology; respiratory chain; variant of uncertain significance
    DOI:  https://doi.org/10.3390/ijms26157128
  3. J Neuromuscul Dis. 2025 Aug 14. 22143602251369227
    Congenital-onset MLASA2 from a novel YARS2 variant: A literature review.
    Astrid Eisenkölbl, Hanns Lochmüller, Melissa T Carter, Leslie E Hamilton, Hugh J McMillan.
      IntroductionMLASA (myopathy, lactic acidosis and sideroblastic anemia) is a rare, autosomal recessive mitochondrial disorder. Symptom onset typically occurs in childhood and differs considerably in disease severity. Congenital-onset disease is uncommon.MethodsWhole genome sequencing was performed which identified two heterozygous, rare YARS2 (NM_001040436.3) variants in trans, one of which was novel. The diagnosis was confirmed with muscle biopsy and mitochondrial enzyme activity testing. To compare the clinical phenotype of our patient to those previously described in the literature, we reviewed all YARS2-related cases in literature to identify age of symptom onset and associated clinical features.ResultsThe maternally-inherited variant, c.948G > T, p.(Arg316Ser), was previously reported with MLASA; the paternally-inherited variant, c.917T > C, p.(Phe306Ser) has not been previously reported. Muscle biopsy showed non-specific changes, that can be seen with mitochondrial dysfunction. Mitochondrial enzyme activity testing on frozen muscle tissue confirmed reduced complex I, III and IV activities.DiscussionIn our case report we describe a patient with MLASA, caused by compound heterozygous variants in YARS2. Our child with congenital-onset disease remains stable at 23 months old. Her stable course differs from two other children with congenital-onset disease who died in the first few days to months after birth. Mitochondrial enzyme activity testing is important to establish pathogenicity of novel variants in patients with this rare and clinically heterogeneous disease.
    Keywords:  YARS2 – MLASA2 – mitochondrial myopathy – sideroblastic anemia
    DOI:  https://doi.org/10.1177/22143602251369227
  4. J Biol Methods. 2025 ;12(2): e99010055
    Extraocular features of Leber hereditary optic neuropathy: A scoping review.
    Layla Ali, Iyawnna Hazzard, Niloufar S Tehrani, Ubaid Ansari, Adam Ali, Preyasi Kumar, Nadia Ali, Gurkiranjeet Gakhal, Forshing Lui.
       Background: Leber hereditary optic neuropathy (LHON) is a rare inherited mitochondrial disease that leads to mitochondrial dysfunction, resulting in optic nerve damage and vision loss. Systemic involvement has been reported in several LHON cases, referred to as LHON+ disorders. However, the causes and presentations of such conditions have been poorly studied. It is suggested that 90% of mitochondrial dysfunction is caused by one of three primary point mutations in mitochondrial DNA that affect respiratory complex I (referred to as mtDNA LHON), with unresolved cases of LHON being caused by other variants, known as autosomal recessive LHON. The cardiac, musculoskeletal, neurological, and auditory systems are commonly affected in LHON. For example, hypertrophic cardiomyopathy and sudden cardiac death have been linked to specific mutations. Neurological effects - such as dystonia, epilepsy, polyneuropathy, and ataxia - as well as hearing loss, have also been observed in patients with specific mitochondrial mutations. These findings highlight the need for a more comprehensive evaluation beyond standard ophthalmic assessments. LHON is typically diagnosed based on a combination of ophthalmic imaging, patient age and gender, clinical course (bilateral, rapidly progressive, and sequential visual loss), family history, maternal inheritance, and fundus appearance. However, the advent of genetic testing has significantly expanded the recognized phenotype. In terms of treatment, idebenone is the only FDA-approved therapy for LHON; however, intravitreal gene therapy yields promising improvement, especially for the most common m.11778G>A mutation, which accounts for 70% of causative mutations. At present, these therapies are confined to ocular treatment.
    Objective: This review highlights the importance of recognizing systemic manifestations of LHON, which are frequently overlooked in clinical practice.
    Conclusion: Early detection of these systemic manifestations, especially in cardiac and neurological systems, could help with prompt intervention and improve patient outcomes. Further research into gene therapy and mitochondrial replacement techniques holds promising potential for developing more effective treatment strategies.
    Keywords:  Genetics; Leber hereditary optic neuropathy; Systemic involvement; Treatment
    DOI:  https://doi.org/10.14440/jbm.2024.0113
  5. Nat Commun. 2025 Aug 09. 16(1): 7367
    Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
    Bishal Basak, Erika L F Holzbaur.
      Mutations that disrupt the clearance of damaged mitochondria via mitophagy are causative for neurological disorders including Parkinson's. Here, we identify a Mitophagic Stress Response (MitoSR) activated by mitochondrial damage in neurons and operating in parallel to canonical Pink1/Parkin-dependent mitophagy. Increasing levels of mitochondrial stress trigger a graded response that induces the concerted degradation of negative regulators of autophagy including Myotubularin-related phosphatase (MTMR)5, MTMR2 and Rubicon via the ubiquitin-proteasome pathway and selective proteolysis. MTMR5/MTMR2 inhibit autophagosome biogenesis; consistent with this, mitochondrial engulfment by autophagosomes is enhanced upon MTMR2 depletion. Rubicon inhibits lysosomal function, blocking later steps of neuronal autophagy; Rubicon depletion relieves this inhibition. Targeted depletion of both MTMR2 and Rubicon is sufficient to enhance mitophagy, promoting autophagosome biogenesis and facilitating mitophagosome-lysosome fusion. Together, these findings suggest that therapeutic activation of MitoSR to induce the selective degradation of negative regulators of autophagy may enhance mitochondrial quality control in stressed neurons.
    DOI:  https://doi.org/10.1038/s41467-025-62379-5
  6. J Parkinsons Dis. 2025 Aug 14. 1877718X251365253
    Platelet mitochondrial complex I and IV activities are not reliable stratification biomarkers in Parkinson's disease.
    Simon Ulvenes Kverneng, Sepideh Mostafavi, Yana Mikhaleva, Gard Aasmund Skulstad Johanson, Haakon Berven, Katarina Lundervold, Geir Olve Skeie, Erika Sheard, Mona Søgnen, Solveig Af Geijerstam, Therese Vetås, Michele Brischigliaro, Erika Fernandez-Vizarra, Yamila N Torres Cleuren, Christian Dölle, Charalampos Tzoulis.
      BackgroundMitochondrial dysfunction, particularly complex I (CI) deficiency, is considered an integral feature of Parkinson's disease (PD). However, recent findings indicate that widespread neuronal CI deficiency in the brain is only present in a subpopulation of 20-30% of cases. This stratification may be relevant for selecting participants for clinical trials, emphasizing the need for clinically applicable biomarkers. We previously reported CI deficiency in skeletal muscle biopsies of a subpopulation of persons with PD (PwPs), suggesting potential for mitochondrial stratification using extra-neural tissues. Platelets are another tissue previously reported to exhibit mitochondrial respiratory defects in PD. However, studies have generally involved small sample sizes and reported variable results.ObjectiveTo determine whether platelets exhibit impaired mitochondrial respiratory chain complex activity in PwPs, or in a subpopulation of PwPs.MethodsUsing spectrophotometric activity assays, we assessed CI and complex IV (CIV) activities in platelet samples from 61 PwPs and 31 neurologically healthy controls from a well-characterized prospective cohort. The correlation between activities measured in platelets and skeletal muscle was also explored in 51 of the same individuals.ResultsPlatelet CI and CIV activities showed no difference between PwPs and controls at the group level, nor evidence of a subgroup with deficiency of either complex. There was no correlation between complex activities in platelet samples and skeletal muscle biopsies from the same individuals.ConclusionsBased on these results, we propose that platelet CI or CIV activities are not sensitive markers of mitochondrial dysfunction in PD.
    Keywords:  Parkinson's disease; biomarkers; blood platelets; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1177/1877718X251365253
  7. Front Pharmacol. 2025 ;16 1588426
    Zagociguat prevented stressor-induced neuromuscular dysfunction, improved mitochondrial physiology, and increased exercise capacity in diverse mitochondrial respiratory chain disease zebrafish models.
    Leonard Burg, Heeyong Yoon, Min Peng, Peter Germano, Emily Reesey Gretzmacher, Rui Xiao, Vernon E Anderson, Eiko Nakamaru-Ogiso, Marni J Falk.
       Background: Zagociguat (zag) is a CNS-penetrant, soluble guanylate cyclase (sGC) stimulator that has been evaluated in phase 2a, with phase 2b ongoing, clinical studies of primary mitochondrial disease (PMD) subjects with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS). To explore its utility in a broader array of PMDs and secondary mitochondrial disorders, we performed prfeclinical modeling of zag across larval and adult zebrafish models with biochemical deficiencies in diverse respiratory chain (RC) complexes or dihydrolipoamide dehydrogenase (Dldh).
    Methods: Zag was evaluated for tissue uptake, gross toxicity, protection from RC toxin-induced brain death, neuromuscular dysfunction, heartbeat loss, and biochemical dysfunction in transgenic or toxin-exposed zebrafish with mitochondrial enzyme deficiencies in complex I (ndufs2 -/- or rotenone-exposed wild type (WT)), complex IV (surf1 -/- or azide-exposed WT), multiple RC complexes (fbxl4 -/- ), or pyruvate dehydrogenase complex (dldh -/- ). Zag effects were also studied on the whole-body oxygen consumption capacity (MO2) and swimming activity of WT and complex IV disease adult zebrafish.
    Results: Similar zag levels were observed in adult brains and tail muscle. No morphological or functional toxic effects of zag were observed on larvae viability. Zag provided neuromuscular protection in complex I deficient genetic and pharmacologic inhibitor models. In complex IV deficient models, prevention from brain death occurred at 100 nM zag in high-dose azide-exposed WT larvae; however, no rescue of swimming or neuromuscular phenotypes in low-dose azide-exposed surf1 -/- larvae was observed. A total of 100 nM zag rescued MO2 and maximum swimming speed in adult surf1 -/- zebrafish. Larval swimming activity was also preserved with 10 nM zag treatment in azide-stressed fbxl4 -/- larvae but not at 10 nM, 100 nM, or 1 µM zag in dldh -/- larvae. Zag (10 nM) enhanced complex I enzyme activity that is suggestive of mitochondrial biogenesis and key aspects of mitochondrial physiology in azide-exposed surf1 -/- and fbxl4 -/- larvae.
    Conclusion: Preclinical evaluation of zag demonstrated its safety, significant protection of neuromuscular dysfunction and/or acute RC stressor-induced decompensation, and improved mitochondrial physiology across multiple different genetic and/or pharmacologic models of RC-deficient PMD. Thus, zag may yield therapeutic potential for an array of diseases with mitochondrial dysfunction beyond MELAS, potentially including Leigh syndrome spectrum disorder and primary mitochondrial myopathies.
    Keywords:  mitochondrial disease; mitochondrial physiology; preclinical modeling; soluble guanylate cyclase; therapy
    DOI:  https://doi.org/10.3389/fphar.2025.1588426
  8. Expert Rev Mol Diagn. 2025 Aug 15.
    How mitochondrial DNA complicates pre-implantation genetic screening and management.
    Danyang Li, Joerg Patrick Burgstaller, Joanna Poulton.
      
    Keywords:  embryo; heteroplasmy; mitochondrial DNA; mitochondrial donation; mtDNA inheritance; pre-implantation genetic screening
    DOI:  https://doi.org/10.1080/14737159.2025.2545967
  9. J Rare Dis (Berlin). 2025 ;4(1): 47
    Severe clinical manifestation of mitochondrial disease due to the m.3243A>T variant: a case report of early-onset, multi-organ involvement and premature death.
    Hannah Gillespie, Yi Shiau Ng, Katrina M Wood, Sila Hopton, Charlotte L Alston, Emma L Blakely, Nick Thompson, Robert W Taylor, Andrew C Browning, Robert McFarland, John A Sayer.
      The spectrum of disease associated with pathogenic mitochondrial DNA (mtDNA) variants is wide. Most often, heteroplasmic mitochondrial DNA disease is the result of an adenine to guanine transition at position 3243 of mtDNA (m.3243A > G) in the MT-TL1 gene encoding tRNALeu(UUR). Here, we present a case of a patient with a rarer m.3243A > T variant whose phenotype was severe and included delayed growth, developmental delay, myoclonic jerks and tonic-clonic seizures, progressive myopathy, cerebellar ataxia, severe malnutrition due to intestinal dysmotility despite naso-jejunal feeding requiring total parenteral nutrition, bilateral sensorineural hearing loss, and visual impairment, including bilateral cataracts requiring treatment and pigmentary retinopathy. At age 18 years, he developed severe nephrotic syndrome secondary to a membranoproliferative pattern of glomerular injury, which was resistant to treatment and led to premature death.
    Keywords:  MELAS; Membranoproliferative glomerulonephritis; Mitochondrial disorders; Nephrotic syndrome; mtDNA
    DOI:  https://doi.org/10.1007/s44162-025-00110-0
  10. Sci China Life Sci. 2025 Aug 13.
    Mitochondrial stress orchestrates chromatin remodeling and longevity via phosphoregulation of the NuRD component LIN-40.
    Jun Zhou, Di Zhu, Yibing Wang, Zilun Wang, Ning Zhang, Xiahe Huang, Yiqian Zhang, Yingchun Wang, Xueying Wu, Ye Tian.
      Mitochondrial dysfunction is a hallmark of aging that elicits adaptive nuclear responses, yet how chromatin remodeling is coordinated under stress remains unclear. Here, we uncover a phosphorylation-dependent mechanism by which mitochondrial stress regulates the activity of the NuRD (nucleosome remodeling and deacetylase) complex via LIN-40, the Caenorhabditis elegans homolog of mammalian MTA proteins. Mitochondrial stress triggers dephosphorylation of LIN-40, enhancing its interaction with the transcription factor DVE-1 to activate the mitochondrial unfolded protein response (UPRmt) and chromatin remodeling. Phosphorylation of LIN-40 is mediated by p38 MAPK/PMK-3 and reversed by PP1c/GSP-2. Furthermore, the LIN-40(T654D) variant abolishes mitochondrial stress-induced lifespan extension. These findings establish a direct link between mitochondrial stress signaling and chromatin remodeling via NuRD, revealing an evolutionarily conserved strategy to coordinate cellular resilience and organismal longevity.
    Keywords:   C. elegans ; LIN-40/MTA; NuRD; UPRmt ; longevity; mitochondrial stress
    DOI:  https://doi.org/10.1007/s11427-025-2954-3
  11. EMBO Mol Med. 2025 Aug 11.
    Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.
