bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–09–07
73 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. MitoTraP: mitochondrial protection for cellular proteostasis.
  2. Replication competition drives the selective mtDNA inheritance in Drosophila ovary.
  3. Mitochondrial Quality Control.
  4. Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity.
  5. Insights into the translational activation mechanisms of the COX1 mRNA in yeast mitochondria.
  6. Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
  7. Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
  8. Potentiating the integrated stress response.
  9. Mitochondrial Biogenesis in Skeletal Muscle.
  10. Dynamic TOM-TIM23 supercomplex directs mitochondrial protein translocation and sorting.
  11. The Juvenile Parkinson's Disease Mutation C212Y Impairs Mitochondrial Homeostasis in a Caenorhabditis elegans Model.
  12. Alterations in mitochondrial base editors enhance targeted editing efficiency for mouse model generation.
  13. Combination treatment with antioxidants and creatine alleviates common and variant-specific mitochondrial impairments in Leber's hereditary optic neuropathy patient-derived fibroblasts.
  14. Underestimation of mitochondrial respiratory capacity in gray matter voxels of the human brain map due to limited OXPHOS and TCA cycle in astrocytes.
  15. Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.
  16. Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
  17. PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.
  18. Temporal transcriptional regulation of mitochondrial morphology primes activity-dependent circuit connectivity.
  19. Metformin may alter the course of Leber's hereditary optic neuropathy: a case report.
  20. Abnormal mitochondrial structure and function in brown adipose tissue of SLC35A4-MP knockout mice.
  21. Mitochondrial protein import stress augments α-synuclein aggregation and neural damage independent of bioenergetics.
  22. Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.
  23. Molecular mechanisms of mitochondrial quality control.
  24. Improved AAV9-based gene therapy design for SURF1-related Leigh syndrome with minimal toxicity.
  25. Vesicle-guided mitochondria: A new perspective for brain mitochondrial transplantation.
  26. Mitochondrial Complex V Deficiency Caused by a Homozygous Splice Variant in ATP5PO.
  27. Nucleos(t)ide Therapy for TK2-Deficient Mitochondrial Myopathy: Small Molecules With Big Potential.
  28. Saccharomyces cerevisiae malate dehydrogenase Mdh1p lacking mitochondrial targeting signal can be re-localized to peroxisomes.
  29. Effects of nutrients and diet on mitochondrial dysfunction: An opportunity for therapeutic approaches in human disease.
  30. Mitochondria: Key Mediator for Environmental Toxicant-Induced Neurodegeneration.
  31. Late-onset Leber's hereditary optic neuropathy and antiandrogens for prostate cancer: is there a causative link?
  32. Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.
  33. Neuromodulator control of energy reserves in dopaminergic neurons.
  34. The molecular mechanisms and physiological roles of mitochondria dynamics in Saccharomyces cerevisiae.
  35. Mitochondrial diagnostics reveal diffuse impairments in skeletal muscle energetics in aging mice.
  36. Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
  37. Respiratory Resilience as Form Fades: Skeletal Muscle Mitochondrial Adaptation in Aging.
  38. Proteasomes suppress anticancer drug-induced cytotoxicity by inhibiting mitochondrial protein import and promoting ROS-BNIP3-mediated mitophagy.
  39. FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes.
  40. Dnm1 Is Required for the Focal Clustering of Fis1 on the Mitochondrial Outer Membrane.
  41. Mitochondria-ER contact site components regulate the formation and localization of specialized high-capacity mitochondria in the C. elegans anchor cell.
  42. Accumulation of pathogenic mitochondrial DNA mutations in the kidney.
  43. Optimizing gene prioritization for clinical diagnosis of metabolic genetic disorders.
  44. Mitochondrial quality control as a therapeutic target in cardiovascular disease: Mechanistic insights and future directions.
  45. Hepatic ferredoxin reductase modulates mitochondrial function and iron homeostasis in metabolic dysfunction-associated steatotic liver disease.
  46. Patterns of Mitochondrial ATP Predict Tissue Folding.
  47. Cardiomyocyte mitochondrial mono-ADP-ribosylation dictates cardiac tolerance to sepsis by configuring bioenergetic reserve in male mice.
  48. Neonatal diabetes mellitus is a significant feature of COXPD-24 caused by recessive NARS2 variants.
  49. Impacts of mitochondrial dysfunction on axonal microtubule bundles as a potential mechanism of neurodegeneration.
  50. PRKN/PINK1 Mutations in a Chinese Patient With Early-Onset Parkinson's Disease.
  51. Iron Lion ZIPion: ZIP13 Zips Iron to Heart Mitochondria.
  52. Novel Peptide Therapeutics Targeting the L-Type Calcium Channel Prevent Hypertrophic Cardiomyopathy by Decreasing Mitochondrial Energetics.
  53. Renalase activates mitochondrial leak metabolism in response to cellular stress and to repair damage after injury.
  54. Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.
  55. Mitochondrial Retinopathy Complicated with Choroidal Neovascularization.
  56. Nuclear mitochondrial DNA transfer revisited: From genomic noise to hallmark of aging.
  57. SFXN2 contributes mitochondrial dysfunction-induced apoptosis as a substrate of Parkin.
  58. Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance.
  59. Metformin alters mitochondria-related metabolism and enhances human oligodendrocyte function.
  60. Genetic suppression features ABHD18 as a Barth syndrome therapeutic target.
  61. A streamlined base editor engineering strategy to reduce bystander editing.
  62. Galactose treatment rescues neuromuscular junction transmission in glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) deficient mice.
  63. Machine learning-based penetrance of genetic variants.
  64. MitoCOMON: whole mitochondrial DNA sequencing by primer design and long overlapping amplicon assembly.
  65. Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients.
  66. Advancements in Nonviral Gene Editing Strategies for Rare Diseases.
  67. Synthetic trap-peptides identify a TOM complex phosphatase - PP2A dephosphorylates Tom6.
  68. Mitochondrial dysfunction reveals H2S-mediated synaptic sulfhydration as a potential mechanism for autism-associated social defects.
  69. Diagnostic yield of whole exome sequencing in a cohort of 825 patients.
  70. Histone deacetylase 7 mediates lipopolysaccharide-inducible mitochondrial fission in macrophages.
  71. Spatial joint profiling of DNA methylome and transcriptome in tissues.
  72. Addressing global regulatory challenges in rare disease drug development.
  73. TPI deficiency: A case report and review of the literature.
  1. Trends Biochem Sci. 2025 Aug 27. pii: S0968-0004(25)00193-8. [Epub ahead of print]
    MitoTraP: mitochondrial protection for cellular proteostasis.
    Michaela Oborská-Oplová, Michael A Ruoss, Vikram G Panse.
      Cells depend on the efficient import of thousands of nuclear-encoded mitochondrial proteins to maintain mitochondrial function. A new study by Flohr et al. reveals a quality control strategy that traps a subset of mitochondrial precursors in the intermembrane space during energy stress, preventing their toxic accumulation in the cytosol or nucleus.
    Keywords:  mitochondrial import; mitochondrial intermembrane space; mitochondrial quality control; mitochondrial ribosomal proteins (MRPs); mitochondrial stress; proteotoxic stress
    DOI:  https://doi.org/10.1016/j.tibs.2025.08.004
  2. Cell Rep. 2025 Sep 04. pii: S2211-1247(25)00992-1. [Epub ahead of print]44(9): 116221
    Replication competition drives the selective mtDNA inheritance in Drosophila ovary.
    Cheng Zhang, Zhe Chen, Hansong Ma, Hong Xu.
      Purifying selection that limits the transmission of harmful mitochondrial DNA (mtDNA) mutations has been observed in both human and animal models. Yet, the precise mechanism underlying this process remains undefined. Here, we present a highly specific and efficient in situ imaging method capable of visualizing mtDNA variants that differ by only a few nucleotides at single-molecule resolution in Drosophila ovaries. Using this method, we revealed that selection primarily occurs within a narrow developmental window during germline cyst differentiation. At this stage, the proportion of the deleterious mtDNA variant decreases without a reduction in its absolute copy number. Instead, the healthier mtDNA variant replicates more frequently, thereby outcompeting the co-existing deleterious variant. These findings provide direct evidence that mtDNA selection is driven by replication competition rather than by active elimination processes, shedding light on a fundamental yet previously unresolved mechanism governing mitochondrial genome transmission.
    Keywords:  CP: Molecular biology; germline; mitochondria; mitophagy; mtDNA inheritance; mtDNA mutation; mtDNA replication; oogenesis; purifying selection; rolling circle amplification; single-molecule imaging
    DOI:  https://doi.org/10.1016/j.celrep.2025.116221
  3. Adv Exp Med Biol. 2025 ;1478 51-60
    Mitochondrial Quality Control.
    Yuntian Guan, Zhen Yan.