    María J Pérez, Rocío B Colombo, Sebastián M Real, María T Branham, Sergio R Laurito, Carlos T Moraes, Lía Mayorga.
      Mitochondrial diseases, caused by mutations in nuclear or mitochondrial DNA (mtDNA), have limited treatment options. For mtDNA mutations, reducing the mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising strategy, though it currently faces challenges. Previous research showed that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, through changes in DNA methylation, absent or less important for subtle mitochondrial impairment. Therefore, we hypothesized that targeting nuclear DNA methylation could impair cells with high-mutant mtDNA load while sparing those with lower levels, reducing overall heteroplasmy. Using cybrid models harboring two disease-causing mtDNA mutations-m.13513 G > A and m.8344 A > G-at varying heteroplasmies, we discovered that both the mutation type and load distinctly shape the nuclear DNA methylome. We found this methylation pattern critical for the survival of high-heteroplasmy cells but not for low-heteroplasmy ones. Treatment with FDA-approved DNA methylation inhibitors selectively impacted high-heteroplasmy cybrids and reduced heteroplasmy. These findings were validated in cultured cells and xenografts. Our findings highlight nuclear DNA methylation as a key regulator of heteroplasmic cell survival and a potential therapeutic target for mitochondrial diseases.
    Keywords:  DNA Methylation; Epigenetics; Heteroplasmy; Mitochondrial DNA; Mitochondrial Diseases
    DOI:  https://doi.org/10.1038/s44321-025-00285-5
  12. Autophagy. 2025 Aug 11.
    A novel mitochondrial regulon for ferroptosis during fungal pathogenesis.
    Qing Shen, Madiha Natchi Samu Shihabdeen, Fan Yang, Naweed I Naqvi.
      Ferroptosis remains an underexamined iron- and lipid peroxides-driven cell death modality despite its importance to several human and plant diseases and to immunity thereof. Here, we utilized chemical cell biology, molecular genetics and biochemical analyses to gain insights into how the fungal pathogen Magnaporthe oryzae undergoes ferroptosis strictly in the spore cells to successfully transit to infectious development. We reveal a complex functional interdependency and crosstalk between intrinsic ferroptosis and autophagy-mediated mitochondrial degradation. Mechanistically, the requirement of mitophagy for ferroptotic cell death was attributed to its ability to maintain a pool of metabolically active mitochondria. Pharmacological disruption of the electron transport chain or membrane potential led to complete inhibition of ferroptosis, thus simulating the loss of mitophagy phenotypes. Conversely, increased mitochondrial membrane potential in a mitophagy-defective mutant alleviated the ferroptosis defects therein. Graded inhibition of mitochondrial coenzyme Q biosynthesis with or without ferroptosis inhibitor liproxstatin-1 distinguished its antioxidant function in such regulated cell death. Membrane potential-dependent regulation of ATP synthesis and iron homeostasis, as well as dynamics of tricarboxylic acid cycle enzyme AcoA (aconitase A) in the presence or absence of mitophagy, mitochondrial poisoning or iron chelation further linked mitochondrial metabolism to ferroptosis. Last, we present an important bioenergetics- and redox-based mitochondrial regulon essential for intrinsic ferroptosis and its precise role in fungal pathogenesis leading up to the establishment of the devastating rice blast disease.
    Keywords:  Cell death; coenzyme Q; iron; mitochondrial metabolism; mitophagy; rice blast
    DOI:  https://doi.org/10.1080/15548627.2025.2546944
  13. Mol Genet Metab. 2025 Aug 11. pii: S1096-7192(25)00211-2. [Epub ahead of print]146(1-2): 109220
    Elamipretide in the Management of Barth Syndrome: Current Evidence and a Case Report.
    Neil Jacob, Daniel Schecter, Molly Marshall, Neha Bansal, Jacqueline Lamour, Hilary Vernon, Eva Morava, Ibrahim Elsharkawi.
      Barth syndrome is an exceedingly rare and potentially fatal X-linked mitochondrial disease arising from pathogenic variants in TAFAZZIN (TAZ), leading to defects in mature cardiolipin synthesis and its integration into the mitochondrial inner mitochondrial membrane. Clinical features that may be severe include cardiomyopathy, cyclic neutropenia, skeletal myopathy, and growth delay. Currently, no FDA-approved therapies exist. Elamipretide (ELAM) has been shown to stabilize cardiolipin and improve mitochondrial bioenergetics in pre-clinical and clinical studies in older individuals with Barth syndrome. Here we describe a case of prenatally identified Barth syndrome-related severe left ventricle (LV) non-compaction cardiomyopathy, where ELAM was initiated shortly after birth for clinical heart failure and was associated with significant and sustained clinical improvement leading to an inactive status on the heart transplant list with eventual anticipated delisting. We provide a review of the current literature including the pathophysiology of Barth syndrome, the mechanism of action of ELAM, and its clinical applications.
    Keywords:  Barth Syndrome; Elamipretide; MTP-131; Primary Mitochondrial Myopathy; SS-31; and Bendavia™
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109220
  14. J Peripher Nerv Syst. 2025 Sep;30(3): e70048
    Mitochondrial Trifunctional Protein Deficiency due to HADHA Variants Masquerading as Charcot-Marie-Tooth Disease.
    Farkhanda Qaiser, John McHugh, Gerard Mullins, Michael Farrell, Loai Shakerdi, James O Byrne, Sinéad M Murphy.
       BACKGROUND AND AIMS: Mitochondrial trifunctional protein deficiency (MTPD) is an inherited disorder of fatty acid β-oxidation caused by mutations in HADHA or HADHB genes. It typically presents with cardiomyopathy or hepatic failure in early childhood; however, it may rarely present in adulthood with the neuromyopathic form.
    METHODS: We describe a patient with MTPD with isolated neuropathy mimicking Charcot-Marie-Tooth disease (CMT) as the first and only presenting symptom. Clinical and electrophysiological examinations were conducted, including nerve conduction studies, needle electromyography, muscle and nerve biopsies. The diagnosis was confirmed with genetic testing and enzymatic analysis of cultured skin fibroblasts.
    RESULTS: We report a 40-year-old man diagnosed with axonal CMT2 in childhood. He had pes cavus and hammer toes, mild distal lower limb weakness, and loss of vibration sense with areflexia. He later developed fatigability, improved exercise tolerance with alcohol and an episode of chest infection causing neurological decompensation without evidence of rhabdomyolysis. Neurophysiology showed non-length-dependent axonal sensorimotor neuropathy without myopathic features. Genetic testing confirmed that he was compound heterozygous for two HADHA variants, one of them novel, and enzymatic analysis of cultured skin fibroblasts confirmed MTPD.
    INTERPRETATION: We report a very rare isolated neuropathic phenotype of MTPD and confirm the pathogenicity of the novel variant c.1003G>A, p.(Glu335Lys). This case also highlights the need for HADHA and HADHB to be included in neuropathy gene panels as MTPD may present as CMT. Given that dietary management may prevent some complications of MTPD, achieving a diagnosis early is important.
    Keywords:  Charcot–Marie–Tooth disease (CMT); HADHA; inherited neuropathy; mitochondrial trifunctional protein deficiency (MTPD); neuromyopathic
    DOI:  https://doi.org/10.1111/jns.70048
  15. Front Pharmacol. 2025 ;16 1607343
    Peptide-mimetics derived from leucyl-tRNA synthetase are potential agents for the therapy of mt-tRNA related diseases.
    Annalinda Pisano, Sara Belloli, Maria Gemma Pignataro, Paolo Rainone, Silvia Valtorta, Angela Coliva, Valeria de Turris, Luciana Mosca, Patrizio Di Micco, Rosa Maria Moresco, Giulia d'Amati, Veronica Morea.
       Introduction: Mitochondrial diseases caused by point mutations in mitochondrial tRNA (mt-tRNA) genes, including MELAS and MERRF syndromes, represent a significant unmet clinical need, due to the lack of effective treatments. We previously identified peptide molecules derived from human leucyl-tRNA synthetase, whose features make them attractive leads for the development of therapeutic agents against mt-tRNA point mutations-related diseases. Indeed, we demonstrated that, upon exogenous administration, these peptides penetrate human cell and mitochondrial membranes; stabilize mitochondrial tRNA structures; and rescue severe mitochondrial defects in cells bearing the point mutations m.3243A>G and m.8344A>G, responsible for MELAS and MERRF syndromes, respectively.
    Results: To progress towards therapeutic applications, in this work we designed three peptide-mimetic derivatives (PMTs). These are composed entirely of D-amino acids and potentially endowed with enhanced stability in human plasma and resistance to enzymatic degradation. We show that, like the parent peptide, the PMTs have mitochondrial localization and improve cell viability and oxygen consumption in human cybrid cell lines bearing the aforementioned point mutations. Additionally, as anticipated, the PMTs had significantly higher plasma stability than the parent peptide. The most promising PMT was radiolabelled with Cu-64 and used in in vivo biodistribution and tolerability studies. Importantly, i. v. administered PMT reached all body districts, including heart, muscle and even brain, thus revealing an intrinsic ability to cross the blood-brain barrier. Finally, PMT was safe in adult wild-type mice at dosages up to 10 mg/kg.
    Discussion: These findings represent a significant step towards the implementation of therapeutic strategies for mttRNA-related mitochondrial diseases.
    Keywords:  Cu-64 radioisotope; MELAS and MERRF cybrids; PET; biodistribution; peptide-mimetic molecules; plasma stability; rescuing effect; tolerability
    DOI:  https://doi.org/10.3389/fphar.2025.1607343
  16. Aging Dis. 2025 Jul 31. 16(5): 2495-2497
    Mitochondrial Dysfunction in Aging and Age-related Disorders.
    Aida Adlimoghaddam.
      Mitochondrial dysfunction is increasingly recognized as a unifying mechanism underlying aging and a wide range of age-related diseases. This special issue brings together recent advances that elucidate how impaired mitochondrial function contributes to neurodegenerative, cardiovascular, and metabolic disorders. The featured articles highlight molecular pathways of mitochondrial decline, its systemic consequences, and potential interventions aimed at restoring mitochondrial health. Collectively, these studies reinforce the concept that targeting mitochondrial integrity holds significant promise for promoting healthy aging and preventing chronic disease.
    DOI:  https://doi.org/10.14336/AD.2025.10731
  17. Science. 2025 Aug 14. 389(6761): eadr6326
    Mitochondria protect against an intracellular pathogen by restricting access to folate.
    Tânia Catarina Medeiros, Jana Ovciarikova, Xianhe Li, Patrick Krueger, Tim Bartsch, Silvia Reato, John C Crow, Michelle Tellez Sutterlin, Bruna Martins Garcia, Irina Rais, Kira Allmeroth, Matías D Hartman, Martin S Denzel, Martin Purrio, Andrea Mesaros, Kit-Yi Leung, Nicholas D E Greene, Lilach Sheiner, Patrick Giavalisco, Lena Pernas.
      As major consumers of cellular metabolites, mitochondria are poised to compete with invading microbes for the nutrients that they need to grow. Whether cells exploit mitochondrial metabolism to protect from infection is unclear. In this work, we found that the activating transcription factor 4 (ATF4) activates a mitochondrial defense based on the essential B vitamin folate. During infection of cultured mammalian cells with the intracellular pathogen Toxoplasma gondii, ATF4 increased mitochondrial DNA levels by driving the one-carbon metabolism processes that use folate in mitochondria. Triggered by host detection of mitochondrial stress induced by parasite effectors, ATF4 limited Toxoplasma access to folates required for deoxythymidine monophosphate synthesis, thereby restricting parasite growth. Thus, ATF4 rewires mitochondrial metabolism to mount a folate-based metabolic defense against Toxoplasma.
    DOI:  https://doi.org/10.1126/science.adr6326
  18. Front Neurol. 2025 ;16 1609033
    Technological advances in the diagnosis and management of inherited optic neuropathies.
    John O T Britton, Patrick Yu-Wai-Man, Benson S Chen.
      Preferential degeneration of retinal ganglion cells (RGCs) is a defining feature of the inherited optic neuropathies (IONs), a group of monogenic eye diseases predominately comprising Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). Their pathogenesis is characterised by mitochondrial dysfunction, which causes loss of RGCs leading to irreversible vision loss. Although currently incurable, there are several emerging therapeutic avenues encompassing gene therapies, precision medicine strategies and neuroprotection. These are underscored by recent technological advances such as next-generation sequencing and improved disease modelling. In this review, we discuss these advances and the impact these will have on future diagnostic and treatment capabilities. We first focus on the clinical presentation and pathogenic mechanisms of LHON and DOA, followed by a discussion of emerging technology to facilitate diagnosis and treatment. We highlight the current unmet clinical demand of IONs, and the promise of current and future research developments.
    Keywords:  autosomal dominant; hereditary; leber; optic atrophy; retinal ganglion cells
    DOI:  https://doi.org/10.3389/fneur.2025.1609033
  19. Clin Genet. 2025 Aug 11.
    RePOWER: An International, Prospective, Non-Interventional Registry of Patients With Primary Mitochondrial Myopathy.
    RePOWER, MMPOWER‐3, and MOTOR investigators
      Primary mitochondrial myopathies (PMMs), a group of genetic mitochondrial oxidative phosphorylation disorders, primarily affect skeletal muscle function. No approved treatments for PMM exist, and patient information is limited. The international RePOWER registry (NCT03048617) assessed genotypic and phenotypic relationships in PMM and identified patients for MMPOWER-3 (elamipretide Phase 3 study). RePOWER enrolled screened and ambulatory patients aged 16-80 years. With signs and/or symptoms of PMM (N = 376; 60.4% female; mean [SD] age 42.6 [14.4] years; ~75% with an mtDNA variant and ~25% with an nDNA variant). Baseline information, current symptoms, qualityoflife, and functional assessments (6-Minute Walk Test [6MWT], Triple-Timed Up-and-Go [3TUG] Test, and 5-Times Sit-to-Stand Test [5XSST]) were captured. Accredited laboratory and genetic testing methods were available to most patients. The majority of enrolled PMM patients presented with progressive external ophthalmoplegia and fatigue. US patients were observed to use more medical interventions. Compared to non-US patients, US patients did not perform as well on the 6MWT (mean 364.6 vs. 375.2 m) and 5XSST (mean 21.6 vs. 18.6 s); US patients performed better on the 3TUG test (mean 40.2 vs. 45.0 s). The RePOWER registry provided data on patients with genetically confirmed PMM, thereby improving our understanding of PMM diagnosis and treatment and the differences in global mitochondrial clinical practice.