      Mitochondria, the power plants of cells, are essential for various cellular functions. In skeletal muscle, mitochondria form a network, called mitochondrial reticulum, which fuels muscle contractile and metabolic functions. The high degree of structure-to-function specialization of mitochondria in skeletal muscle implies that it is closely gauged and regulated to maintain energy production capacity to match the functional demands. The processes that regulate the overall structure and function of mitochondrial reticulum are collectively referred to as mitochondrial quality control. Mitochondrial quality control consists of mitochondrial biogenesis, dynamics (i.e., fission and fusion), and selective degradation via proteolysis and mitophagy. In this chapter, we will discuss different aspects of contemporary understanding of mitochondrial quality control, their respective mechanisms, and their adaptability to exercise training.
    Keywords:  Adaptation; Exercise; Mitochondrial biogenesis; Mitochondrial fission; Mitochondrial fusion; Mitochondrial reticulum; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_3
  4. bioRxiv. 2025 Aug 27. pii: 2025.08.27.672715. [Epub ahead of print]
    Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity.
    Monil Shah, Ilika Ghosh, Luca Pishos, Valentina Villani, Tristano Pancani, Ryohei Yasuda, Chao Sun, Naomi Kamasawa, Vidhya Rangaraju.
      The brain is a metabolically demanding organ as it orchestrates and stabilizes neuronal network activity through plasticity. This mechanism imposes enormous and prolonged energetic demands at synapses, yet it is unclear how these needs are met in a sustained manner. Mitochondria serve as a local energy supply for dendritic spines, providing instant and sustained energy during synaptic plasticity. However, it remains unclear whether dendritic mitochondria restructure their energy production unit to meet the sustained energy demands. We developed a correlative light and electron microscopy pipeline with deep-learning-based segmentations and 3D reconstructions to quantify mitochondrial remodeling at 2 nm pixel resolution during homeostatic plasticity. Using light microscopy, we observe global increases in dendritic mitochondrial length, as well as local increases in mitochondrial area near spines. Examining the mitochondria near spines using electron microscopy, we reveal increases in mitochondrial cristae surface area, cristae curvature, endoplasmic reticulum contacts, and ribosomal cluster recruitment, accompanied by increased ATP synthase clustering within mitochondria using single-molecule localization microscopy. Using mitochondria- and spine-targeted ATP reporters, we demonstrate that the local structural remodeling of mitochondria corresponds to increased mitochondrial ATP production and spine ATP levels. These findings suggest that mitochondrial structural remodeling is a key underlying mechanism for meeting the energy requirements of synaptic and network function.
    DOI:  https://doi.org/10.1101/2025.08.27.672715
  5. J Cell Sci. 2025 Aug 15. pii: jcs263694. [Epub ahead of print]138(16):
    Insights into the translational activation mechanisms of the COX1 mRNA in yeast mitochondria.
    Angelica Zamudio-Ochoa, Yolanda Camacho-Villasana, Ulrik Pedroza-Dávila, Aldo E García-Guerrero, Xochitl Pérez-Martínez.
      Mitochondrial translation is a crucial regulatory step in mitochondrial genome expression. In Saccharomyces cerevisiae, translational activators are believed to bind to the 5' UTRs of their target mRNAs to position the mitochondrial ribosome at the start codon. Pet309 and Mss51 are translational activators of COX1 mRNA, which encodes subunit one of cytochrome c oxidase. Pet309 physically interacts with COX1 mRNA, but no direct interaction of Mss51 with its target mRNA has been detected. Currently, the mechanisms underlying translational activation of COX1, or any other mitochondrial gene, remain poorly understood. To explore in depth the mechanism of COX1 mRNA translational activation, we studied the association of Pet309 and Mss51 with the mitochondrial ribosome. Both Pet309 and Mss51 interact with the mitoribosome regardless of the presence of COX1 mRNA or of each other. The association of Pet309 with the ribosome and with COX1 mRNA depends on its N-terminal domain. These findings indicate that Pet309 and Mss51 stably interact with the mitoribosome independently of active translation. By integrating our data with previously published research, we propose a new mechanism of COX1 mRNA translation activation.
    Keywords:   COX1 mRNA; Mitochondria; Mitoribosome; Mss51; Pet309; Translation
    DOI:  https://doi.org/10.1242/jcs.263694
  6. EMBO Rep. 2025 Aug 29.
    Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
    Tak Shun Fung, Amrapali Ghosh, Maite R Zavala, Zuzana Nichtova, Dhavalkumar Shukal, Marco Tigano, Gyorgy Csordas, Henry N Higgs, Rajarshi Chakrabarti.
      Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.
    Keywords:  Actin; Arp2/3 Complex; ER; LC3; Parkin
    DOI:  https://doi.org/10.1038/s44319-025-00561-y
  7. Cell. 2025 Aug 25. pii: S0092-8674(25)00916-X. [Epub ahead of print]
    Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
    Jingchuan Luo, Stuti Khandwala, Jingjie Hu, Song-Yi Lee, Kelsey L Hickey, Zebulon G Levine, J Wade Harper, Alice Y Ting, Jonathan S Weissman.
      Localized translation broadly enables spatiotemporal control of gene expression. Here, we present LOV-domain-controlled ligase for translation localization (LOCL-TL), an optogenetic approach for monitoring translation with codon resolution at any defined subcellular location under physiological conditions. Application of LOCL-TL to mitochondrially localized translation revealed that ∼20% of human nuclear-encoded mitochondrial genes are translated on the outer mitochondrial membrane (OMM). Mitochondrially translated messages form two classes distinguished by encoded protein length, recruitment mechanism, and cellular function. An evolutionarily ancient mechanism allows nascent chains to drive cotranslational recruitment of long proteins via an unanticipated bipartite targeting signal. Conversely, mRNAs of short proteins, especially eukaryotic-origin electron transport chain (ETC) components, are specifically recruited by the OMM protein A-kinase anchoring protein 1 (AKAP1) in a translation-independent manner that depends on mRNA splicing. AKAP1 loss lowers ETC levels. LOCL-TL thus reveals a hierarchical strategy that enables preferential translation of a subset of proteins on the OMM.
    Keywords:  AKAP1; OXPHOS; cis-element analysis; cotranslational targeting; localized translation; mitochondrial bipartite targeting signal; outer mitochondrial membrane; oxidative phosphorylation; translation-independent mRNA targeting
    DOI:  https://doi.org/10.1016/j.cell.2025.08.002
  8. Nat Rev Drug Discov. 2025 Sep 03.
    Potentiating the integrated stress response.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-025-00147-2
  9. Adv Exp Med Biol. 2025 ;1478 19-50
    Mitochondrial Biogenesis in Skeletal Muscle.
    David A Hood, Jonathan M Memme, Ashley N Oliveira, Neushaw Moradi, Sabrina Champsi.
      Mitochondrial biogenesis refers to the synthesis of nuclear- and mitochondrially encoded proteins, along with phospholipids, that aid in the expansion of the mitochondrial network. In skeletal muscle, mitochondria are organized as a reticulum, as this ideal morphology complements the elongated shape of a myofibre. This allows for efficient substrate diffusion and supports the vigorously dynamic metabolic capabilities of this tissue type. Mitochondria are central responders to deviations in metabolic homeostasis and are thus required to support acute or chronic bouts of endurance exercise, cold exposure, starvation, or other externally imposed stimuli. This chapter marks the introduction to skeletal muscle mitochondrial adaptability as we discuss the subcellular events that contribute to mitochondrial biogenesis. Topics range from mitochondrial content and subpopulations in different muscle fibre types to signaling cascades and regulatory elements that support this mechanism. The characterization of mitochondrial biogenesis was made possible through clever models of both exercise and muscle disuse, at times with genetic modifications to important regulators, and is incorporated in this discussion. The chapter concludes with reviews on changes to signaling towards biogenesis with age. Altogether, our review attempts to highlight the vast revelations on the targeting, contribution, and significance of mitochondrial biogenesis in skeletal muscle.
    Keywords:  Aging; Calcium; Exercise signaling; Exercise training; Gene expression; Mitochondria; Mitochondrial dynamics; Muscle disuse; Protein import; ROS
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_2
  10. Nat Struct Mol Biol. 2025 Aug 28.
    Dynamic TOM-TIM23 supercomplex directs mitochondrial protein translocation and sorting.
    Yuqi Yang, Shanshan Wang, Guopeng Wang, Yuke Lian, Lingfeng Xue, Wenhong Jiang, Qiang Guo, Chen Song, Long Li.