    Keywords:   MMPOWER ; PMM ; RePOWER ; elamipretide; primary mitochondrial myopathy
    DOI:  https://doi.org/10.1111/cge.70026
  20. Free Radic Biol Med. 2025 Aug 12. pii: S0891-5849(25)00891-3. [Epub ahead of print]
    A novel application of LC-MS/MS accurately quantifies the labile redox pools of cellular coenzymes Q9 and Q10.
    Akash Jain, Vince W Li, Julia Salem, Srinivasa T Reddy, Nicolaos J Palaskas, David Meriwether.
      The antioxidant coenzyme Q (CoQ) plays an essential role in the electron transport chain (ETC). CoQ cycles between oxidized and reduced forms. Redox balance changes in the CoQ pool are associated with altered mitochondrial function. Thus, determining the CoQ redox pool is important for investigating cellular redox regulation. Existing quantification methods inadequately account for artefactual sample oxidation. To overcome these limitations, we found that a reduced stable isotope-labeled internal standard (IS) can correct for oxidation of extracted CoQ9 and CoQ10. The reduced IS oxidizes at the same rate as both CoQ isoforms. Employing this correction factor rescues artefactual oxidation of the CoQ redox pool when measured by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). We validated our method within murine and human cellular systems. Statin treatment dose-dependently decreased total CoQ, while directional perturbation of the mitochondrial ETC altered the CoQ redox pool as expected. The pro-oxidant tert-butyl hydroperoxide partially oxidized the cellular CoQ redox pool. Finally, we found that primary murine macrophages deficient in PON2, a mitochondrial antioxidant enzyme, contain a partially oxidized CoQ9 redox pool. These results were revealed only after correcting for sample oxidation. Whereas prior LC-MS/MS methods for measuring the CoQ redox pool inadequately account for artefactual oxidation, the presented method rescues this error and potentiates accurate measurement of murine and human CoQ redox pools.
    Keywords:  Coenzyme Q; liquid chromatography-mass spectrometry; mitochondria; oxidative stress; redox measurement
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.022
  21. Redox Biol. 2025 Aug 12. pii: S2213-2317(25)00325-8. [Epub ahead of print]86 103812
    ROS-dependent localization of glycolytic enzymes to mitochondria.
    Pau B Esparza-Moltó, Arvind V Goswami, Süleyman Bozkurt, Christian Münch, Laura E Newman, Alexandra G Moyzis, Gladys R Rojas, Deann Guan, Jeffrey R Jones, Fred H Gage, Gerald S Shadel.
      Mitochondrial reactive oxygen species (mtROS) regulate cellular signaling pathways, but also cause oxidative stress when de-regulated during aging and pathological conditions such as neurodegenerative diseases. The dynamic redistribution of proteins between cellular compartments is a common mechanism to control their stability and biological activities. By targeting the BirA∗ biotin ligase to the outer mitochondrial membrane in HEK293 cells, we identified proteins whose labeling increased or decreased in response to treatment with menadione, consistent with a dynamic change in their mitochondrial localization in response to increased mtROS production. These proteins represent potential candidates for future studies of mitochondrial oxidative stress signaling. A subset of glycolytic enzymes was found in this screen and confirmed, by mitochondrial fractionation and imaging, to increase localization to mitochondria in response to menadione, despite no change in their overall abundance. Submitochondrial fractionation studies are consistent with import of a pool of these enzymes to the mitochondrial intermembrane space. Localization of glycolytic enzymes to mitochondria was also increased in cells grown under hypoxia or that express a mitochondria-targeted d-amino-acid oxidase (conditions that induce increased mtROS production), and inhibited basally under normal growth conditions by the mitochondrial antioxidant MnTBAP. Finally, primary Alzheimer's disease fibroblasts also had glycolytic enzymes associated with mitochondria that was reduced by antioxidants, consistent with increased mtROS altering their relative distribution between the cytoplasm and mitochondria. We speculate that the increased mitochondrial localization of glycolytic enzymes is an adaptive response to mtROS that alters glucose flux toward the antioxidant pentose phosphate pathway, creates distinct regulatory pools of mitochondrial metabolites or new metabolic circuits, and/or provides cytoprotection or other adaptive responses via moonlighting functions unrelated to their enzymatic activity.
    Keywords:  Alzheimer's disease; Glycolytic enzymes; Mitochondria; Proximity labeling; Reactive oxygen species; Stress signaling
    DOI:  https://doi.org/10.1016/j.redox.2025.103812
  22. Mol Biol Cell. 2025 Aug 13. mbcE25030128
    Mitochondrial dysfunction and lipid dysregulation in yeast lacking phosphatidylserine.
    Alaumy Joshi, Zakery N Baker, Rachel A Stanfield, Dimitris T Kalafatis, David J Pagliarini, Vishal M Gohil.
      Mitochondrial membrane phospholipids impact mitochondrial structure and function by influencing the assembly and activity of membrane proteins. While the specific roles of the three most abundant mitochondrial phospholipids, phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL), have been extensively studied, the precise function of less abundant phosphatidylserine (PS) is not yet determined. Here, we used genetic and nutritional manipulation to engineer a set of yeast mutants, including a mutant completely devoid of PS, to assess its role in mitochondrial bioenergetics and lipid homeostasis. To circumvent the confounding effect of downstream PS products, PE and PC, we exogenously supplied ethanolamine that allows their biosynthesis via an alternate pathway. Using this system, we demonstrate that PS does not impact the abundance or the assembly of mitochondrial respiratory chain complexes; however, mitochondrial respiration is impaired. PS-lacking mitochondria cannot maintain mitochondrial membrane potential and exhibit leaky membranes. A mass spectrometry-based analysis of the cellular and mitochondrial lipidomes revealed an unexpected increase in odd-chain fatty acid-containing lipids in PS-lacking cells that may impact mitochondrial bioenergetics. Our study uncovers novel roles of PS in mitochondrial membrane biogenesis and bioenergetics and provides a viable eukaryotic system to unravel the cellular functions of PS.
    DOI:  https://doi.org/10.1091/mbc.E25-03-0128
  23. PLoS One. 2025 ;20(8): e0323980
    The mitochondrial aspartate transporter Ucp4a regulates muscle aging and animal lifespan in Drosophila melanogaster.
    Minwoo Baek, Wijeong Jang, Changsoo Kim.
      Mild distress of mitochondria extends animal lifespan, yet the underlying mechanisms are not completely understood. Here we screened mitochondrial proteins for effects on longevity and found that flies mutant in Uncoupling protein 4a (Ucp4a), which encodes a mitochondrial aspartate transporter, have extended lifespans. Tissue-specific experiments revealed knockdown of Ucp4a in muscles, but not neurons, fat, or intestine, to extend lifespan and also eliminate polyubiquitinated protein aggregates, which accumulate with aging and are associated with lifespan. These findings suggest a retrograde mitochondrial signaling process initiated by reduced cytosol aspartate level culminates in muscle protein aggregate removal and lifespan extension.
    DOI:  https://doi.org/10.1371/journal.pone.0323980
  24. Front Genet. 2025 ;16 1628178
    Loss of dynamin 1-like protein impairs mitochondrial function and self-renewal, and activates the integrated stress response in human embryonic stem cells.
    Artur Cieslar-Pobuda, Safak Caglayan.
      Dynamin 1-like protein (DNM1L/DRP1) is a crucial regulator of mitochondrial fission in cells and pathogenic mutations in DNM1L are linked to developmental and metabolic disorders in humans. While the role of DNM1L has been described in patient-derived fibroblasts, its function in early human development remains unclear. In this study, we generated DNM1L deficient human embryonic stem cells (hESCs) using CRISPR/Cas9 to investigate the consequences of DNM1L deficiency and impaired mitochondrial fission on stem cell function. DNM1L -/- hESCs exhibited hyperfused mitochondrial networks, reduced mitochondrial membrane potential, and elevated oxidative stress, indicating compromised mitochondrial fitness. Functionally, DNM1L -/- hESCs showed diminished self-renewal, and reduced expression of the core pluripotency factor OCT4, while NANOG expression was unaffected. We further found that differentiation potential toward the early ectodermal lineage was impaired, whereas early endodermal and mesodermal differentiation remained intact. Notably, integrated stress response (ISR) pathway was activated in DNM1L -/- hESCs, as shown by increased phosphorylated eIF2a and upregulation of downstream targets including activating transcription factor 4 (ATF4), ATF3, ATF5, and DDIT3. Restoring DNM1L expression by reintroduction of DNM1L into the AAVS1 locus rescued mitochondrial morphology and function, normalized ISR activation, and restored self-renewal and OCT4 expression in DNM1L -/- hESCs. These findings demonstrate that DNM1L is essential for maintaining mitochondrial homeostasis, stress response, self-renewal, and pluripotency in hESCs, and emphasize the importance of mitochondrial fission in stem cell function.
    Keywords:  DNM1L; DRP1; human embryonic stem cells; integrated stress response; mitochondrial dysfunction; mitochondrial fission; pluripotency; self-renewal
    DOI:  https://doi.org/10.3389/fgene.2025.1628178
  25. bioRxiv. 2025 Aug 06. pii: 2025.08.04.667739. [Epub ahead of print]
    The Malate-Aspartate Shuttle supports thermogenic lipid mobilization in brown adipocytes.
    Michaela Veliova, Caroline M Ferreira, Katrina Montales, Francisco Villalobos, Alexandra J Brownstein, Rebeca Acín-Pérez, Gabrielly S Ferreira, Linsey Stiles, Marc Liesa, Orian S Shirihai, Marcus F Oliveira.
      Brown adipose tissue (BAT) plays a central role in thermogenesis by coupling fatty acid oxidation to heat production. Efficient BAT thermogenic activity requires enhanced glycolytic flux, which in turn depends on continuous regeneration of cytosolic NAD⁺ to sustain glyceraldehyde-3-phosphate dehydrogenase activity. This regeneration is mediated by three main pathways: lactate dehydrogenase, the glycerol-3-phosphate shuttle, and the malate-aspartate shuttle (MASh). We previously showed that inhibition of the mitochondrial pyruvate carrier increases energy expenditure in brown adipocytes via MASh activation. However, the specific contribution of MASh to BAT energy metabolism remains poorly defined. Here, we show that MASh is functional and directly regulates lipid metabolism in BAT. Enzymatic activities of cytosolic and mitochondrial malate dehydrogenases and glutamic-oxaloacetic transaminases in BAT were comparable to those in the liver. Using a reconstituted system of isolated BAT mitochondria and cytosolic MASh enzymes, we demonstrated that extra-mitochondrial NADH is efficiently reoxidized in a glutamate-dependent manner via MASh. Genetic silencing of the mitochondrial carriers critical to MASh-namely the oxoglutarate carrier (OGC1) and aspartate-glutamate carrier (Aralar1) had no apparent effects on respiratory rates. However, silencing either OGC1 or Aralar1 led to the accumulation of small lipid droplets and impaired norepinephrine-induced lipolysis. Taken together, our data indicate a novel role of MASh in regulating BAT lipid homeostasis with potential implications to body energy expenditure and thermogenesis.
    DOI:  https://doi.org/10.1101/2025.08.04.667739
  26. Front Endocrinol (Lausanne). 2025 ;16 1595557
    Predictors of powerhouse: a perspective of mitochondrial biomarkers in type 2 diabetes.
    Mónica Muñoz-Úbeda, Surjya Narayan Dash.
      Mitochondria play a critical role in maintaining the metabolic balance of the cell. The onset and progression of diabetes have been linked to mitochondrial dysfunction, leading to oxidative stress and dysregulation of metabolic intermediates, ultimately leading to a loss of energy production. Mitochondria play a crucial role in glucose stimulated-insulin secretion in pancreatic β-cells and oxidative phosphorylation in beta cells and skeletal muscles. In type-2 diabetes, impaired oxidative phosphorylation and insulin release is linked to insulin resistance (IR). Given the possible involvement of mitochondrial activity in the pathophysiology of diabetes, it would be highly desirable to investigate possible biomarkers or indicators that may provide details on the onset, severity or progression of the disease. The use of biomarkers is essential both for the diagnosis of mitochondrial diseases and for monitoring their metabolic status. The discovery and characterization of numerous biomarkers that correlate with mitochondrial diseases has led to the development of a number of new biomarkers. Biomarkers associated with human mitochondrial dysfunction are critical for the development of targeted therapies and early diagnosis of diabetes. Based on an investigation of the literature, this perspective outlines the state of knowledge on mitochondrial biomarkers and examines the data supporting their application in the early diagnosis, prognosis, and monitoring of diabetes.
    Keywords:  insulin resistance; metabolic syndrome; mitochondrial biomarkers; mitochondrial dysfunction; type-2 diabetes
    DOI:  https://doi.org/10.3389/fendo.2025.1595557
  27. Neuromuscul Disord. 2025 Jul 29. pii: S0960-8966(25)00179-8. [Epub ahead of print] 105452
    McLeod syndrome mimicking mitochondrial myopathy due to a novel in-frame duplication in the XK gene.
    Maelle Garnier, Juliette Nectoux, Thomas Smol, Alexandre Bauchet, Christophe Verny, Franck Genevieve, Franck Letournel, Naig Gueguen, Marco Spinazzi.
      McLeod syndrome (MLS) is an ultra-rare X-linked multisystem disorder characterized by neurological involvement and distinctive hematological features, including acanthocytosis and specific blood group antigens. The clinical picture is typically dominated by central nervous system manifestations, such as movement disorders, cognitive and psychiatric disturbances, and epilepsy, while subclinical neuromuscular involvement is common. The function of the XK protein and the disease pathophysiology remain poorly understood. We report a unique case of MLS presenting with exercise intolerance due to isolated myopathy associated with mitochondrial Complex I deficiency, in the absence of central nervous system involvement or neuropathy. Whole-genome sequencing identified a novel in-frame duplication introducing an additional leucine at a highly conserved site within the transmembrane domain of the XK protein, resulting in impaired XK protein expression. This case expands the phenotypic spectrum of MLS and underscores the need to include MLS in the differential diagnosis of unexplained metabolic myopathies. Further studies are warranted to elucidate a potential role of the XK protein in mitochondrial function.
    Keywords:  Acanthocytosis; Complex I; Exercise intolerance; McLeod syndrome; Metabolic myopathy; Mitochondria; XK
    DOI:  https://doi.org/10.1016/j.nmd.2025.105452
  28. Sens Actuators B Chem. 2025 Nov 01. pii: 138043. [Epub ahead of print]442
    A Quinolinium-Functionalized Hemicyanine Dye for Ratiometric NAD(P)H Sensing in Live Cells, Kidney Tissues, and Drosophila melanogaster.
    Sushil K Dwivedi, Henry Lanquaye, May Waters, Adonis Amoli, Crystal Wang, Peter Agyemang, Omowunmi Rebecca Aworinde, Tyler Gregersen, Micaela Geborkoff, Yan Zhang, Athar Ata, Thomas Werner, Haiying Liu.
      NAD+ (Nicotinamide adenine dinucleotide) and NADP+ (its phosphorylated variation) are key coenzymes regulating cellular metabolism, biosynthesis, and redox balance. Variations in NAD(P)H activity reflect metabolic activity and are associated with diseases like cancer, metabolic disorders, and neurodegeneration. Live tracking of NAD(P)H is important for comprehending these processes and their dysregulation in disease. However, existing ratiometric emission sensors are hindered by spectral interference from NADH emission, limiting their sensitivity and accuracy in complex biological systems. We present a ratiometric emission sensor based on a 3-quinolinium-hemicyanine dye with amine linkage, designed to address these limitations. By using a longer excitation wavelength (470 nm), the sensor avoids interference from NADH emission, enabling precise monitoring of NAD(P)H activity. Binding to NAD(P)H triggers a photo-induced electron transfer (PET) mechanism, resulting in an increase in visible emission at 519 nm and subtle reduction in near-infrared emission at 711 nm, providing a clear ratiometric signal. We demonstrate the sensor's effectiveness in live cells, tissues, and whole organisms. In HeLa cells, exposure to glucose, maltose, fludarabine or cisplatin induced dose-dependent ratiometric emission changes, reflecting metabolic shifts and oxidative stress. The sensor also successfully detected NAD(P)H fluctuations in Drosophila melanogaster larvae and mammalian kidney tissues, including disease models like ADPKD (autosomal dominant polycystic kidney disease). Importantly, the sensor can distinguish NAD(P)H dynamics from high NADH levels, overcoming a key limitation of current sensors. Co-localization with a mitochondrial dye confirmed the sensor's selective targeting to mitochondria, highlighting its suitability for studying Mitochondrial energy processes and redox changes. This ratiometric sensor provides a sensitive, interference-free tool for live tracking of NAD(P)H kinetics in complex biological systems. Its high sensitivity, accuracy, and versatility offer new opportunities for investigating cellular metabolism, disease mechanisms, and therapeutic interventions in both cellular and in vivo models.
    Keywords:  3-Quinolinium acceptor; Fluorescent sensor; Hemicyanine; NAD(P)H; Ratiometric Imaging
    DOI:  https://doi.org/10.1016/j.snb.2025.138043
  29. Life Med. 2025 Aug;4(4): lnaf019
    Mitochondrial sirtuins, key regulators of aging.
    Zhejun Ji, Guang-Hui Liu, Jing Qu.
      Mitochondrial dysfunction is a hallmark of aging, characterized by a decline in mitochondrial biogenesis and quality control, compromised membrane integrity, elevated ROS production, damaged mitochondrial DNA (mtDNA), impaired mitochondrial-nuclear crosstalk, and deregulated metabolic balance. Among the key longevity regulators, sirtuin family members SIRT3, SIRT4, and SIRT5 are predominantly localized to mitochondria and play crucial roles in maintaining mitochondrial function and homeostasis. This review explores how mitochondrial sirtuins mitigate aging-related mitochondrial dysfunctions and their broader implications in aging-related diseases. By elucidating the intricate interplay between mitochondrial dysfunction and mitochondrial sirtuins, we aim to provide insights into therapeutic strategies for promoting healthy aging and combating age-related pathologies.
    Keywords:  aging; mitochondrial dysfunction; mitochondrial sirtuins
    DOI:  https://doi.org/10.1093/lifemedi/lnaf019
  30. bioRxiv. 2025 Jul 18. pii: 2025.07.16.664929. [Epub ahead of print]
    ndufs2 -/- zebrafish have impaired survival, neuromuscular activity, morphology, and one-carbon metabolism treatable with folic acid.
    Dana V Mitchell, Donna M Iadarola, Neal D Mathew, Kelsey Keith, Christoph Seiler, Sanghyeon Yu, Man S Kim, Niki Woodard, Vernon E Anderson, Eiko Nakamaru-Ogiso, Deanne M Taylor, Marni J Falk.
      Mitochondrial complex I (CI) deficiency represents a common biochemical pathophysiology underlying Leigh syndrome spectrum (LSS), manifesting with progressive multi-system dysfunction, lactic acidemia, and early mortality. To facilitate mechanistic studies and rigorous screening of therapeutic candidates for CI deficient LSS, we used CRISPR/Cas9 to generate an ndufs2 -/- 16 bp deletion zebrafish strain . ndufs2 -/- larvae exhibit markedly reduced survival, severe neuromuscular dysfunction including impaired swimming capacity, multiple morphologic malformations, reduced growth, hepatomegaly, uninflated swim bladder, yolk retention, small intestines, and small eyes and pupils with abnormal retinal ganglion cell layer. Transcriptome profiling of ndufs2 -/- larvae revealed dysregulation of the electron transport chain, TCA cycle, fatty acid beta-oxidation, and one-carbon metabolism. Similar transcriptomic profiles were observed in ndufs2 -/- missense mutant C. elegans ( gas-1(fc21) ) and two human CI-disease fibroblast cell lines stressed in galactose media. ndufs2 -/- zebrafish had 80% reduced CI enzyme activity. Unbiased metabolomic profiling showed increased lactate, TCA cycle intermediates, and acyl-carnitine species. One-carbon metabolism associated pathway alterations appear to contribute to CI disease pathophysiology, as folic acid treatment rescued the growth defect and hepatomegaly in ndufs2 -/- larvae. Overall, ndufs2 -/- zebrafish recapitulate severe CI deficiency, complex metabolic pathophysiology, and relevant LSS neuromuscular and survival phenotypes, enabling future translational studies of therapeutic candidates.
    DOI:  https://doi.org/10.1101/2025.07.16.664929
  31. Open Biol. 2025 Aug;15(8): 240202
    Selective loss of ATP carriers in favour of SLC25A43 orthologues in metamonad mitochondria adapted to anaerobiosis.
    Natalia Janowicz, Vít Dohnálek, Justyna Zítek, Priscila Peña-Diaz, Eva Pyrihová, Martin S King, Michaela Husová, Vojtěch Žárský, Edmund Kunji, Alena Zikova, Vladimír Hampl, Pavel Dolezal.
      Metamonada is a eukaryotic supergroup of free-living and parasitic anaerobic protists. Their characteristic feature is the presence of highly reduced mitochondria that have lost the ability to produce ATP by oxidative phosphorylation and in some cases even by substrate phosphorylation, with all ATP being imported from the cytosol. Given this striking difference in cellular ATP metabolism when compared to aerobic mitochondria, we studied the presence of mitochondrial carrier proteins (MCPs) mediating the transport of ATP across the inner mitochondrial membrane. Our bioinformatic analyses revealed remarkable reduction of MCP repertoire in Metamonada with striking loss of the major ADP/ATP carrier (AAC). Instead, nearly all species retained carriers orthologous to human SLC25A43 protein, a little-characterized MCP. Heterologous expression of metamonad SLC25A43 carriers confirmed their mitochondrial localization, and functional analysis revealed that SLC25A43 orthologues represent a distinct group of ATP transporters, which we designate as ATP-importing carriers (AIC). Together, our findings suggest that AIC facilitate the ATP import into highly reduced anaerobic mitochondria, compensating for their diminished or absent energy metabolism.
    Keywords:  ADP/ATP carrier; Metamonada; SLC25A43; mitochondrial carrier protein; mitochondrial evolution; mitochondrion-related organelle
    DOI:  https://doi.org/10.1098/rsob.240202
  32. Elife. 2025 Aug 11. pii: RP99936. [Epub ahead of print]13
    Redistribution of fragmented mitochondria ensures symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotes.
    Haruna Gekko, Ruri Nomura, Daiki Kuzuhara, Masato Kaneyasu, Genpei Koseki, Deepak Adhikari, Yasuyuki Mio, John Carroll, Tomohiro Kono, Hiroaki Funahashi, Takuya Wakai.
      In cleavage-stage embryos, preexisting organelles partition evenly into daughter blastomeres without significant cell growth after symmetric cell division. The presence of mitochondrial DNA within mitochondria and its restricted replication during preimplantation development makes their inheritance particularly important. While chromosomes are precisely segregated by the mitotic spindle, the mechanisms controlling mitochondrial partitioning remain poorly understood. In this study, we investigate the mechanism by which Dynamin-related protein 1 (Drp1) controls the mitochondrial redistribution and partitioning during embryonic cleavage. Depletion of Drp1 in mouse zygotes causes marked mitochondrial aggregation, and the majority of embryos arrest at the 2 cell stage. Clumped mitochondria are located in the center of mitotic Drp1-depleted zygotes with less uniform distribution, thereby preventing their symmetric partitioning. Asymmetric mitochondrial inheritance is accompanied by functionally inequivalent blastomeres with biased ATP and endoplasmic reticulum Ca2+ levels. We also find that marked mitochondrial centration in Drp1-depleted zygotes prevents the assembly of parental chromosomes, resulting in chromosome segregation defects and binucleation. Thus, mitochondrial fragmentation mediated by Drp1 ensures proper organelle positioning and partitioning into functional daughters during the first embryonic cleavage.
    Keywords:  Dynamin-related protein 1; binuclear formation; chromosome segregation; developmental biology; mitochondrial dynamics; mouse; organelle inheritance; preimplantation development
    DOI:  https://doi.org/10.7554/eLife.99936
  33. Elife. 2025 Aug 11. pii: RP89225. [Epub ahead of print]12
    Hexokinase regulates Mondo-mediated longevity via the PPP and organellar dynamics.
    Raymond Laboy, Marjana Ndoci, Shamsh Tabrez Syed, Maximilian Vonolfen, Eugen Ballhysa, Tim Droth, Klara Schilling, Anna Loehrke, Ilian Atanassov, Adam Antebi.
      The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in Caenorhabditis elegans. These transcription factors coordinate nutrient sensing with carbohydrate and lipid metabolism across the evolutionary spectrum. While most studies have focused on the downstream outputs, little is known about the upstream inputs that regulate these transcription factors in a live organism. Here, we found that knockdown of various glucose metabolic enzymes decreases MML-1 localization in the nucleus and identified two hexokinase isozymes, hxk-1 and hxk-2, as the most vigorous regulators of MML-1 function. Upon hexokinase knockdown, MML-1 redistributes to mitochondria and lipid droplets (LDs), and concomitantly, transcriptional targets are downregulated and germline longevity is abolished. Further, we found that hxk-1 regulates MML-1 through mitochondrial β-oxidation, while hxk-2 regulates MML-1 by modulating the pentose phosphate pathway (PPP) and its coordinated association with LDs. Similarly, inhibition of the PPP rescues mammalian MondoA nuclear translocation and transcriptional function upon starvation. These studies reveal how metabolic signals and organellar communication regulate a key convergent metabolic transcription factor to promote longevity.
    Keywords:  C. elegans; MML-1; MondoA; cell biology; hexokinase; human; longevity; metabolism
    DOI:  https://doi.org/10.7554/eLife.89225
  34. Neural Regen Res. 2025 Aug 13.
    Nigrostriatal dopaminergic vulnerability in Parkinson's disease: Neuroprotective strategies.
    Estefanía Santana-Román, Luis O Soto-Rojas, Elias Manjarrez, Oscar Arias-Carrión.
      The selective vulnerability of nigrostriatal dopaminergic neurons is a hallmark of Parkinson's disease and underlies its progressive motor decline. These neurons are uniquely susceptible to degeneration due to their extensive axonal arborization, high energy demands, sustained pacemaking activity, and cytosolic dopamine metabolism, which collectively promote oxidative stress and mitochondrial dysfunction. Advances in single-nucleus RNA sequencing and spatial transcriptomics have revealed transcriptionally distinct dopaminergic subtypes within the human substantia nigra pars compacta, such as AGTR1 + /SOX6 + and RIT2 + populations, which exhibit subtype-specific transcriptional stress signatures and are preferentially lost in Parkinson's disease. These findings underscore the role of intrinsic vulnerability, influenced by genetic risk loci, mitochondrial stress, and protein misfolding pathways, including α-synuclein aggregation. Furthermore, neuroinflammation, iron accumulation, and vascular dysfunction act synergistically to amplify neuronal loss. This review integrates molecular, cellular, and systems-level mechanisms contributing to dopaminergic degeneration and evaluates emerging neuroprotective strategies. These include anti-oxidative, anti-inflammatory, mitochondrial therapies, novel biomarkers, gene editing, and cell replacement techniques. Understanding the selective vulnerability of nigrostriatal subtypes offers a promising path toward precision-targeted, disease-modifying treatments for Parkinson's disease.
    Keywords:  Parkinson's disease; dopamine metabolism; dopaminergic neurons; iron accumulation; neurodegeneration; neurovascular factors; nigrostriatal pathway; oxidative stress; plasticity; α-synuclein
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00380
  35. bioRxiv. 2025 Aug 05. pii: 2025.08.04.668575. [Epub ahead of print]
    RNA triggers chronic stress during neuronal aging.
    Kevin Rhine, Elle Epstein, Natasha M Carlson, Xuezhen Ge, Orel Mizrahi, Anika Kamat, Anita Hermann, William R Brothers, John Ravits, Eric J Bennett, Gülçin Pekkurnaz, Gene W Yeo.
      Neurodegenerative diseases are linked with dysregulation of the integrated stress response (ISR), which coordinates cellular homeostasis during and after stress events. Cellular stress can arise from several sources, but there is significant disagreement about which stress might contribute to aging and neurodegeneration. Here, we leverage directed transdifferentiation of human fibroblasts into aged neurons to determine the source of ISR activation. We demonstrate that increased accumulation of cytoplasmic double-stranded RNA (dsRNA) activates the eIF2α kinase PKR, which in turn triggers the ISR in aged neurons and leads to sequestration of dsRNA in stress granules. Aged neurons accumulate endogenous mitochondria-derived dsRNA that directly binds to PKR. This mitochondrial dsRNA leaks through damaged mitochondrial membranes and forms cytoplasmic foci in aged neurons. Finally, we demonstrate that PKR inhibition leads to the cessation of stress, resumption of cellular translation, and restoration of RNA-binding protein expression. Together, our results identify a source of RNA stress that destabilizes aged neurons and may contribute to neurodegeneration.