      The mitochondrial translocase of the outer membrane (TOM) and translocase of the inner membrane 23 (TIM23) complexes are coupled to control protein import across the outer and inner membranes, respectively. However, the mechanisms of protein recognition and sorting in the TOM-TIM23 pathway remain unclear. Here we report cryo-electron microscopy structures of a translocating polypeptide substrate captured in the active TOM-TIM23 supercomplex from Saccharomyces cerevisiae. In the TOM complex, the polypeptide substrate adopts multiple conformations stabilized by hydrophilic residues from distinct regions of the Tom40 channel. In the TIM23 complex, the Tim17 and Mgr2 subunits create the translocation pathway, with a central restriction formed by four highly conserved hydrophobic residues. The substrate primarily interacts with hydrophobic residues along the Tim17-Mgr2 pathway. Substrate hydrophobicity modulates the association of Mgr2 with Tim17, enabling dynamic regulation of protein sorting toward either the matrix or membrane. These findings reveal a sophisticated translocation mechanism of the TOM-TIM23 supercomplex that ensures the efficient import of diverse mitochondrial proteins.
    DOI:  https://doi.org/10.1038/s41594-025-01662-x
  11. FASEB J. 2025 Aug 31. 39(16): e70835
    The Juvenile Parkinson's Disease Mutation C212Y Impairs Mitochondrial Homeostasis in a Caenorhabditis elegans Model.
    Eyal Spector, Lirin Michaeli, Anat Nitzan, Hanna Grobe, Gabriel Axel, Ulrike Bening Abu-Shach, Hen Zinger, Cátia A Carvalho, Ronen Zaidel-Bar, Limor Broday.
      Inherited Parkinson's disease (PD) often involves missense mutations in the PRKN2 gene, encoding for Parkin protein. The PDR-1 protein is the C. elegans ortholog of human Parkin. Using a CRISPR/Cas9 genome editing approach, we generated the PDR-1C169Y point mutation on a conserved cysteine residue in the RING0 domain. This mutation in human Parkin, C212Y, has been identified in autosomal recessive juvenile Parkinsonism patients. The PDR-1C169Y homozygous mutant animals exhibited a shorter lifespan and decreased thrashing rate compared with wild-type or heterozygous animals. Unique mitochondrial phenotypes were observed, including an increased mitochondrial area and mitochondrial membrane potential. However, these phenotypes did not activate the mitochondrial unfolded protein response. Pan-neuronal analysis revealed decreased mitophagy. Dopaminergic neurodegeneration in aged animals was not enhanced when compared to WT. Our findings suggest that analysis of the recessive missense point mutations found in early-onset PD using the C. elegans model system has the potential to advance our understanding of the molecular mechanisms that lead to neurodegeneration.
    Keywords:   Parkin C212Y ; PDR‐1C169Y; Parkinson's disease; missense mutations; mitochondria
    DOI:  https://doi.org/10.1096/fj.202402785RRR
  12. Mol Ther Nucleic Acids. 2025 Sep 09. 36(3): 102678
    Alterations in mitochondrial base editors enhance targeted editing efficiency for mouse model generation.
    Seongho Hong, Sol Pin Kim, Sanghun Kim, Soo Kyung Kang, Sungmo Jung, Yeji Oh, Seung Hee Choi, Su Bin Lee, Hou Cha, Jieun Kim, Jiyoung Bae, Jiyoon Park, Kyoungmi Kim, Chang Geun Choi, Soo-Ji Park, Do Hyun Kim, Lark Kyun Kim, Je Kyung Seong, Hyunji Lee.
      Mitochondrial DNA (mtDNA) base editors are powerful tools for investigating mitochondrial diseases. However, their editing efficiency can vary significantly depending on the target site within the mtDNA. In this study, we developed two improved versions of the mitochondrial adenine base editor (Hifi-sTALED and αnHifi-sTALED) by modifying components other than the TadA8e-V28R deaminase variant. These enhancements significantly increased editing efficiency while preserving minimal off-target effects across the transcriptome. Using these optimized editors, we achieved improved mtDNA editing in mouse embryos and successfully generated mt-Rnr1 mutant mice with high heteroplasmic loads. Functional analyses revealed that the mt-Rnr1 mutation impaired mitochondrial function, as indicated by reduced ATP production and decreased oxygen consumption rate (OCR). These findings demonstrate the utility of the enhanced base editors in generating mitochondrial disease models and advancing research in mitochondrial genetics.
    Keywords:  MT: RNA/DNA Editing; TALED; base editing; mitochondria; mitochondrial editing; mtDNA
    DOI:  https://doi.org/10.1016/j.omtn.2025.102678
  13. Hum Mol Genet. 2025 Aug 29. pii: ddaf125. [Epub ahead of print]
    Combination treatment with antioxidants and creatine alleviates common and variant-specific mitochondrial impairments in Leber's hereditary optic neuropathy patient-derived fibroblasts.
    Donald Xhuti, Alessandra Chiarot, Mahek Minhas, Samantha Tobia, Nicoletta de Maat, Katherine Manta, Sean Y Ng, Mark A Tarnopolsky, Joshua P Nederveen.
      Leber's hereditary optic neuropathy (LHON) is characterized by painless and rapidly progressive central vision loss, caused by various mutations in mitochondrial DNA, leading to a high genetic and phenotypic heterogeneity. Currently, the only approved therapy is idebenone, a CoQ10 synthetic analogue, that improved visual acuity in some LHON patients; however, results are highly variable due its dependency on functional NAD(P)H oxidoreductase I (NQO1) protein levels, thus limiting broader applicability. Targeting the biochemical respiratory chain defect and mitigating reactive oxygen species emission using alternative treatments which act independent of NQO1 protein content, represent a promising therapeutic strategy for all LHON patients. Here, we first characterized mitochondrial biology of three distinct LHON mutations in patient-derived fibroblasts and evaluated the effects of a nutraceutical combination treatment in addressing these shared pathophysiological mechanisms. We identified a range of mitochondrial characteristics common among various LHON mutations, including higher ROS levels, altered autophagy programming, and reduced mitochondrial bioenergetics. Repeated antioxidant and creatine-based treatment (ACT) conferred a favorable stress-resistant phenotype in LHON cells, which was similar to, and in some cases superior to, the effects observed with idebenone treatment, irrespective of NQO1 protein expression. This phenotype was associated with enhanced mitochondrial biology, as evidenced by reduced reactive oxygen species levels, increased cellular respiration, and correction of autophagic flux. Overall, our findings reveal both common and divergent mitochondrial phenotypes among LHON-related mutations and highlight the potential of accessible multi-ingredient nutraceutical interventions that could benefit all LHON patients.
    Keywords:  Antioxidant; Autophagy; Creatine; Leber hereditary optic neuropathy; Mitochondria
    DOI:  https://doi.org/10.1093/hmg/ddaf125
  14. Front Cell Neurosci. 2025 ;19 1661231
    Underestimation of mitochondrial respiratory capacity in gray matter voxels of the human brain map due to limited OXPHOS and TCA cycle in astrocytes.
    Christos Chinopoulos.
      Considering that the aerobic energetic landscape of the brain is shaped by its mitochondria, Mosharov et al. generated an atlas of mitochondrial content and enzymatic OXPHOS activities at a resolution comparable to MRI by physically voxelizing frozen human brain tissue. However, astrocytes in the adult human brain lack expression of several TCA cycle and OXPHOS enzymes. Therefore, their formula expressing mitochondrial respiratory capacity (MRC) -defined as tissue respiratory capacity normalized to mitochondrial density- underestimates actual values by a factor proportional to the square root of the fraction of respiration-capable cells (primarily neurons) in gray matter voxels.
    Keywords:  MRI; OXPHOS; astrocytes; mitochondria; neurons; respiratory capacity
    DOI:  https://doi.org/10.3389/fncel.2025.1661231
  15. Adv Exp Med Biol. 2025 ;1478 343-363
    Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.
    Jonathan Wanagat, Robert Musci, Allen Herbst, Judd M Aiken.
      This chapter describes a molecular basis for age-induced muscle fiber loss involving the mammalian mitochondrial genome (mtDNA). Early studies of human mitochondrial myopathies, which display many phenotypes associated with muscle aging, led to the search for and subsequent discovery of similar genetic and histopathological changes in aging skeletal muscle. A diverse spectrum of mtDNA deletion mutations increase in abundance with age and clonally accumulate to high abundance within individual cells. Deletion accumulation results in a focal loss of electron transport and oxidative phosphorylation. These metabolic derangements activate apoptosis, leading to necrosis, fiber splitting, and eventual fiber loss. We have identified a number of interventions that are capable of modulating mtDNA deletion mutation frequency and the abundance of electron transport chain deficient fibers. Interestingly, in each case, the genetic and histological measures of mtDNA quality predict the lifespan effects of these interventions. We highlight the value of incorporating a geroscience view into the study of sarcopenia. The sequence of events from the deletion mutation of a single mtDNA molecule to muscle fiber death is not limited to skeletal muscle and has been observed in most other aging tissues, where these events likely contribute to cell loss.