    DOI:  https://doi.org/10.1101/2025.08.04.668575
  36. Sci Adv. 2025 Aug 15. 11(33): eadr6012
    Complex II assembly drives metabolic adaptation to OXPHOS dysfunction.
    Roopasingam Kugapreethan, Sheik Nadeem Elahee Doomun, Joanna Sacharz, Ann E Frazier, Tanavi Sharma, Yau Chung Low, Shuai Nie, Michael G Leeming, Linden Muellner-Wong, Karena Last, Tegan Stait, David P De Souza, David R Thorburn, Malcolm J McConville, David A Stroud.
      During acute oxidative phosphorylation (OXPHOS) dysfunction, reversal of succinate dehydrogenase (complex II) maintains the redox state of the Coenzyme Q (Q)-pool by using fumarate as terminal electron acceptor in certain tissues and cell lines. We identified the action of SDHAF2 protein, a complex II assembly factor, as critical for metabolic adaptation during complex III dysfunction in HEK293T cells. SDHAF2 loss during complex III inhibition led to a net reductive TCA cycle from loss of succinate oxidation, loss of SDHA active site-derived reactive oxygen species (ROS) signaling, insufficient glycolytic adaptation, and a severe growth impairment. Glycolysis adapted cells, however, did not accumulate SDHAF2 upon Q-pool stress, exhibited a net reductive TCA cycle and mild growth phenotypes regardless of SDHAF2 presence. Thus, our study reveals how complex II assembly controls a balance between dynamics of TCA cycle directionality, protection from Q-pool stress, and an ability to use ROS-meditated signaling to overcome acute OXPHOS dysfunction in cells reliant on mitochondrial respiration.
    DOI:  https://doi.org/10.1126/sciadv.adr6012
  37. J Biol Chem. 2025 Aug 12. pii: S0021-9258(25)02437-8. [Epub ahead of print] 110586
    Reduced complex I activity in the retinal pigment epithelium, but not in rod photoreceptors, affects light signaling without impacting cell survival.
    Alexander M Warwick, Lin Yu, Mikael Klingeborn, Amanda M Travis, Vipul M Parmar, Howard M Bomze, Goldis Malek, Sidney M Gospe Iii.
      Mutations in the mitochondrial respiratory complex I accessory subunit NADH:ubiquinone oxidoreductase subunit S4 (ndufs4) can cause the mitochondrial disease Leigh syndrome, which may be associated with vision loss. We previously demonstrated that mice with global deletion of ndufs4 exhibited impaired in vivo photoreceptor light responses prior to the early death of the mice around postnatal day 50. However, ex vivo electrophysiology recordings performed on retinas from ndufs4-/- mice were normal, suggesting that the in vivo phenotype may reflect altered homeostasis of the extracellular environment of photoreceptors rather than their intrinsic metabolic dysfunction. To test this hypothesis, we have generated mouse strains with cell-specific deletions of ndufs4 from rod photoreceptors and from the retinal pigment epithelium (RPE), a key supporting cell to photoreceptors. We now demonstrate that despite efficient depletion of NDUFS4 protein and consequent reduction of complex I activity in rods, scotopic electroretinography (ERG) responses are essentially normal and rod survival is not impacted by rod-specific ndufs4 deletion. Interestingly, while RPE-specific deletion of ndufs4 depletes NDUFS4 protein and reduces complex I activity in RPE, a ∼15% reduction in ERG amplitudes is observed, much less than the 50% reduction previously reported in global ndufs4-/- mice. This suggests that a more complex metabolic relationship exists between photoreceptors, RPE, and other cells of the retina to establish the homeostatic physiological conditions necessary for normal light signaling.
    Keywords:  complex I; electrophysiology; mitochondrial disease; photoreceptor; retina; retinal pigment epithelium
    DOI:  https://doi.org/10.1016/j.jbc.2025.110586
  38. Sci Rep. 2025 Aug 12. 15(1): 29507
    Morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neurons.
    Vyron Gorgogietas, Amélie Weiss, Loïc Cousin, David Hoffmann, Karen Schmitt, Arnaud Ogier, Peter A Barbuti, Bruno F R Santos, Ibrahim Boussaad, Annika Wittich, Andrea Zaliani, Ole Pless, Rejko Krüger, Peter Sommer, Johannes H Wilbertz.
      Parkinson's disease (PD) involves multiple pathological processes in midbrain dopaminergic (mDA) neurons, including protein degradation defects, vesicular trafficking disruption, endolysosomal dysfunction, mitochondrial issues, and oxidative stress. Current PD models often lack complexity and focus on single phenotypes. We used patient-derived SNCA triplication (SNCA-4x) and isogenic control (SNCA-corr) mDA neurons, applying high-content imaging-based morphological profiling to identify and rescue multiple phenotypes. Screening 1,020 compounds, we identified top-scoring compounds that restored healthy profiles in SNCA-4x neurons, increasing Tyrosine hydroxylase (TH) and decreasing α-synuclein (αSyn) levels. Several hits were linked to mitochondrial biology. Tyrphostin A9, a mitochondrial uncoupler, and several of its structural analogues decreased ROS levels, normalized mitochondrial membrane potential, and increased respiration. Western blotting confirmed that Tyrphostin A9 reduces αSyn levels. Our study highlights the neuroprotective potential of mild mitochondrial uncoupling in mDA neurons.
    DOI:  https://doi.org/10.1038/s41598-025-14735-0
  39. Nat Commun. 2025 Aug 15. 16(1): 7595
    MacroD1 sustains mitochondrial integrity and oxidative metabolism.
    Ann-Katrin Hopp, Lorenza P Ferretti, Lisa Schlicker, Amalia Ruiz-Serrano, Udo Hetzel, Francesco Prisco, Anja Kipar, Lukas Muskalla, Elena Ferrari, Carsten C Scholz, Karsten Hiller, Francisco Verdeguer, Deena M Leslie Pedrioli, Michael O Hottiger.
      The mono-ADP-ribosylhydrolase MacroD1 has been recently reported to localize to mitochondria exclusively. However, the extent and means by which MacroD1 regulates metabolic homeostasis remains unclear. Here we show that the absence of MacroD1 in mice decreased mitochondrial load and negatively impacted muscle function, reducing maximal exercise capacity. Knockdown of MacroD1 in C2C12 myoblast cells amplified the production of reactive oxygen species which ultimately resulted in increased mitochondrial fission. Proteomic and metabolomic profiling showed that loss of MacroD1 re-routed metabolite flux from glucose to the pentose-phosphate cycle instead of the tricarboxylic acid cycle to support the production of antioxidants, including glutathione and NADPH. This resulted in increased glucose uptake and dependency both in vitro and in vivo. Hence, our research establishes MacroD1 as a regulator of metabolic homeostasis, which ensures the coordination of cellular carbohydrate flux and optimal mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-025-62410-9
  40. Am J Physiol Endocrinol Metab. 2025 Aug 12.
    Resilience of the Mitochondrial Reticulum in Aging.
    Robert G Leija, José Pablo Vázquez-Medina, George A Brooks.
      Resting and maximal exercise respiratory rates (V̇O2) decline in aging. Those losses have been attributed to impaired mitochondrial function, but the data are inconsistent with healthy aging. To interrogate the hypothesis of mitochondrial dysregulation in aging, we studied hind limb skeletal muscles from young and older, male and female, NIA C57BL/6JN mice. We observed no age-associated changes in coupling efficiency (ADP:O) of mitochondrial reticulum preparations, but respiratory control (RCR) was decreased in older mice. Additionally, older skeletal muscle exhibited subtle yet significant reductions in the expression of proteins functionally related to substrate uptake and oxidation (mMCT1, mPC1, CPT1b, HADH). While there were no differences in mitochondrial contents per mg of muscle in older mice, there were significant losses of muscle, and hence mitochondrial mass as well as proteins associated with membrane dynamics (DRP1, FIS1, and MFN2). Further, 2D and 3D, cross- and longitudinal muscle sections showed alterations in mitochondrial reticulum organization in muscles of older mice. Therefore, aging is associated with subtle, but significant changes in the organization and functioning of muscle mitochondrial reticula.
    Keywords:  Aging; Mitochondria; Mitochondrial Reticulum; Sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00110.2025
  41. Orphanet J Rare Dis. 2025 Aug 13. 20(1): 430
    ECHS1: pathogenic mechanisms, experimental models, and emerging therapeutic strategies.
    Qiang Fu, Rui Qiu, Shang Li, Yuxiang Qin, Ziyi Lu, Shanxin Liyao, Zimo Yang, Xiang Cheng, Yuewen Chen, Huan Xu, Yong Cheng.
      The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. Mutations in ECHS1 lead to severe mitochondrial dysfunction and are implicated in rare metabolic and neurodegenerative disorders. This review summarizes current understanding of how ECHS1 participates in key molecular processes, including energy metabolism, oxidative stress regulation, and apoptosis, and discusses its influence on mitochondrial function. It also highlights advances in experimental models, including mouse, Drosophila, and induced pluripotent stem cell (iPSC) -based systems, which have illuminated the gene's physiological roles while revealing model-specific limitations. Therapeutic approaches, such as dietary interventions, gene therapy, enzyme replacement therapy, and stem cell therapy, are critically evaluated, emphasizing their potential and current challenges. Despite significant progress, gaps remain in understanding ECHS1's tissue-specific and developmental-stage-specific functions. This review underscores the need for advanced human-relevant models and integrative technologies to address these gaps and foster the development of personalized treatments for ECHS1-related disorders.
    Keywords:   ECHS1 protein, human; Beta-oxidation; Fatty acids, volatile; Genetic therapy; Mitochondrial diseases
    DOI:  https://doi.org/10.1186/s13023-025-03959-y
  42. J Immunol. 2025 Aug 14. pii: vkaf198. [Epub ahead of print]
    Brucella abortus induces dynamin-related protein 1 (DRP1)-dependent mitochondrial fission in infected macrophages via stress sensor IRE1α altering metabolic function.
    Erika S Guimarães, Marco Túlio R Gomes, Pedro M Moraes-Vieira, Sergio C Oliveira.
      Brucella abortus exploits the endoplasmic reticulum as a site for replication, triggering the unfolded protein response (UPR). While various pathogens have developed strategies to manipulate mitochondrial dynamics, the mechanisms underlying bacterial infection and mitochondrial dynamics interactions remain poorly understood. Here, we demonstrate that B. abortus induces mitochondrial fragmentation via IRE1α. Our findings reveal that Brucella-induced mitochondrial fission is mediated by dynamin-related protein 1 (DRP1), a pivotal regulator of mitochondrial fission. Moreover, we have demonstrated that DRP1 is activated by the UPR. Brucella-induced fragmentation leads to mitochondrial energetic dysfunction, marked by impaired mitochondrial ATP production and compromised bioenergetic capacity. Furthermore, we reveal a novel role for DRP1 in regulating type I IFN production and signaling during B. abortus infection. Mechanistically, mitochondrial fission facilitates the release of mitochondrial DNA, a potent inducer of type I IFN responses. Despite its impact on mitochondrial function and IFN signaling, DRP1 does not influence the control of B. abortus infection. Our findings uncover a unique mechanism by which B. abortus-induced UPR triggers mitochondrial fragmentation affecting innate immune signaling and cellular metabolism.
    Keywords:   Brucella abortus ; UPR; innate immunity; mitochondrial dysfunction
    DOI:  https://doi.org/10.1093/jimmun/vkaf198
  43. bioRxiv. 2025 Jul 17. pii: 2025.07.11.664452. [Epub ahead of print]
    Mitochondrial clone tracing within spatially intact human tissues.
    Sydney A Bracht, Jiazhen Rong, Rodrigo A Gier, Maureen DeMarshall, Hailey Golden, Diya Dhakal, Jayne C McDevitt, Feiyan Mo, Emma E Furth, Alexandra Strauss Starling, Amanda B Muir, Gary W Falk, Bryson W Katona, Ben Z Stanger, Nancy R Zhang, Sydney M Shaffer.
      Understanding tissue development and intra-tissue evolution requires the ability to trace clones in intact tissues coupled with high-plex molecular profiling preserving spatial context. However, current lineage tracing tools are incompatible with spatial omics. Here, we present SUMMIT (Spatially Unveiling Mitochondrial Mutations In Tissues), a spatially-resolved lineage tracing technology that integrates gene expression profiling with mitochondrial mutation-based clone identification. Unlike synthetic lineage recording methods, SUMMIT relies only on endogenous mutations and thus can be applied to human tissues. To address the compositional mixing of cell types within spatial spots, SUMMIT includes a rigorous statistical framework to confidently assign variants to specific cell subpopulations and achieves high power for spatially localized clones by pooling information across neighboring spots. We validated SUMMIT using a controlled model in which we mixed two cancer cell lines in a mouse tumor, then demonstrated it on multiple human tissues including Barrett's esophagus, gastric cardia, small bowel, and colorectal cancer. Across these samples, we distinguished between global mutations and mutations marking locally restricted clones. The coupled transcriptomic data allowed us to characterize the cell type composition within each clone and delineate their spatial configuration. This integrated approach provides a framework to understand spatially-defined clonal evolution in preserved human tissue.
    DOI:  https://doi.org/10.1101/2025.07.11.664452
  44. J Inherit Metab Dis. 2025 Sep;48(5): e70077
    Personalized Genome-Scale Modeling Reveals Metabolic Perturbations in Fibroblasts of Methylmalonic Aciduria Patients.
    Almut Heinken, Hussein Awada, Vito R T Zanotelli, D Sean Froese, Rosa-Maria Guéant-Rodriguez, Jean-Louis Guéant.
      Cobalamin (vitamin B12) is an essential cofactor for two human enzymes, methionine synthase and methylmalonyl-CoA mutase. Inborn errors of cobalamin metabolism (IECMs) are inherited genetic defects resulting in improper transport, modification, or utilization of cobalamin and include inherited methylmalonic acidurias, a group of IECMs most frequently caused by a defect in the methylmalonyl-CoA mutase enzyme. Here, we performed genome-scale modeling of IECMs to gain insight into their metabolic perturbations. First, we simulated deficiencies in 11 IECM-related genes and demonstrated that they cluster based on impaired metabolic pathways. Next, we leveraged RNA sequencing data from fibroblasts of 202 individuals with methylmalonic aciduria and 19 unaffected controls to construct and interrogate personalized metabolic models. Finally, we analyzed fluxes differing between patients depending on reported symptom presentation. Our findings reveal that (i) metabolic pathways including fatty acid metabolism and heme biosynthesis have reduced flux in IECMs, (ii) in personalized simulations, succinate and fumarate production and heme biosynthesis are impaired, especially in methylmalonyl-CoA mutase deficiency, (iii) one-carbon metabolism reactions such as serine hydroxymethyltransferase and folylglutamate synthase have reduced flux in all individuals with methylmalonic aciduria, and (iv) specific metabolic pathways are up- or down-regulated according to symptoms, including failure to thrive and hematological abnormalities, and treatments, such as antibiotics and protein restriction. Overall, our study delineates metabolic pathways perturbed in IECMs. In future applications, our modeling framework could be applied to other rare genetic diseases or used to predict personalized therapeutic or dietary interventions.
    DOI:  https://doi.org/10.1002/jimd.70077
  45. Biochem Biophys Res Commun. 2025 Aug 08. pii: S0006-291X(25)01156-8. [Epub ahead of print]780 152441
    LDS 698: A highly sensitive probe for tracking mitochondrial membrane potential in live cells.
    Pooja Gupta, Shikha Shree, Richa Agrawal, Soumyaditya Mula, Birija Sankar Patro.
      Monitoring active mitochondria is crucial for gaining insights into essential cellular processes, including energy production, apoptosis, cancer, and neurodegenerative diseases. However, current commercial tools have limitations in detecting subtle changes in mitochondrial membrane potential and tracking the dynamics of these changes in live cells. Here, we report a novel application of LDS 698, a hemicyanine solid-state laser dye, for staining functional mitochondria based on their membrane potential. LDS 698 exhibits high sensitivity and specificity in detecting subtle changes in mitochondrial membrane potential, making it suitable for various analytical techniques, including fluorescence microscopy, flow cytometry, and plate reader assays. Its robustness, photostability, and non-toxicity enable prolonged live-cell imaging for the detection and quantification of mitochondrial morphology and membrane potential. The use of LDS 698 can be extended to study cellular mitochondrial homeostasis and membrane potential dynamics, offering new opportunities for biological research.
    Keywords:  LDS 698; Live cell imaging; Mitochondrial membrane potential
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152441
  46. Nat Biotechnol. 2025 Aug;43(8): 1214
    Children with rare genetic diseases get CRISPR Cures center.
      
    DOI:  https://doi.org/10.1038/s41587-025-02795-6
  47. bioRxiv. 2025 Jul 16. pii: 2025.07.11.664289. [Epub ahead of print]
    Estrogens protect bone mass by inhibiting NAD + metabolism in osteoclasts.
    Adriana Marques-Carvalho, Gareeballah Osman Adam, Ankita Chalke, Ana Resende-Coelho, Olivia Reyes-Castro, Aaron Warren, Luis F Grilo, Claudia Cs Chini, Benjamin Stronach, Farah Alturkmani, Elena Ambrogini, Eduardo N Chini, Ha-Neui Kim, Maria Almeida.
      Estrogens protect against bone loss by reducing osteoclast number and bone resorption, primarily via direct actions on osteoclast precursors. In these cells, estrogens attenuate RANKL-induced stimulation of mitochondrial complex I, which is crucial for ATP generation through NADH oxidation. NAD + promotes redox reactions and activates NAD + -dependent enzymes, including the mitochondrial deacetylase SIRT3. However, the contribution of NAD + to the skeletal effects of estrogens remains unknown. We show that NAD + levels and SIRT3 activity are upregulated by RANKL and inhibited by 17β-estradiol (E 2 ) in mouse and human osteoclast precursors. Increasing NAD + or the mitochondrial NAD + /NADH ratio reverses the inhibitory effects of E 2 on SIRT3 activity and osteoclastogenesis in vitro . Deletion of Nampt , a key NAD salvage enzyme, reduces NAD + and prevents bone loss in ovariectomized mice. Similarly, deletion of Sirt3 in osteoclast precursors mitigates estrogen deficiency-induced bone resorption. These findings indicate that suppression of NAD + levels and mitochondrial redox metabolism by estrogens contributes to their anti-resorptive effects via inhibition of SIRT3.
    DOI:  https://doi.org/10.1101/2025.07.11.664289
  48. J Cell Biol. 2025 Oct 06. pii: e202411169. [Epub ahead of print]224(10):
    The yeast Mkt1/Pbp1 complex promotes adaptive responses to respiratory growth.
    Daniel Caballero, Benjamin M Sutter, Zheng Xing, Caroline Wang, Emma Choo, Yun Wang, Yu-San Yang, Sina Ghaemmaghami, Andrew Lemoff, Benjamin P Tu.
      An amino acid polymorphism in the Rad2/XPG protein Mkt1 (Mkt1-G30D) reportedly underlies variation in mitochondrial phenotypes among laboratory yeast, but the function of Mkt1 and the effects of the polymorphism are unknown. We confirm with genetics and biochemical assays guided by AlphaFold structure predictions that Mkt1 forms a complex with Pbp1, a messenger RNP protein that supports adaptations to respiratory conditions, such as Pumilio protein Puf3-dependent mitochondrial protein expression and TORC1-dependent autophagy. Using CEN.PK (Mkt1-G30) yeast, we show that, like Pbp1, Mkt1 is required for Puf3-dependent mitochondrial protein expression and autophagy during respiratory growth. Notably, we found the Mkt1-G30D mutation destabilizes the Mkt1/Pbp1 complex, helping to explain its loss-of-function effects. A HAP1+ S288C strain exhibited defects in mitochondrial biogenesis and autophagy, which were rescued by replacing its Mkt1-D30 allele with the Mkt1-G30 allele. Thus, the Mkt1/Pbp1 complex supports adaptive processes during respiratory growth, and the Mkt1-G30D mutation is an evolutionary adaptation that tempers respiratory processes by destabilizing the Mkt1/Pbp1 complex.
    DOI:  https://doi.org/10.1083/jcb.202411169
  49. Cardiovasc Pathol. 2025 Aug 13. pii: S1054-8807(25)00049-3. [Epub ahead of print] 107764
    Immuhistochemically-confirmed mitochondrial cardiomyopathy presenting as a conduction system hamartoma: A case report.
    Ryo Kaimori, Kentaro Sakai, Atsuhito Takeda, Rina Hayata, Shinji Yano, Haruto Nishida, Tsutomu Daa, Shinjiro Mori.
      Conduction system hamartoma (CSH) is a rare cardiac lesion characterized by the abnormal proliferation of Purkinje-like myocytes. It predominantly affects female infants and is often associated with sudden cardiac death. Recent studies have linked mitochondrial dysfunction, particularly complex I deficiency, with CSH. We report an autopsy case of an eight-month-old female infant who died suddenly following mild gastrointestinal symptoms. A gross examination revealed mild cardiac hypertrophy without nodular lesions. Histological analysis identified multifocal aggregates of Purkinje-like cells with clear or foamy cytoplasm, some forming well-circumscribed nodules in the non-compacted myocardium. Immunohistochemistry demonstrated a marked reduction in complex I expression, supporting mitochondrial dysfunction. Although prominent trabeculations and deep recesses suggestive of left ventricular noncompaction were observed, they did not meet the strict diagnostic criteria. This case supports the potential role of mitochondrial complex I deficiency as a key pathogenic mechanism in CSH and highlights the significance of detailed histopathological and immunohistochemical analyses for an accurate diagnosis, especially in cases of sudden unexplained infant death.
    Keywords:  autopsy; conduction system hamartoma; infantile sudden death; mitochondrial cardiomyopathy
    DOI:  https://doi.org/10.1016/j.carpath.2025.107764
  50. Elife. 2025 Aug 12. pii: e103844. [Epub ahead of print]14
    Glaucoma-associated Optineurin mutations increase transcellular degradation of mitochondria in a vertebrate optic nerve.
    Yaeram Jeong, Chung-Ha O Davis, Aaron Muscarella, Hector H Navarro, Viraj Deshpande, Lucy G Moore, Keun-Young Kim, Mark H Ellisman, Nicholas Marsh-Armstrong.
      We previously described a process whereby mitochondria shed by retinal ganglion cell (RGC) axons are transferred to and degraded by surrounding astrocytes in the optic nerve head of mice. Since the mitophagy receptor Optineurin (OPTN) is one of few large-effect glaucoma genes and axonal damage occurs at the optic nerve head in glaucoma, here we explored whether OPTN mutations perturb the transcellular degradation of mitochondria. Live-imaging of Xenopus laevis optic nerves revealed that diverse human mutant but not wildtype OPTN increase stationary mitochondria and mitophagy machinery and their colocalization within, and in the case of the glaucoma-associated OPTN mutations also outside of, RGC axons. These extra-axonal mitochondria are degraded by astrocytes. Our studies demonstrate that expression of OPTN carrying a glaucoma-associated mutation results in increased transcellular degradation of axonal mitochondria.
    Keywords:  neuroscience; xenopus
    DOI:  https://doi.org/10.7554/eLife.103844
  51. Mol Genet Metab. 2025 Jul 30. pii: S1096-7192(25)00204-5. [Epub ahead of print]146(1-2): 109213
    Childhood POLG-related disorders: Focus on polyradiculoneuropathy.
    Claire-Marine Bérat, Marie Hully, Agnès Rötig, Giulia Barcia, Zahra Assouline, Marie-Thérèse Abi-Warde, Christine Barnerias, Elise Payen, Marianne Jaroussie, Pauline Gaignard, Elise Lebigot, Agathe Roubertie, Nathalie Boddaert, Charles-Joris Roux, Pascale de Lonlay, Isabelle Desguerre, Arnold Munnich, Manuel Schiff, Cyril Gitiaux.
      Pathogenic variants in POLG are involved in a large spectrum of neurological, gastrointestinal and liver impairments. Children affected with POLG-related disorders rarely exhibit peripheral neuropathy, the latter being most often described in adults as axonal polyneuropathy. Our aim was to focus on electrophysiological findings in young children affected with POLG-related disorder. We report herein 6 unrelated early-onset POLG patients presenting with an atypical and severe polyradiculoneuropathy mimicking Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). All these patients also exhibited severe intestinal dysmotility and liver disease. Different compound heterozygous pathogenic variants in POLG were found and 4/6 patients shared the same heterozygous R232H variation. POLG-related disorders should therefore be considered in the setting of atypical childhood onset CIDP with gastrointestinal and liver impairments.
    Keywords:  CIDP; POLG; chronic inflammatory demyelinating polyneuropathy; mitochondria; mitochondrial disorders
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109213
  52. Int J Mol Sci. 2025 Jul 23. pii: 7117. [Epub ahead of print]26(15):
    Distinct Mitochondrial DNA Deletion Profiles in Pediatric B- and T-ALL During Diagnosis, Remission, and Relapse.
    Hesamedin Hakimjavadi, Elizabeth Eom, Eirini Christodoulou, Brooke E Hjelm, Audrey A Omidsalar, Dejerianne Ostrow, Jaclyn A Biegel, Xiaowu Gai.
      Mitochondria are critical for cellular energy, and while large deletions in their genome (mtDNA) are linked to primary mitochondrial diseases, their significance in cancer is less understood. Given cancer's metabolic nature, investigating mtDNA deletions in tumors at various stages could provide insights into disease origins and treatment responses. In this study, we analyzed 148 bone marrow samples from 129 pediatric patients with B-cell (B-ALL) and T-cell (T-ALL) acute lymphoblastic leukemia at diagnosis, remission, and relapse using long-range PCR, next-generation sequencing, and the Splice-Break2 pipeline. Both T-ALL and B-ALL exhibited significantly more mtDNA deletions than did the controls, with T-ALL showing a ~100-fold increase and B-ALL a ~15-fold increase. The T-ALL samples also exhibited larger deletions (median size > 2000 bp) and greater heterogeneity, suggesting increased mitochondrial instability. Clustering analysis revealed distinct deletion profiles between ALL subtypes and across disease stages. Notably, large clonal deletions were detected in some B-ALL remission samples, including one affecting up to 88% of mtDNA molecules, which points toward treatment-driven selection or toxicity. A multivariate analysis confirmed that disease type, timepoint, and WHO subtype significantly influenced mtDNA deletion metrics, while age and gender did not. These findings suggest that mtDNA deletion profiling could serve as a biomarker for pediatric ALL and may indicate mitochondrial toxicity contributing to late effects in survivors.
    Keywords:  B-ALL; T-ALL; acute lymphoblastic leukemia; chemotherapy effects; mitochondrial DNA deletions; pediatric leukemia
    DOI:  https://doi.org/10.3390/ijms26157117
  53. J Cell Physiol. 2025 Aug;240(8): e70083
    Mitochondrial Pyruvate Carrier Differentially Controls the Self-Renewal and Differentiation of Human Pluripotent Stem Cells.
    Dacheng Jiang, Yuchen Wang, Yanhao Chen, Cheng Tian, Xin Li, Shuang Li, Xiaosong Gu, Chunping Jiang, Qiurong Ding.
      Mitochondria are crucial for cell fate determination, yet their roles in human pluripotent stem cell (hPSC) fate changes have remained underexplored. Here, we designed a CRISPR library targeting 661 mitochondrial proteins and identified the MPC (mitochondrial pyruvate carrier) as a critical regulator of hPSC self-renewal and pluripotency. Notably, MPC inhibition reduced hPSC self-renewal and endoderm differentiation while promoting mesoderm differentiation, with no effect on ectoderm differentiation, all mediated by influencing glycolytic acetyl-CoA production. Specifically, the decrease in acetyl-CoA following MPC inhibition affected histone acetylation in hPSCs, compromising self-renewal. In contrast, MPC inhibition did not impact histone acetylation in differentiated cells; instead, it reduced the acetylation of non-histone proteins-EP300 and SMAD2-thereby enhancing mesoderm differentiation and repressing endoderm differentiation, respectively. These findings suggest that distinct effector proteins respond to variations in acetyl-CoA levels at different developmental stages, leading to a context-dependent regulation of cell fate determination by glycolytic acetyl-CoA in hPSCs.
    Keywords:  acetyl‐CoA; definitive endoderm differentiation; human pluripotent stem cells; mesoderm differentiation; mitochondrial pyruvate carrier; protein acetylation; self‐renewal
    DOI:  https://doi.org/10.1002/jcp.70083
  54. Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2501681122
    Global profiling of N-terminal cysteine-dependent degradation mechanisms.
    Aizat Bekturova, Yaara Makaros, Shahar Ben-David, Itay Koren.