    Keywords:  Mitochondria; Mitochondrial DNA; Mutations; Sarcopenia
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_14
  16. J Cell Biol. 2025 Oct 06. pii: e202410130. [Epub ahead of print]224(10):
    Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
    Maria Pia Rodriguez Salazar, Sprihaa Kolanukuduru, Valentina Ramirez, Boyu Lyu, Gracie Manigault, Gabrielle Sejourne, Hiromi Sesaki, Guoqiang Yu, Cagla Eroglu.
      Dysfunctional mitochondrial dynamics are a hallmark of devastating neurodevelopmental disorders such as childhood refractory epilepsy. However, the role of glial mitochondria in proper brain development is not well understood. We show that astrocyte mitochondria undergo extensive fission while populating astrocyte distal branches during postnatal cortical development. Loss of mitochondrial fission regulator, dynamin-related protein 1 (Drp1), decreases mitochondrial localization to distal astrocyte processes, and this mitochondrial mislocalization reduces astrocyte morphological complexity. Functionally, astrocyte-specific conditional deletion of Drp1 induces astrocyte reactivity and disrupts astrocyte organization in the cortex. These morphological and organizational deficits are accompanied by loss of perisynaptic astrocyte process (PAP) proteins such as gap junction protein connexin 43. These findings uncover a crucial role for mitochondrial fission in coordinating astrocytic morphogenesis and organization, revealing the regulation of astrocytic mitochondrial dynamics as a critical step in neurodevelopment.
    DOI:  https://doi.org/10.1083/jcb.202410130
  17. Autophagy. 2025 Aug 27.
    PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.
    Soumya Ranjan Mishra, Priyadarshni Mishra, Kewal Kumar Mahapatra, Bishnu Prasad Behera, Gajanan Kendre, Moureq Rashed Alotaibi, Vijay Pandey, Birija Sankar Patro, Daniel J Klionsky, Sujit Kumar Bhutia.
      The inorganic pyrophosphatase PPA2, a matrix-localized protein, maintains mitochondrial function. Here, we identified the role of PPA2 in activating mitochondrial fission signaling. We found that PPA2 overexpression promotes mitochondrial fission by upregulating the mitochondrial translocation of phosphorylated DNM1L S616. Moreover, PPA2 interacts with MTFP1, a mitochondrial inner membrane protein, to induce fission signaling; cells knocked down for MTFP1 and overexpressing PPA2 failed to induce DNM1L activation and subsequent mitochondrial fission. Furthermore, in physiological conditions, PPA2 directed mitochondrial fission at the midzone through MFF-DNM1L, leading to mitochondrial proliferation. Interestingly, during mitochondrial stress following CCCP treatment, PPA2 triggers peripheral fission through FIS1 and DNM1L to segregate parts of damaged mitochondria, which is essential for mitophagy. In addition, PPA2 utilized the C-terminal LC3-interacting region (LIR) of MTFP1 for mitophagy-mediated clearance of damaged mitochondria. In conclusion, PPA2 activates mitochondrial fission signaling through MTFP1-DNM1L and is essential in defining the site of mitochondrial fission, leading to mitochondrial proliferation or mitophagy for maintaining mitochondrial homeostasis.
    Keywords:  MTFP1; Mitochondria; PPA2; mitochondrial fission; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2552900
  18. Nat Commun. 2025 Sep 01. 16(1): 8173
    Temporal transcriptional regulation of mitochondrial morphology primes activity-dependent circuit connectivity.
    Iryna Mohylyak, Maheva Andriatsilavo, Mercedes Bengochea, Carlos Pascual-Caro, Noemi Asfogo, Sara Fonseca-Topp, Natasha Danda, Marlene Cassar, Corentine Marie, Zeynep Kalender Atak, Maxime De Waegeneer, Stein Aerts, Olga Corti, Jaime de Juan-Sanz, Bassem A Hassan.
      Synaptic connectivity during development is known to require rapid local regulation of axonal organelles. Whether this fundamental and conserved aspect of neuronal cell biology is orchestrated by a dedicated developmental program is unknown. We hypothesized that developmental transcription factors regulate critical parameters of organelle structure and function which contribute to circuit wiring. We combined cell type-specific transcriptomics with a genetic screen to discover such factors. We identified Drosophila CG7101, which we rename mitochondrial integrity regulator of neuronal architecture (Mirana), as a temporal developmental regulator of neuronal mitochondrial quality control genes, including Pink1. Remarkably, a brief developmental downregulation of either Mirana or Pink1 suffices to cause long-lasting changes in mitochondrial morphology and abrogates neuronal connectivity which can be rescued by Pink1 expression. We show that Mirana has functional homology to the mammalian transcription factor TZAP whose loss leads to changes in mitochondrial function and reduced neurotransmitter release in hippocampal neurons. Our findings establish temporal developmental transcriptional regulation of mitochondrial morphology as a prerequisite for the priming and maintenance of activity-dependent synaptic connectivity.
    DOI:  https://doi.org/10.1038/s41467-025-62908-2
  19. Front Med (Lausanne). 2025 ;12 1609941
    Metformin may alter the course of Leber's hereditary optic neuropathy: a case report.
    Shenoda Abd Elmaseh, Danielle A Gauthier, Maryam Golmohammadi, Nutsa Pargalava, Valerio Carelli, Alfredo A Sadun.
      Leber's hereditary optic neuropathy (LHON) is a rare inherited mitochondrial disease caused by variants in mitochondrial DNA (mtDNA) transmitted exclusively through the maternal line. The disease predominantly affects young males and is characterized by progressive bilateral vision loss. Idebenone, a well-studied drug, modestly enhances the mitochondrial function and visual acuity in many patients with LHON. In this study, we report the case of a 48-year-old woman diagnosed with LHON (m.11778G>A/MT-ND4) and type 2 diabetes mellitus who experienced visual field improvement following metformin treatment after 26 months of progressive vision loss unresponsive to idebenone, nicotinamide adenine dinucleotide (NAD+), and hormone replacement therapy (HRT). Our findings offer an intriguing perspective on LHON management but require more investigations, particularly on the molecular effects of metformin on the mitochondrial function in LHON patients.
    Keywords:  LHON; NAD+; idebenone; metformin; mitochondrial dysfunction; vision Loss
    DOI:  https://doi.org/10.3389/fmed.2025.1609941
  20. Sci Adv. 2025 Aug 29. 11(35): eads7381
    Abnormal mitochondrial structure and function in brown adipose tissue of SLC35A4-MP knockout mice.
    Andréa L Rocha, Christian Schmedt, Guy Perkins, Antonio Pinto, Jolene K Diedrich, Huanqi Shan, Kaja Plucińska, Eduardo Vieira de Souza, Joan M Vaughan, Mark Foster, Srinath C Sampath, Srihari C Sampath, Paul Cohen, Mark H Ellisman, Alan Saghatelian.
      Uncovering the role of upstream open reading frames (uORFs) challenges conventional views of one protein per messenger RNA and reveals the capacity of some uORFs to encode microproteins that contribute to cellular biology and physiology. This study explores the functional role of a recently identified mitochondrial microprotein, SLC35A4-MP, in the brown adipose tissue of mice. Our findings reveal dynamic regulation of SLC35A4-MP expression during primary brown adipocyte differentiation in vitro and during cold exposure or high-fat diet (HFD)-induced obesity in mice. Using a knockout mouse model, we show that loss of SLC35A4-MP disrupts mitochondrial lipid composition, decreasing cardiolipins and phosphatidylethanolamine in brown adipose tissue from HFD-fed mice. SLC35A4-MP deficiency also impairs mitochondrial activity, alters mitochondrial number and morphology, and promotes inflammation. Knockout mice accumulate acylcarnitines during cold exposure, indicating defective fatty acid oxidation. These findings reveal SLC35A4-MP as a previously unrecognized microprotein in regulating mitochondrial function and tissue lipid metabolism, adding to the growing list of functional endogenous microproteins.
    DOI:  https://doi.org/10.1126/sciadv.ads7381
  21. Res Sq. 2025 Aug 18. pii: rs.3.rs-3136613. [Epub ahead of print]
    Mitochondrial protein import stress augments α-synuclein aggregation and neural damage independent of bioenergetics.
    Xin Jie Chen, Liam Coyne, Arnav Rana, Xiaowen Wang, Sanaea Bhagwagar, Yumiko Umino, Eduardo Solessio, Frank Middleton.
      Genetic and environmental factors are known to converge on mitochondria to cause Parkinson's disease (PD). However, the mechanisms by which mitochondrial dysfunction contributes to neurodegeneration remain incompletely understood. Non-bioenergetic pathways of the mitochondria are increasingly appreciated, but confounding bioenergetic defects are a major barrier to experimental validation. Here, we show that mild mitochondrial protein import stress augments neural damage independent of bioenergetics. We induce protein import stress in a mouse model of PD expressing α-synuclein(A53T). The double mutant mice demonstrate increased size of α-synuclein aggregates, increased aggregation of mitochondrial preproteins, heightened neuroinflammation and worsened motor defect relative to α-synuclein(A53T) single mutants. Importantly, we found no evidence of bioenergetic defects in any of the mutant mice. These data suggest that mitochondrial protein import stress, which can be induced by many types of mitochondrial injuries, can contribute to neural damage through cytosolic proteostatic stress and possible co-aggregation of mitochondrial and neuropathogenic proteins independent of bioenergetics.