      Hypoxia, a condition characterized by insufficient oxygen supply, challenges cellular homeostasis and energy production, triggering adaptive responses to promote survival under these stressful conditions. One key strategy involves enzymatic oxidation of N-terminal cysteine residues coupled with proteolysis through the Cys-Arg/N-degron pathway. Despite hundreds of human proteins possessing N-terminal cysteine, very few have been identified as substrates of this pathway, and its substrate selectivity remains unclear. Moreover, the biological role of this pathway in the cellular response to hypoxia is not well defined. Here, by systematically screening protein stability using an N-terminome library, we reveal a broad set of cysteine-initiating proteins regulated by this pathway. Mutagenesis experiments further revealed the specificity of Cys-Arg/N-degron pathway, showing a preference for hydrophobic and positively charged residues following cysteine. Additionally, we uncovered full-length substrates that are regulated by this pathway during hypoxia, including IP6K1. Loss of IP6K1 impaired glucose uptake, glycolytic ATP production, and overall mitochondrial function. Consequently, IP6K1-deficient cells exhibited disrupted metabolic adaptation under hypoxic conditions and reduced survival under stress. These findings underscore the importance of the Cys-Arg/N-degron pathway in regulating metabolic responses and highlight its potential importance in hypoxia-related disorders.
    Keywords:  E3 ligases; N-degron; cysteine; hypoxia; protein degradation
    DOI:  https://doi.org/10.1073/pnas.2501681122
  55. Bioessays. 2025 Aug 11. e70054
    Defective Ribosome Recycling: A Bridge Between Translation Fidelity, Organelle Dysfunction, and Diseases: Exploring How Flawed Ribosome Recycling Factors Impact Ribosome Metabolism and Organelle Homeostasis, Leading to Human Diseases.
    Foozhan Tahmasebinia, Zhihao Wu.
      Ribosome recycling is a fundamental biological process crucial for cellular health. Defective recycling disrupts ribosome biogenesis and organelle function, particularly in mitochondria, contributing to ribosomopathies, neurodegenerative diseases, and cancer. While not directly linked to human diseases via known genetic mutations, emerging evidence suggests a critical interplay between ribosome recycling and organelle quality control. Impaired ribosome recycling leads to aberrant ribosome production, compromised translational quality control, protein misfolding, and subsequent organelle dysfunction and cellular stress. These cascading defects underscore the critical need for effective ribosome reutilization, especially under stress, as disruptions can cause translational arrest and heightened stress signaling, perturbing cellular homeostasis. Our analyses establish an indirect but significant link between ribosome recycling and human disease, offering new perspectives on how translational fidelity and organelle maintenance converge to support cellular well-being.
    Keywords:  40S subunit recycling; CAT‐tailing; cancer; mitochondria; neurodegenerative diseases; ribosome recycling; ribosome‐associated quality control (RQC)
    DOI:  https://doi.org/10.1002/bies.70054
  56. Nat Biotechnol. 2025 Aug 12.
    Targeted delivery of diverse biomolecules with engineered bacterial nanosyringes.
    Joseph Kreitz, Victoria Yang, Mirco J Friedrich, Julie Pham, Rhiannon K Macrae, Feng Zhang.
      The Photorhabdus virulence cassette is a microbial nanosyringe that can be engineered to deliver protein cargos into human cells. Here we further modify this system to incorporate exogenous cargos and targeting moieties in vitro. We show that this method, termed SPEAR, enables loading of different types of cargo (including folded ribonucleoproteins and single-stranded DNA) and targeting of defined cell types both in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s41587-025-02774-x
  57. Ann Neurol. 2025 Aug 15.
    Biallelic Variants in the DARS2 Gene as a Novel Cause of Axonal Charcot-Marie-Tooth Disease.
    Berta Estévez-Arias, Siiri Sarv, Nathalie Bonello-Palot, Laura Carrera-García, Carlos Ortez, Jesica Expósito-Escudero, Delia Yubero, Jordi Muchart, Emilien Delmont, Eve Õiglane-Shlik, Teele Meren, Sanna Puusepp, Ülle Murumets, Gajja S Salomons, Bjarne Udd, Liis Väli, Lara Cantarero, Carsten G Bönnemann, Andrés Nascimento, Santiago Ramón-Maiques, Katrin Õunap, Janet Hoenicka, Daniel Natera-de Benito, Francesc Palau.
       OBJECTIVE: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic neuropathies, with >90 genes identified. Several aminoacyl-tRNA synthetases have been linked to CMT. DARS2, encoding the mitochondrial aspartyl-tRNA synthetase, has been typically associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation. This study aimed to investigate the association between biallelic DARS2 variants and axonal CMT.
    METHODS: We investigated 5 individuals from 3 unrelated families with axonal CMT and biallelic DARS2 variants. Functional studies in fibroblasts assessed their effects on DARS2 expression, localization, and mitochondrial function. Enzymatic activity was evaluated in HEK293 cells.
    RESULTS: The 5 individuals, including 4 adults, presented with childhood-onset progressive axonal CMT. None had leukoencephalopathy, but one showed central nervous system involvement, with intellectual disability and epilepsy. Genetic analysis identified compound heterozygous DARS2 variants: family A, p.Ser238Phe and p.Arg336Cys; family B, p.Ser238Phe and p.Ile25Thrfs*38; family C, c.492+2T>C and p.Pro503Leu. Functional studies revealed reduced DARS2 protein levels, mitochondrial network abnormalities, and impaired mitochondrial function. p.Ser238Phe behaves as a hypomorphic allele, whereas p.Pro503Leu reduced DARS2 enzymatic activity by 75%.
    INTERPRETATION: Our findings expand the DARS2-related disease spectrum, establishing a novel association with axonal CMT. Hypomorphic variants, such as p.Ser238Phe, when paired with more deleterious variants, result in isolated axonal CMT, whereas more severe combinations-although not as deleterious as those seen in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation-result in axonal CMT with central nervous system involvement, albeit without leukoencephalopathy. These observations raise the possibility that DARS2-associated diseases form a continuum rather than representing strictly distinct central or peripheral nervous system disorders. ANN NEUROL 2025.
    DOI:  https://doi.org/10.1002/ana.78005
  58. Science. 2025 Aug 14. 389(6761): 685-686
    Mitochondria hoard folate to starve a parasite.
    Anu Suomalainen, Joni Nikkanen.
      Metabolic immunity contributes to cells' defenses against Toxoplasma gondii.
    DOI:  https://doi.org/10.1126/science.aea0875
  59. STAR Protoc. 2025 Aug 09. pii: S2666-1667(25)00423-X. [Epub ahead of print]6(3): 104017
    Protocol for the spatiotemporal profiling of RNA within nuclear compartments in human cell lines using SLAM-RT&Tag.
    Nadiya Khyzha, Kami Ahmad, Steven Henikoff.
      Measuring RNA residence time within nuclear compartments provides insight into their roles as either storage sites or transient processing hubs. This protocol describes SLAM-RT&Tag, a genomic technique that integrates RNA metabolic labeling with RT&Tag, an RNA proximity labeling method. We detail steps for RNA labeling, library preparation, and computational quantification of T-to-C conversion events to infer RNA dynamics within nuclear compartments in human cell lines. For complete details on the use and execution of this protocol, please refer to Khyzha et al.1.
    Keywords:  Bioinformatics; Cell Biology; Gene Expression; Genomics; Molecular Biology; Molecular/Chemical Probes; RNA-seq; Sequence analysis; Sequencing
    DOI:  https://doi.org/10.1016/j.xpro.2025.104017
  60. Redox Biol. 2025 Aug 10. pii: S2213-2317(25)00330-1. [Epub ahead of print]86 103817
    α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons.
    Plamena R Angelova, Noemi Esteras, James Evans, Marko Kostic, Ronald Melki, Jochen H M Prehn, Sonia Gandhi, Andrey Y Abramov.
      One of the major histopathological features of Parkinsons's disease - intracellular Lewy bodies - consists of misfolded α-synuclein. This protein can self-assemble, spread through the brain and seed its own aggregation. Aggregated α-synuclein is shown to induce mitochondrial dysfunction that leads to neuronal loss. Using human iPSC-derived SNCA triplication (3xSNCA) and isogenic control (ISO) neurons we studied whether acute exposure to fibrillar α-synuclein, or its seeding properties, induce effects on mitochondrial function and toxicity. Chronic exposure of neurons to fibrillar α-synuclein (up to 3 weeks) induces a gradual increase of endogenous α-synuclein seeding in neurons, with a decrease in the exogenous fibrillar α-synuclein in ISO and 3xSNCA neurons. Application of exogenous fibrillar α-synuclein induced mitochondrial depolarisation, impairment of complex I function, increased ROS production, oxidative stress and cell death. Notably, α-synuclein seeding following weeks of incubation almost completely restored mitochondrial function and redox balance of human neurons. Thus, mitochondrial dysfunction and oxidative stress in human neurons can be induced acutely only by transient exogenous fibrillar α-synuclein, but seeding is irrelevant to long-term mitochondrial dysfunction or toxicity. This study also indicates an acute, transient toxic insult followed by a remarkable period of adaptation and functional recovery, highlighting the resilience of human neurons.
    Keywords:  Neurotoxicity; Parkinson's disease; Seeding; Snca; α-synuclein
    DOI:  https://doi.org/10.1016/j.redox.2025.103817
  61. Cell Mol Neurobiol. 2025 Aug 14. 45(1): 79
    Mitochondrial Quality Control: Insights into Intracerebral Hemorrhage.
    Tong Shang, Binglin Kuang, Lei Zheng, Baiwen Zhang, Xueting Liu, Yaxin Shang, Jia Zheng, Baochun Luo, Wei Zou.
      Mitochondrial dysfunction has been identified as a key factor in the pathophysiological changes associated with intracerebral hemorrhage (ICH). As the core of intracellular energy metabolism, mitochondrial homeostasis is highly dependent on the precise regulation of its mitochondrial quality control (MtQC) system. After ICH, dysfunctional mitochondria lead to impaired oxidative phosphorylation and cellular bioenergetic stress, inducing oxidative stress, inflammatory responses, and programmed cell death, further exacerbating cellular damage. To counteract this injury, cells activate a series of MtQC mechanisms for compensatory repair, including mitochondrial dynamics, mitochondrial biogenesis, mitophagy, and intercellular mitochondrial transfer. These stringent mechanisms help maintain the mitochondrial network, restore the integrity of mitochondrial structural and functional integrity, improve neural function, and mitigate brain injury. In this review, we discuss key evidence regarding the role of mitochondrial dysfunction in ICH, focusing on the MtQC mechanisms involved in ICH. We also summarize potential therapeutic strategies targeting MtQC to intervene in ICH, providing valuable insights for clinical applications.
    Keywords:  Intercellular mitochondrial transfer; Intracerebral hemorrhage; Mitochondrial dynamics; Mitochondrial dysfunction; Mitochondrial quality control; Mitophagy
    DOI:  https://doi.org/10.1007/s10571-025-01599-1
  62. Aging Cell. 2025 Aug 11. e70198
    Oxytocin Enhances Demethylation Through TET Enzyme Expression in Neurons of Aged Mice: Oxytocin as a Potential Antiaging Peptide.
    Yuko Maejima, Shoko Yokota, Megumi Yamachi, Shizu Hidema, Tomoyuki Ono, Shu Taira, Katsuhiko Nishimori, Heidi de Wet, Kenju Shimomura.
      While it is well-documented that plasma oxytocin (OXT) levels decline with age, the underlying mechanisms remain elusive. This study aimed to elucidate the physiological mechanisms contributing to this age-related decrease in plasma OXT and the possible use of OXT supplementation on improving age-related decline of neural function. Comparing young (9 weeks) and aged (> 45 weeks) mice, aged mice showed reduced plasma OXT levels, an increase in the inflammation marker hs-CRP, and decreased OXT-positive neurons in the hypothalamus. Aged mice showed signs of epigenetic changes in the hypothalamus as indicated by decreased ten-eleven translocation (TET) family mRNA expression, decreased 5-hydroxymethylcytosine (5hmC) positive neurons, and downregulated mitochondrial respiratory complex IV (COX IV) expression. Nasal application of OXT (10 μg/day) for 10 days to aged mice resulted in normalized plasma OXT and inflammation levels and a recovery of OXT-positive neurons, TET2 mRNA levels, 5hmC positive neurons, and COX IV expression. Directly confirming a role for OXTR signaling, TET2, COX IV, and 5hmC in the hypothalamus and hippocampus were also found to be decreased in oxytocin receptor (OXTR) null mice, compared with age-matched WT mice. Furthermore, we show that methylation as a result of aging decreases OXT production in hypothalamic neurons, thereby reducing circulating plasma OXT levels, which can be reversed by nasal OXT treatment. The data presented here suggest that aging, DNA methylation, mitochondrial dysfunction, inflammation, and senescence are interconnected in a vicious cycle, which can be successfully interrupted by OXT treatment.
    Keywords:  TET enzyme; antiaging; methylation; mitochondria; neurons; oxytocin
    DOI:  https://doi.org/10.1111/acel.70198
  63. Nature. 2024 May;629(8012): 518-520
    How to kill the 'zombie' cells that make you age.
    Carissa Wong.
      
    Keywords:  Ageing; Drug discovery; Gene therapy; Immunology
    DOI:  https://doi.org/10.1038/d41586-024-01370-4
  64. Annu Rev Biomed Data Sci. 2025 Aug;8(1): 605-632
    Methylation Data Analysis and Interpretation.
    Yuehua Zhu, Weiguang Mao, Rezwan Hosseini, Maria Chikina.
      DNA methylation, a covalent modification, fundamentally shapes mammalian gene regulation and cellular identity. This review examines methylation's biochemical underpinnings, genomic distribution patterns, and analytical approaches. We highlight three distinctive aspects that separate methylation from other epigenetic marks: its remarkable stability as a silencing mechanism, its capacity to maintain distinct states independently of DNA sequence, and its effectiveness as a quantitative trait linking genotype to disease risk. We also explore the phenomenon of methylation clocks and their biological significance. The review addresses technical considerations across major assay types-both array-based technologies and sequencing approaches-with emphasis on data normalization, quality control, cell proportion inference, and the specialized statistical models required for next-generation sequencing analysis.
    Keywords:  RRBS; WGBS; differential methylation; methylation; methylation array; methylation clocks
    DOI:  https://doi.org/10.1146/annurev-biodatasci-120924-091033
  65. Tissue Barriers. 2025 Aug 14. 2537991
    Mitochondrial dysfunction and oxidative stress in Parkinson's disease: mechanisms, biomarkers, and therapeutic strategies.
    Pothu Usha Kiran, Jigar Haria, Reena Rani, Sudhir Singh.
       BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by motor symptoms and progressive degeneration of dopaminergic neurons. Accumulating evidence indicates that mitochondrial dysfunction and oxidative stress are major contributors to PD pathogenesis.
    OBJECTIVES: This review explores the molecular mechanisms underlying PD, emphasizing mitochondrial dysfunction and oxidative stress. It also examines genetic and environmental contributors, emerging biomarkers, and future treatment strategies.
    METHODS: An extensive literature review was conducted, focusing on mitochondrial biology, oxidative stress, genetic mutations, and environmental toxins relevant to PD. Investigations into treatment options - including redox therapies, gene therapies, and lifestyle approaches - were also examined.
    RESULTS: Mitochondrial dysfunction in PD includes disrupted oxidative phosphorylation and elevated reactive oxygen species (ROS). This also affects calcium homeostasis, especially in substantia nigra neurons. Genetic mutations (PINK1, Parkin, DJ-1, LRRK2, GBA) impair mitophagy and antioxidant defenses. Environmental toxins (e.g. MPTP, rotenone) further damage mitochondrial function and contribute to dopaminergic neuron loss. Emerging biomarkers involve measurements of lipid peroxidation and mitochondrial DNA damage. Promising therapeutic strategies include mitochondria-targeted antioxidants (e.g. MitoQ), PINK1-based gene therapy, Parkin activation, ketogenic diet, and exercise-induced mitochondrial biogenesis.
    CONCLUSIONS: Mitochondrial dysfunction and oxidative stress are central to PD pathophysiology. Strategies targeting these mechanisms may slow disease progression. Future research should emphasize combination therapies and early intervention trials, alongside biomarker integration, to enhance clinical outcomes.
    Keywords:  Mitochondrial dysfunction; Parkinson’s disease; oxidative stress
    DOI:  https://doi.org/10.1080/21688370.2025.2537991
  66. Front Syst Biol. 2024 ;4 1351555
    Advancing precision medicine therapeutics for Parkinson's utilizing a shared quantitative systems pharmacology model and framework.
    Christopher Denaro, Diane Stephenson, Martijn L T M Müller, Benedetto Piccoli, Karim Azer.
      A rich pipeline of therapeutic candidates is advancing for Parkinson's disease, many of which are targeting the underlying pathophysiology of disease. Emerging evidence grounded in novel genetics and biomarker discoveries is illuminating the true promise of precision medicine-based therapeutic strategies for PD. There has been a growing effort to investigate disease-modifying therapies by designing clinical trials for genetic forms of PD - providing a clearer link to underlying pathophysiology. Leading candidate genes based on human genetic findings that are under active investigation in an array of basic and translational models include SNCA, LRRK2, and GBA. Broad investigations across mechanistic models show that these genes signal through common molecular pathways, namely, autosomal lysosomal pathways, inflammation and mitochondrial function. Therapeutic clinical trials to date based on genetically defined targets have not yet achieved approvals; however, much is to be learned from such pioneering trials. Fundamental principles of drug development that include proof of pharmacology in target tissue are critical to have confidence in advancing such precision-based therapies. There is a clear need for downstream biomarkers of leading candidate therapies to demonstrate proof of mechanism. The current regulatory landscape is poised and primed to support translational modeling strategies for the effective advancement of PD disease-modifying therapeutic candidates. A convergence of rich complex data that is available, the regulatory framework of model informed drug development (MIDD), and the new biological integrated staging frameworks when combined are collectively setting the stage for advancing new approaches in PD to accelerate progress. This perspective review highlights the potential of quantitative systems pharmacology (QSP) modeling in contributing to the field and hastening the pace of progress in advancing collaborative approaches for urgently needed PD disease-modifying treatments.
    Keywords:  Parkinson; biomarkers; disease modifying therapy; genetics; precision medicine; quantitative systems pharmacology; translational research
    DOI:  https://doi.org/10.3389/fsysb.2024.1351555
  67. Nat Neurosci. 2025 Aug 11.
    Potentiation of mitochondrial function by mitoDREADD-Gs reverses pharmacological and neurodegenerative cognitive impairment in mice.
    Antonio C Pagano Zottola, Rebeca Martín-Jiménez, Gianluca Lavanco, Geneviève Hamel-Côté, Carla Ramon-Duaso, Rui S Rodrigues, Yamuna Mariani, Mehtab Khan, Filippo Drago, Stephanie Jean, Itziar Bonilla-Del Río, Daniel Jimenez-Blasco, Jon Egaña-Huguet, Abel Eraso-Pichot, Sandra Beriain, Astrid Cannich, Laura Vidal-Palencia, Rosmara Infantino, Francisca Julio-Kalajzić, Doriane Gisquet, Ania Goncalves, Inas Al-Younis, Yann Baussan, Stephane Duvezin-Caubet, Anne Devin, Edgar Soria-Gomez, Nagore Puente, Juan P Bolaños, Pedro Grandes, Sandrine Pouvreau, Arnau Busquets-Garcia, Giovanni Marsicano, Luigi Bellocchio, Etienne Hebert-Chatelain.
      Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (Gs) could rapidly promote the activity of the organelle and possibly compensate for bioenergetic dysfunction. Here, we show that a mitochondria-targeted recombinant designer receptor exclusively activated by designer drugs (mitoDREADD-Gs) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-Gs abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer's disease and frontotemporal dementia. Thus, mitoDREADD-Gs enables the establishment of causal relationships between mitochondria and biological or disease-related processes and represents an innovative potential therapeutic approach for disorders associated with mitochondrial impairment.
    DOI:  https://doi.org/10.1038/s41593-025-02032-y
  68. Nucleic Acids Res. 2025 Jul 19. pii: gkaf730. [Epub ahead of print]53(14):
    High-fidelity and differential nonsense suppression in live cells and a frontotemporal dementia allele with human transfer RNAs.
    Aruun Beharry, Cian Ward, Henry Moore, Kyle S Hoffman, Patricia P Chan, Todd M Lowe, Patrick O'Donoghue.
      Nonsense mutations generate premature termination codons (PTCs) that are responsible for 11% of genetic disease alleles. The arginine (Arg, CGA) to stop (UGA) mutation is the most common PTC. Humans encode >600 transfer RNA (tRNA) genes with many identical and similar copies. We developed a dual fluorescent reporter to quantify PTC readthrough in live cells and found single nucleotide mutations of human tRNAArg gene variants enabled differential nonsense suppression that depended on the tRNA sequence and the cell type. We investigated G36A variants of all six human tRNAArgUCG isodecoders, and only the TCG-6-1 tRNA, where G36A occurs in 0.01% of human genomes, was unable to translate nonsense codons. With tRNA sequencing, we showed that a suppressor tRNA derived from the TCG-3-1 gene was expressed 2.1-fold higher and generated 1.8-fold more nonsense suppression than a tRNA derived from the TCG-4-1 gene. In a neuroblastoma model of frontotemporal dementia, we observed >70% readthrough of progranulin R493X with a suppressor tRNA that represented 5%-18% of the total tRNAArg pool. The tRNAs outperformed aminoglycoside-induced nonsense suppression in efficacy, tolerability to the cells, and translation fidelity according to mass spectrometry. Our studies show that human nonsense suppressor tRNAs can correct genetic defects that cause disease.
    DOI:  https://doi.org/10.1093/nar/gkaf730
  69. Brain. 2025 Aug 05. pii: awaf290. [Epub ahead of print]
    Design considerations for C9orf72 disease prevention trials.
    Michael Benatar, Adam M Staffaroni, Joanne Wuu, Michael P McDermott, Melanie Quintana, Jean Swidler, Gail Andersen, Edward D Huey, Martin R Turner, Eric A Macklin, James D Berry, Corey T McMillan, Tania Gendron, Chiadi Onyike, Howard Rosen, Hilary W Heuer, Anne-Laure Grignon, Kuldip D Dave, Calaneet Balas, Amanda Gleixner, Andrew Satlin, Billy Dunn, Penny Dacks, Adam L Boxer.
      The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10-15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum. Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and the ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this Workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks, and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities, and the broader drug development community.
    Keywords:  amyotrophic lateral sclerosis (ALS); biomarker; frontotemporal dementia (FTD); phenoconversion; pre-symptomatic; regulatory considerations
    DOI:  https://doi.org/10.1093/brain/awaf290
  70. Nat Commun. 2025 Aug 12. 16(1): 7487
    REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate.
    Korin Sahinyan, Darren M Blackburn, Marie-Michelle Simon, Felicia Lazure, Tony Kwan, David H Wilson, Maryam Vahidyeganeh, Nawal Alsadi, Julia von Maltzahn, Yasuhiro Yamada, Arezu Jahani-Asl, Guillaume Bourque, Michael A Rudnicki, Vahab D Soleimani.
      Cell fate and identity require timely activation of lineage-specific and concomitant repression of alternate-lineage genes. How this process is epigenetically encoded remains largely unknown. In skeletal muscle stem cells, the myogenic regulatory factors are well-established drivers of muscle gene activation but less is known about how non-muscle gene repression is achieved. Here, we show that the master epigenetic regulator, Repressor Element 1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a key regulator of this process. We show that many non-lineage genes retain permissive chromatin state but are actively repressed by REST. Loss of functional REST in muscle stem cells and progenitors disrupts muscle specific epigenetic and transcriptional signatures, impairs differentiation, and triggers apoptosis in progenitor cells, leading to depletion of the stem cell pool. Consequently, REST-deficient skeletal muscle exhibits impaired regeneration and reduced myofiber growth postnatally. Collectively, our data suggests that REST plays a key role in safeguarding muscle stem cell identity by repressing multiple non-muscle lineage and developmentally regulated genes in adult mice.
    DOI:  https://doi.org/10.1038/s41467-025-62758-y
  71. Transl Pediatr. 2025 Jul 31. 14(7): 1402-1413
    Clinical and variant spectrum of patients harboring ATAD3A variants.
    Hongfang Mei, Xinyin Zhang, Taixiang Liu, Mingyan Chen, Jiajing Ge, Dingwen Wu, Xiaolu Ma, Liping Shi, Wei Shi, Zheng Chen.
       Background: ATAD3A deficiency may lead to respiratory chain deficits. This observational study aimed to summarize the clinical features and variant spectrum of patients harboring ATAD3A variants.
    Methods: We examined patients harboring ATAD3A variants who attended the Children's Hospital of Zhejiang University School of Medicine, further examined similar cases reported in the literature, analyzed the clinical and variation data.
    Results: Five new patients harboring ATAD3A variants were encountered at Children's Hospital of Zhejiang University School of Medicine. New phenotypes including noncompaction of ventricular myocardium and recurrent asphyxia were observed. Whole-exome sequencing revealed six new variants, including c.1376T>C, c.649G>A, c.1492dup, and three copy number variants. In total, data from 88 patients harboring ATAD3A variants were collected, including those from our center, but only 31.8% were alive at the last follow-up. In total, 54 variants were identified, with deletions being the most common variant type. Moreover, 29 variants were detected in more than one patient, and the top three most common were g.1391996_1460043 duplication, c.1582C>T, and c.229C>G. Among the 88 patients, 38 (43.2%) had a monoallelic variant and 50 (56.8%) had biallelic variants; additionally, 64 (72.7%) had severe variants and 24 (27.3%) had mild variants. In the monoallelic group, hyperlactatemia (50.0% vs. 95.0%; P=0.02), seizures (22.2% vs. 84.6%; P=0.007), and death (7.7% vs. 96.0%; P<0.001) were more common in patients with severe variants than in those with mild variants. Dysmorphic facies were more common in patients with mild variants in both the monoallelic (90.0% vs. 38.5%; P=0.03) and biallelic (100.0% vs. 38.9%; P=0.02) groups. Monoallelic patients were less likely to have abnormal brain development than biallelic patients, in both the mild (18.2% vs. 100.0%; P=0.001) and severe (18.2% vs. 77.1%; P<0.001) groups. Meanwhile, in patients with severe variants, hypertrophic cardiomyopathy was more common in monoallelic patients than biallelic patients (73.9% vs. 38.1%; P=0.02).
    Conclusions: Our patients have expanded the variant spectrum and clinical landscape in patients harboring ATAD3A variants. The clinical course of patients harboring ATAD3A variants is related to the variant type. Prenatal genetic consultation is necessary in families with ATAD3A variants.
    Keywords:  ATAD3A; Genotype; phenotype
    DOI:  https://doi.org/10.21037/tp-2025-60
  72. NPJ Parkinsons Dis. 2025 Aug 12. 11(1): 238
    Glutamatergic synaptic resilience to overexpressed human alpha-synuclein.
    Patrícia I Santos, Inés Hojas García-Plaza, Ali Shaib, Jeong Seop Rhee, Abed Alrahman Chouaib, Nils Brose, Silvio O Rizzoli, James Daniel, Tiago F Outeiro.
      Alpha synuclein (aSyn) is abundant in the brain and strongly implicated in Parkinson's disease (PD), genetically and through its accumulation in neuronal pathognomonic inclusions. While mutations or increased expression of wild-type aSyn can cause familial PD, it remains unclear whether increased aSyn alone impairs presynaptic function. Here, we overexpressed human aSyn (haSyn) in rodent glutamatergic neurons and analysed presynaptic function. Expression levels mimicked SNCA gene triplications, as seen in certain familial forms of PD. In continental cultures, haSyn overexpression was not toxic nor did it alter the levels of presynaptic SNAP-25 or postsynaptic PSD-95. Analyses of autaptic neurons revealed no significant differences in evoked or spontaneous neurotransmission release, nor in synaptic plasticity. These results indicate that rodent glutamatergic neurons are resilient to aSyn overexpression. Our findings suggest neurotoxicity associated with aSyn overexpression is not universal, and that a deeper understanding of aSyn biology and pathobiology is necessary.
    DOI:  https://doi.org/10.1038/s41531-025-01085-x
  73. J Neurol. 2025 Aug 13. 272(9): 576
    Systemic mitochondrial involvement in mitochondrial myopathy with episodic hyper-creatine kinase-emia: insights from an autopsy case.
    Risa Nagatomo, Yu Hiramatsu, Yusuke Sakiyama, Hiroaki Miyahara, Takuma Nasu, Ieharu Yamazaki, Akiko Yoshimura, Masahiro Ando, Satoshi Nozuma, Yujiro Higuchi, Akio Akagi, Yasushi Iwasaki, Jun-Hui Yuan, Yuji Okamoto, Hiroshi Takashima.
      
    DOI:  https://doi.org/10.1007/s00415-025-13326-3
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