    DOI:  https://doi.org/10.21203/rs.3.rs-3136613/v1
  22. Neurosci Bull. 2025 Aug 30.
    Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.
    Yilin Sun, Chunying Liu, Yakun Liang, An Lv, Wang Nie, Shuyue Bao, Xiaoyi Li, Jing Zhou, Weimin Tong, Yong Tao, Xueling Wang, Tingting Dong.
      Auditory neuropathy (AN) is a sensorineural hearing loss that impairs speech perception, but its mechanisms and treatments remain limited. Mic60, essential for the mitochondrial contact site and cristae organizing system, is linked to neurological disorders, yet its role in the auditory system remains unclear. We demonstrate that Mic60+/- mice develop progressive hearing loss from 6 months of age, with reduced auditory brainstem response amplitudes despite preserved outer hair cell function, consistent with AN. Mitochondrial abnormalities in spiral ganglion neurons (SGNs) emerge by 3 months, followed by mitochondrial loss and SGN degeneration, indicating progressive auditory neuron dysfunction. In vitro, Mic60 deficiency disrupts mitochondrial respiration, reversible by N-acetylcysteine (NAC). NAC treatment preserves mitochondrial integrity and rescues hearing by enhancing mitophagy. Our findings establish Mic60+/- mice as an AN animal model, highlight the role of Mic60 in the mitochondria of primary auditory neurons, and identify NAC as a potential AN treatment.
    Keywords:  Antioxidant; Auditory neuropathy; Mic60; Mitochondria; Mitophagy; N-acetylcysteine
    DOI:  https://doi.org/10.1007/s12264-025-01485-2
  23. Transl Neurodegener. 2025 Sep 01. 14(1): 45
    Molecular mechanisms of mitochondrial quality control.
    Wensheng Li, Yuran Gui, Cuiping Guo, Yuting Huang, Yi Liu, Xuan Yu, Huiliang Zhang, Jianzhi Wang, Rong Liu, Yacoubou Abdoul Razak Mahaman, Qiuhong Duan, Xiaochuan Wang.
      Mitochondria produce adenosine triphosphate (ATP), the main source of cellular energy. To maintain normal function, cells rely on a complex mitochondrial quality control (MQC) system that regulates mitochondrial homeostasis, including mitochondrial dynamics, mitochondrial dynamic localization, mitochondrial biogenesis, clearance of damaged mitochondria, oxygen radical scavenging, and mitochondrial protein quality control. The MQC system also involves coordination of other organelles, such as the endoplasmic reticulum, lysosomes, and peroxisomes. In this review, we discuss various ways by which the MQC system maintains mitochondrial homeostasis, highlight the relationships between these pathways, and characterize the life cycle of individual mitochondria under the MQC system.
    Keywords:  Evidence-based therapies; Mitochondria; Mitochondrial diseases; Mitochondrial homeostasis; Mitochondrial quality control
    DOI:  https://doi.org/10.1186/s40035-025-00505-5
  24. Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101554
    Improved AAV9-based gene therapy design for SURF1-related Leigh syndrome with minimal toxicity.
    Qinglan Ling, Matthew Rioux, Harrison Higgs, Yuhui Hu, Scarlett E Dwyer, Steven J Gray.
      Surfeit locus protein 1 (SURF1)-related Leigh syndrome is an early-onset neurodegenerative disorder characterized by a reduction in complex IV activity that disrupts mitochondrial function. Currently, there are no disease-modifying treatments available. Previously, we reported that a gene replacement therapy for SURF1-related Leigh syndrome was developed, which showed improved complex IV activity and restored exercise-induced lactate acidosis, as well as a high safety profile in wild-type (WT) mice. However, further investigations of this original SURF1 vector design uncovered cytotoxicity in multiple tissues of WT rats despite having minimal immune responses. We hypothesized that this cytotoxicity was elicited by SURF1 protein overexpression driven by a strong ubiquitous promoter, CBh. Here, we report the development of an improved gene therapy for SURF1 Leigh syndrome by utilizing a different promoter and polyadenylation sequence. Our data showed that, with lower SURF1 protein expression, the new design conferred a similar level of efficacy, but with minimal cytotoxicity in mice or rats. We propose this new vector design as a promising therapeutic candidate for SURF1-related Leigh syndrome, warranting further translational studies.
    Keywords:  AAV; Leigh syndrome; SURF1; adeno-associated virus; gene replacement therapy; gene therapy; mitochondrial diseases; overexpression toxicity
    DOI:  https://doi.org/10.1016/j.omtm.2025.101554
  25. Ageing Res Rev. 2025 Aug 26. pii: S1568-1637(25)00227-2. [Epub ahead of print]112 102881
    Vesicle-guided mitochondria: A new perspective for brain mitochondrial transplantation.
    Antonella Girgenti, Laura Palumbo, Gokhan Burcin Kubat, Ibrahim Turkel, Pasquale Picone, Domenico Nuzzo.
      Mitochondrial activity is essential for the proper functioning of higher brain processes, and its impairment has been linked to a wide range of neurological disorders. Increasing evidence shows that under physiological and pathological conditions, mitochondria can be secreted into the extracellular environment to regulate various biological responses, including cellular bioenergetics. Today, the therapeutic modality known as "mitochondrial transplantation" has emerged as a cutting-edge and highly promising intervention for the promotion of cell and tissue regeneration. This innovative approach entails the replacement of dysfunctional mitochondria in the recipient organism with healthy, functional exogenous mitochondria, thereby aiming to restore cellular function and promote tissue repair and recovery. Several studies have demonstrated the beneficial effects of local or systemic administration of mitochondria on in vitro and in vivo models of brain diseases. We discuss the effect of mitochondrial transplantation in various brain diseases and highlight some critical issues. In this regard, we propose vesicles as a delivery system for both whole mitochondria and mitochondrial components to target cells in the central nervous system. Furthermore, the aim of this review is twofold: firstly, to emphasize the significance of brain mitochondrial transplantation, and secondly, to prompt the scientific community to consider the practical applications of brain mitochondrial transplantation. To this end, the text highlights the as yet unresolved issues and challenges that must be addressed and surmounted if this field is to progress. In conclusion, the authors express their support for the development of new potential therapies for mitochondrial diseases of the central nervous system.
    Keywords:  Brain diseases; Mitochondrial dysfunction; Mitochondrial transplantation; Vesicles
    DOI:  https://doi.org/10.1016/j.arr.2025.102881
  26. Am J Med Genet A. 2025 Sep 06. e64239
    Mitochondrial Complex V Deficiency Caused by a Homozygous Splice Variant in ATP5PO.
    Zainab Al Masseri, Laura Guilder, Michal Inbar-Feigenberg, Jessie Cameron, Siddika Venkatachalam, David Chitayat.
      Most complex V subunits are nuclear encoded and so far, were not found in association with recognized Mendelian disorders. ATP5PO is a candidate gene for complex V mitochondrial disease. It encodes the oligomycin sensitivity-conferring protein (OSCP), an essential component of the "stalk" region that links the F1 and F0 domains of the ATP synthase complex. We report a 4-month-old girl, born at 35 weeks' gestation to a consanguineous couple via cesarean section due to fetal growth restriction and antenatal echocardiographic findings of moderate biventricular hypertrophy. At birth, she required intubation, ventilation, and surfactant therapy. The patient experienced intermittent hyperlactatemia, apneic spells, encephalopathy, axial hypotonia, and abnormal neonatal reflexes. She passed away at 4 months of age, and whole-exome sequencing revealed a homozygous splice variant (c.87 + 3A > G; p?) in ATP5PO. This gene was reported as a candidate gene, where additional evidence is needed to establish whether there is a relationship between this gene variant and human disease. So far and to our best knowledge, only four cases with a pathogenic variant in this gene have been reported. Mitochondrial respiratory chain analysis performed on fibroblasts revealed reduced ATPase enzyme activity with approximately 35% of the mean enzyme activity observed in the control reference range, with a decreased enzyme activity ratio relative to citrate synthase. These results suggest that isolated complex V enzyme deficiency is associated with the homozygous VUS identified in the ATP5PO gene in this patient and provide further functional support that ATP5PO is involved in complex V assembly and function.
    Keywords:  ATP synthase; ATP5PO; MC5DN7; OSCP; complex V; encephalopathy; mitochondrial
    DOI:  https://doi.org/10.1002/ajmg.a.64239
  27. Neurology. 2025 Sep 23. 105(6): e214187
    Nucleos(t)ide Therapy for TK2-Deficient Mitochondrial Myopathy: Small Molecules With Big Potential.
    Jennifer L Gannon.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000214187
  28. Biol Open. 2025 Sep 05. pii: bio.062199. [Epub ahead of print]
    Saccharomyces cerevisiae malate dehydrogenase Mdh1p lacking mitochondrial targeting signal can be re-localized to peroxisomes.
    Chutima Chan, Naraporn Sirinonthanawech, Brian K Sato, James E Wilhelm, Chalongrat Noree.
      Yeast mitochondrial malate dehydrogenase, Mdh1p, is known to form supramolecular complexes with other TCA cycle and mitochondrial dehydrogenase enzymes, including the aldehyde dehydrogenase, Ald4p. These complexes have been proposed to facilitate NADH channeling. Here, we demonstrate that in cells grown to saturation and stationary phases, the endogenous Mdh1p, expressed without its mitochondrial targeting signal (MTS), stays outside mitochondria, in both a diffuse cytoplasmic distribution as well as localized to distinct puncta. The puncta formed by MTS-lacking Mdh1p show no co-localization with the MTS-lacking Ald4p, suggesting that they do not co-assemble into a supramolecular complex in the cytoplasm. However, we found that the MTS-lacking Mdh1p does co-localize with its cytoplasmic counterpart, Mdh2p, in puncta. Interestingly, Mdh2p has recently been reported to form heterocomplexes with the peroxisomal Mdh3p and to be transported into peroxisomes to assist in the glyoxylate cycle. We also show that the MTS-lacking Mdh1p co-localizes with a fluorescent peroxisome marker, Pex3p. Our findings suggest that different malate dehydrogenases can enter peroxisomes, potentially as a means to make the glyoxylate pathway more efficient.
    Keywords:  Malate dehydrogenase; Mitochondria; Peroxisome; Supramolecular assembly; Yeast
    DOI:  https://doi.org/10.1242/bio.062199
  29. Biomed Pharmacother. 2025 Aug 28. pii: S0753-3322(25)00687-0. [Epub ahead of print]191 118493
    Effects of nutrients and diet on mitochondrial dysfunction: An opportunity for therapeutic approaches in human disease.
    Lisa H Do, Renata T Da Costa, Maria E Solesio.
      Mitochondria play a crucial role in multiple cellular processes beyond the regulation of bioenergetics. These processes range from apoptosis to intracellular signaling. Accordingly, mitochondrial dysfunction has been broadly described in the etiopathology of multiple human diseases, including cancer, diabetes, and all the main neurodegenerative disorders. Therapeutic interventions aimed at modulating this dysfunction are promising for preventing and/or delaying the development of these pathologies. Recent research has highlighted the potential of dietary interventions to modulate mitochondrial physiology. In this text, we critically review the scientific literature available regarding the effects of different dietary interventions (such as caloric restriction, ketogenic diets, increased omega-3 fatty acid consumption, etc.) on some key components of mitochondrial physiology. Despite the significant advancements in the field that we present in this review, critical gaps remain regarding the molecular mechanisms that underlie the effects of these dietary interventions on mitochondrial physiology, especially under pathological conditions. Future research in this field could underscore these mechanisms, paving the road for the use of dietary interventions against mitochondrial dysfunction as valid pharmacological strategies in human disease.
    Keywords:  Diet; Mitochondria; Mitochondrial physiology; Nutrients; Therapeutic approaches
    DOI:  https://doi.org/10.1016/j.biopha.2025.118493
  30. Int J Toxicol. 2025 Aug 28. 10915818251369414
    Mitochondria: Key Mediator for Environmental Toxicant-Induced Neurodegeneration.
    Nishi Shah, Bhagawati Saxena, Richa Gupta.
      Compiling evidence strongly suggests the involvement of environmental toxicants, including heavy metals (aluminum, arsenic, lead, copper, cadmium, mercury, and manganese), pesticides, and solvents, as the prime culprits of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The pathogenesis of environmental toxicant-induced neurodegenerative disease remains elusive. Studies carried out in the last decade suggest that dysfunctional mitochondria are increasingly recognized as a key factor in the progression of neurodegenerative diseases. Mitochondria, the essential organelles that regulate cellular energy production, are particularly vital in neurons, which have high energy demands and depend on proper mitochondrial function for survival. Environmental toxicants have been shown to impair mitochondrial membranes, disrupt the electron transport chain, increase oxidative stress, and damage mitochondrial DNA, leading to progressive neurodegeneration, with mitochondrial fragmentation and oxidative stress that worsens neurodegeneration. There are currently no disease-modifying treatments available for most neurodegenerative disorders, largely due to the lack of suitable molecular targets. Targeting mitochondria presents a rational strategy for neuroprotective therapy, with the potential to slow or halt disease progression. In view of this, this review highlights the central role of mitochondria in environmental toxicant-induced neurodegeneration, emphasizing how environmental exposures drive mitochondrial dysfunction and accelerate disease progression. Understanding these mechanisms is crucial for identifying environmental risk factors and developing targeted interventions. This will provide a foundation for future research targeting mitochondria and developing suitable therapeutic interventions for neurodegenerative diseases.
    Keywords:  environmental toxicants; heavy metals; mitochondrial dysfunction; neurodegenerative disorders; pesticides
    DOI:  https://doi.org/10.1177/10915818251369414
  31. Front Neurol. 2025 ;16 1616992
    Late-onset Leber's hereditary optic neuropathy and antiandrogens for prostate cancer: is there a causative link?
    Giulia Amore, Michele Carbonelli, Diego D'Angeli, Luigi Bonan, Marco Faustini-Fustini, Alessandra Maresca, Valerio Carelli, Chiara La Morgia.
       Introduction: Leber's hereditary optic neuropathy (LHON) is a maternally inherited condition due to mitochondrial DNA (mtDNA) mutations usually affecting young men within their thirties, while women seem protected by estrogens with a female-to-male ratio of 1:3. Late-onset cases (over 40 years of age) are usually associated to toxic exposure to tobacco smoke or drugs causing mitochondrial dysfunction.
    Results: We describe two cases of LHON remarkable for their late onset (> 60 years) in the absence of classic toxic factors. They were both affected by advanced prostate cancer and developed LHON after introduction of enzalutamide, an antagonist of androgens' receptor, in association with leuprolide, a gonadotropin-releasing hormone (GnRH) analogue, used in the context of Androgen deprivation therapy (ADT). Both patients presented very low serum levels of gonadotropin, estrogens and androgens compatible with hormonotherapy. MtDNA copy number in our probands resulted significantly reduced (like other LHON affected cases), compared to age-matched LHON unaffected mutation carriers and controls.
    Discussion: The role of hormones in LHON pathogenesis remains still debated. Recent evidence suggests a protective effect of estrogens in increasing mitochondrial biogenesis (and mtDNA copy number), partially explaining the gender bias of the disease, while the role of androgens is yet to be fully understood. Considering the effect of the ADT on circulating hormonal levels and their reciprocal interactions, we hypothesize that in a context of already low estrogens levels due to GnRH analogue, the block of androgens receptors by Leuprolide further imbalance the estrogens to androgens ratio and eventually trigger the disease.
    Keywords:  Leber’s hereditary optic neuropathy; androgen deprivation therapy; estrogens; hormones; mitochondrial disease
    DOI:  https://doi.org/10.3389/fneur.2025.1616992
  32. bioRxiv. 2025 Aug 28. pii: 2025.08.28.672006. [Epub ahead of print]
    Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.
    Chuyu Chen, Qianzi He, Giulia Tombesi, Eve Napier, Matthew Jaconelli, Oscar Andrés Moreno-Ramos, Hannah Serio, Yahaira Naaldijk, Vanessa Promes, Amanda Schneeweis, Kaitlyn Quinn, Christopher Nasios, Elisa Greggio, Yevgenia Kozorovitskiy, Daniel Arango, Amir R Khan, Dario R Alessi, Daniel A Dombeck, Sabine Hilfiker, Rajeshwar Awatramani, Loukia Parisiadou.
      The end-stage pathology of Parkinson's disease (PD) involves the loss of dopamine-producing neurons in the substantia nigra pars compacta (SNc). However, synaptic deregulation of these neurons begins much earlier. Understanding the mechanisms behind synaptic deficits is crucial for early therapeutic intervention, yet these remain largely unknown. In the SNc, different dopamine neuron subtypes show varying susceptibility patterns to PD, complicating our understanding. This study uses intersectional genetic mouse models to uncover synaptic perturbations in vulnerable dopamine neurons, focusing on the LRRK2 kinase, a protein closely linked to PD. Through a combination of immunofluorescence and advanced proximity labeling methods, we found higher LRRK2 expression in the most vulnerable dopamine neuron subclusters. High-resolution imaging revealed that pathogenic LRRK2 disrupts release sites in vulnerable dopamine axons, leading to decreased in vivo evoked striatal dopamine release in mice with LRRK2 mutations. Proteomic and biochemical analyses indicate that mutant LRRK2 increases the phosphorylation of RAB3 proteins, reducing their interactions with RIM1/2 effector proteins and impacting their synaptic functions. Overall, this research highlights the cell-autonomous dysfunctions caused by mutant LRRK2 in the neurons that are primarily affected by the disease. It also provides a framework for therapeutic strategies for early nigrostriatal synaptic deficits in PD.
    DOI:  https://doi.org/10.1101/2025.08.28.672006
  33. bioRxiv. 2025 Aug 19. pii: 2025.08.19.671144. [Epub ahead of print]
    Neuromodulator control of energy reserves in dopaminergic neurons.
    Camila Pulido, Matthew S Gentry, Timothy A Ryan.
      The brain is a metabolically vulnerable organ as neurons have both high resting metabolic rates and the need for local rapid conversion of carbon sources to ATP during activity. Midbrain dopamine neurons are thought to be particularly vulnerable to metabolic perturbations, as a subset of these are the first to undergo degeneration in Parkinson's disease (PD), a neurodegenerative disorder long suspected to be in part driven by deficits in mid-brain bioenergetics (1). In skeletal muscle, energy homeostasis under varying demands is achieved in part by its ability to rely on glycogen as a fuel store, whose conversion to ATP is under hormonal regulatory control. In neurons however the absence of easily observable glycogen granules has cast doubt on whether this fuel store is operational, even though brain neurons express the key regulatory enzymes associated with building or burning glycogen (2). We show here that that in primary mid brain dopaminergic neurons, glycogen availability is under the control of dopamine auto receptors (D2R), such that dopamine itself provides a signal to store glycogen. We find that when glycogen stores are present, they provide remarkable resilience to dopamine nerve terminal function under extreme hypometabolic conditions, but loss of this dopamine derived signal, or impairment of access to glycogen, makes them hypersensitive to fuel deprivation. These data show that neurons can use an extracellular cue to regulate local metabolism and suggest that loss of dopamine secretion might make dopamine neurons particularly subject to neurodegeneration driven by metabolic stress.
    Keywords:  Biological Science; Neuroscience; dopamine; glycogen; synapse
    DOI:  https://doi.org/10.1101/2025.08.19.671144
  34. Microb Cell. 2025 ;12 242-254
    The molecular mechanisms and physiological roles of mitochondria dynamics in Saccharomyces cerevisiae.
    Chang-Lin Chen, Wei-Ling Huang, Alexander Rapoport, Rimantas Daugelavičius, Chuang-Rung Chang.
      Mitochondria are essential organelles that form a dynamic network within cells. The fusion, fission, and transport processes among mitochondria must reach a balance, which is achieved through complex regulatory mechanisms. These dynamic processes and regulatory pathways are highly conserved across species and are coordinated to help cells respond to environmental stress. The budding yeast Saccharomyces cerevisiae has become an important model organism for studying mitochondria dynamics due to its genetic tractability and the conservation of key mitochondrial regulators. Previous research on mitochondria dynamics in yeast has provided valuable insights into the regulatory pathways in eukaryotic cells. It has helped to elucidate the mechanisms related to diseases associated with disrupted mitochondria dynamics. This review explores the molecular mechanisms underlying mitochondria dynamics and their physiological roles in Saccharomyces cerevisiae. The knowledge we learned from the primary eukaryotic yeast cell will aid us in advancing future research on the regulatory mechanisms of mitochondria in both health and disease.
    Keywords:  dynamic organelles; mitochondria; yeast
    DOI:  https://doi.org/10.15698/mic2025.08.859
  35. J Appl Physiol (1985). 2025 Sep 04.
    Mitochondrial diagnostics reveal diffuse impairments in skeletal muscle energetics in aging mice.
    Keon D Wimberly, Mia Y Kawaida, Abigail L Tice, Xiaoping Luo, Jacob A Lackey, Samuel Alvarez, Lan Wei-LaPierre, Russell T Hepple, Terence E Ryan.
      Aging is associated with progressive declines in skeletal muscle mass, strength, and endurance, often linked to mitochondrial dysfunction. However, a complete understanding of mitochondrial impairments during aging is lacking. Herein, we examined how biological sex and aging affect muscle function and mitochondrial energy transduction. Methods: Male and female C57BL/6 mice at 16 and 26 months of age (N=48) were assessed for physical function, muscle contractility, histology, and mitochondrial bioenergetics. Using isolated limb muscle mitochondria, we employed a diagnostic approach to evaluate respiration, redox potential, and membrane polarization under physiologically relevant energy demands. Results: Aged mice had significantly lower grip strength (P = 2.7E-09), walking speed (P = 0.024), and endurance capacity (P = 1.24E-08). Muscle mass and contractile function were also significantly lower in 26-mo. old mice regardless of sex. Mitochondrial diagnostics revealed a significant reduction (30-50%) in oxygen consumption rates across a range of energy demands and substrate conditions in both male and female 26-mo. old mice. Redox and membrane potentials were also reduced (P < 0.05) in aged mice resulting in a lower respiratory efficiency when compared to 16-mo. old mice. Notably, aged males exhibited greater mitochondrial deficits with carbohydrate substrates, while aged females showed larger declines with fatty acid substrates. Conclusion: Aging induces diffuse impairments in mitochondrial energy transduction in skeletal muscle of mice of both sexes. The application of mitochondrial diagnostics platform offers new insights into the changes in muscle mitochondria with aging and could enhance the identification of interventions for preserving mitochondrial health in aging.
    Keywords:  aging; metabolism; mitochondria; muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00601.2025
  36. EMBO Rep. 2025 Aug 29.
    Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
    Lin Luo, Ana Victoria Lechuga-Vieco, Clara Sattentau, Mariana Borsa, Anna Katharina Simon.
      Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.
    Keywords:  Asymmetric Cell Division; Mitochondrial Metabolism; Mitochondrial Transfer; Mitophagy; T Cell Ageing
    DOI:  https://doi.org/10.1038/s44319-025-00536-z
  37. Am J Physiol Endocrinol Metab. 2025 Sep 02.
    Respiratory Resilience as Form Fades: Skeletal Muscle Mitochondrial Adaptation in Aging.
    John Noone.
      
    Keywords:  Mitochondria; aging; flux control ratios; morphology; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00369.2025
  38. Drug Resist Updat. 2025 Aug 20. pii: S1368-7646(25)00097-4. [Epub ahead of print]83 101294
    Proteasomes suppress anticancer drug-induced cytotoxicity by inhibiting mitochondrial protein import and promoting ROS-BNIP3-mediated mitophagy.
    Ling Li, Yangyang Feng, Jingbo Zhou, Fangyuan Shao, Yuzhong Peng, Sitian Zang, Josh Haipeng Lei, Heng Sun, Dongyang Tang, Shiqi Lin, Jinghong Chen, Hanghang Li, Xiangpeng Chu, Yunfeng Qiao, Xinyu Guo, Kakun Wu, Xiaoling Xu, Chu-Xia Deng.
      Multidrug resistance (MDR) is associated with increased proteasome activity, which facilitates the clearance of damaged proteins and reduced mitochondrial activity, which contributes to quiescence. However, the mechanistic link between protein damage, mitochondrial dysfunction, and proteasome activity remains elusive. Here, we demonstrate that chemical drugs bind to newly synthesized mitochondrial proteins, which are largely unfolded and are coimported into the mitochondrion before appearing in the lysosome and/or nucleus. This triggers a mitochondrion-lysosome-mediated chain reaction, including the integrity stress response (ISR) and the mitochondrial unfolded protein response (UPRmt), followed by increased lysosome biogenesis and PINK1-Parkin independent but ROS-BNIP3-mediated mitophagy. We further observed that proteasomes are the main controller of the mitochondrion-lysosome reaction by monitoring proteostasis, suppressing mitochondrial protein import and promoting mitophagy under both normal and drug-treated conditions. The combination of chemical drugs and the proteasome inhibitor bortezomib (BTZ) triggered excessive mitochondrial import of damaged proteins, overwhelming mitochondrial capacity, causing mitochondrial membrane damage, profound mitochondrial ROS production, lysosome membrane permeabilization, impaired mitophagy, and proteostasis stress-induced cell death.
    Keywords:  MDR; cell death; lysosome membrane permeabilization; mitochondrial protein import; mitophagy; proteasome activity; protein damage
    DOI:  https://doi.org/10.1016/j.drup.2025.101294
  39. Obesity (Silver Spring). 2025 Sep 02.
    FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes.
    Joshua Peterson, Jayashree Jena, Ayushi Sood, Shelly Roitershtein, David Smith, Renata O Pereira.
       OBJECTIVE: Our previous studies showed that mice lacking the mitochondrial fusion protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) have high metabolic rates and are resistant to diet-induced obesity (DIO) via effects partially mediated by independent actions of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) secretion from BAT. We examined whether FGF21 and GDF15 act synergistically, contributing to the systemic metabolic adaptations reported in OPA1 BKO mice.
    METHODS: We generated mice simultaneously lacking the Opa1, Fgf21, and Gdf15 genes in thermogenic adipocytes (TKO) and assessed energy homeostasis and glucose metabolism after regular chow or high-fat diet feeding.
    RESULTS: Young TKO mice fed regular chow had impaired glucose tolerance, while insulin sensitivity was unchanged. Notably, combined Fgf21 and Gdf15 deletion in OPA1 BKO significantly blunted the resistance to DIO and insulin resistance observed in OPA1 BKO mice.
    CONCLUSIONS: FGF21 and GDF15 act synergistically to maintain glucose homeostasis and promote resistance to DIO in mice lacking OPA1 in BAT, highlighting the potential of combined therapies using FGF21 and GDF15 for the treatment of metabolic disorders.
    Keywords:  Brown Adipose Tissue; FGF21; GDF15; Mitochondrial Stress; Obesity
    DOI:  https://doi.org/10.1002/oby.70004
  40. MicroPubl Biol. 2025 ;2025
    Dnm1 Is Required for the Focal Clustering of Fis1 on the Mitochondrial Outer Membrane.
    Miyu Sasahara, Shunsuke Matsumoto, Yasushi Tamura.
      In yeast, mitochondrial fission is mediated by the dynamin-like GTPase Dnm1, which is recruited to the mitochondrial outer membrane by its receptor, Fis1. To investigate the spatial distribution of Fis1, we used the CRISPR-Cas9 system to insert the gene fragment encoding mNeonGreen into the FIS1 gene for its N-terminal tagging. Fluorescence microscopy revealed that mNeonGreen-Fis1 appeared as discrete puncta on mitochondria, in addition to a diffuse signal. Here, we show that the focal clustering of Fis1 is dependent on Dnm1. Our findings provide insight into the spatial organization of membrane proteins, highlighting a mechanism by which a downstream effector can influence the distribution of its upstream receptor.
    DOI:  https://doi.org/10.17912/micropub.biology.001780
  41. MicroPubl Biol. 2025 ;2025
    Mitochondria-ER contact site components regulate the formation and localization of specialized high-capacity mitochondria in the C. elegans anchor cell.
    Isabel W Kenny-Ganzert, David R Sherwood.
      Mitochondria-endoplasmic reticulum contact sites (MERCS) play crucial roles in mediating calcium signaling and lipid metabolism, and regulate mitochondrial morphology, function, and quality control. Recent studies have found that the C. elegans anchor cell (AC) harbors a specialized pool of high-capacity mitochondria that localize to the invasive front and are enriched with electron transport chain proteins to generate high ATP levels to fuel invasion. We conducted an RNAi screen of 59 MERCS-encoding components and identified over 30 required for high-capacity mitochondria formation. Our results suggest that MERCS may play a key role in the formation of specialized high-capacity mitochondria.
    DOI:  https://doi.org/10.17912/micropub.biology.001679
  42. Nat Rev Nephrol. 2025 Aug 29.
    Accumulation of pathogenic mitochondrial DNA mutations in the kidney.
    Ellen F Carney.
      
    DOI:  https://doi.org/10.1038/s41581-025-01002-8
  43. PLoS One. 2025 ;20(8): e0331038
    Optimizing gene prioritization for clinical diagnosis of metabolic genetic disorders.
    Beatriz Helena Dantas Rodrigues de Albuquerque, Daniel Carlos Ferreira Lanza.
      The expansion of next-generation sequencing has generated vast genomic datasets, but translating this information into clinically actionable tools for inherited metabolic disorders (IMDs) remains challenging. In this study, we systematically mapped gene-phenotype associations in IMDs using curated data from OMIM, ClinVar, Orphanet, and the Genetic Testing Registry (GTR). From 372 OMIM entries, we identified 228 genes definitively associated with metabolic diseases (GAMD). These genes displayed uneven chromosomal distribution, wide variability in pathogenic variant load, and strong clustering of phenotypes, particularly among amino acid metabolism disorders. Autosomal recessive inheritance was predominant. Integrating variant pathogenicity, phenotype prevalence, and diagnostic test availability, we designed two evidence-based diagnostic panels. The Subnotification Panel highlights under-tested but clinically relevant genes linked to more prevalent IMDs, aiming to address diagnostic underrepresentation. The Initial Screening Panel prioritizes genes with a high proportion of pathogenic variants, broad test accessibility, and strong clinical relevance, offering an efficient tool for first-line diagnostics. By bridging the gap between large-scale genomic information and precision clinical application, these panels provide a scalable and strategic framework to enhance diagnostic accuracy, support early intervention, and improve equity in the management of metabolic diseases.
    DOI:  https://doi.org/10.1371/journal.pone.0331038
  44. J Transl Int Med. 2025 Jun;13(3): 211-240
    Mitochondrial quality control as a therapeutic target in cardiovascular disease: Mechanistic insights and future directions.
    Miao Zhang, Tong Zhang, Rongjun Zou, Kunyang He, Ru Huang, Jingrui Feng, Jinlin Hu, Teng Ge, Xiaoping Fan, Hao Zhou, Yang Chen.
      Mitochondrial dysfunction is increasingly recognized as a critical driver in the pathogenesis of cardiovascular diseases. Mitochondrial quality control (MQC) is an ensemble of adaptive mechanisms aimed at maintaining mitochondrial integrity and functionality and is essential for cardiomyocyte viability and optimal cardiac performance under the stress of cardiovascular pathology. The key MQC components include mitochondrial fission, fusion, mitophagy, and mitochondria-dependent cell death, each contributing uniquely to cellular homeostasis. The dynamic interplay among these processes is intricately linked to pathological phenomena, such as redox imbalance, calcium overload, dysregulated energy metabolism, impaired signal transduction, mitochondrial unfolded protein response, and endoplasmic reticulum stress. Aberrant mitochondrial fission is an early marker of mitochondrial injury and cardiomyocyte apoptosis, whereas reduced mitochondrial fusion is frequently observed in stressed cardiomyocytes and is associated with mitochondrial dysfunction and cardiac impairment. Mitophagy is a protective, selective autophagic degradation process that eliminates structurally compromised mitochondria, preserving mitochondrial network integrity. However, dysregulated mitophagy can exacerbate cellular injury, promoting cell death. Beyond their role as the primary energy source of the cell, mitochondria are also central regulators of cardiomyocyte survival, mediating apoptosis and necroptosis in reperfused myocardium. Consequently, MQC impairment may be a determining factor in cardiomyocyte fate. This review consolidates current insights into the regulatory mechanisms and pathological significance of MQC across diverse cardiovascular conditions, highlighting potential therapeutic avenues for the clinical management of heart diseases.
    Keywords:  fusion; mitochondrial death; mitochondrial fission; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.1515/jtim-2025-0030
  45. Res Sq. 2025 Aug 27. pii: rs.3.rs-7014857. [Epub ahead of print]
    Hepatic ferredoxin reductase modulates mitochondrial function and iron homeostasis in metabolic dysfunction-associated steatotic liver disease.
    Tomoaki Tanaka, Ikki Sakuma, Rafael Gaspar, Panu Luukkonen, Brandon Hubbard, Daniel Vatner, Ali Nasiri, Sylvie Dufour, Mario Kahn, Mark Perelis, Yuki Taki, Akitoshi Nakayama, Masanori Fujimoto, Takashi Kono, Takashi Miki, Koutaro Yokote, Kitt Petersen, Varman Samuel, Gerald Shulman.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease globally. Disruptions in iron metabolism and mitochondrial oxidative function may cooperatively contribute to its pathogenesis. Ferredoxin reductase (FDXR), a mitochondrial flavoprotein, plays a critical role in mitochondrial respiratory supercomplex formation and iron-sulfur cluster biosynthesis-both essential for efficient oxidative metabolism. However, its role in MASLD remains unclear. Here, we knocked down hepatic Fdxr expression in the liver of C57BL/6 mice using N -acetyl galactosamine-conjugated antisense oligonucleotides. [ 13 C 5 ]glutamine tracer infusions revealed that FDXR deficiency disrupted mitochondrial oxidative phosphorylation. In contrast, FDXR deficiency increased hepatic iron accumulation, reactive oxygen species, and lipid peroxidation. Mechanistically, FDXR deficiency disrupted iron-sulfur cluster assembly and reduced mitochondrial proteins such as succinate dehydrogenase complex iron-sulfur subunit B (SDHB), leading to mitochondrial dysfunction and steatosis. FDXR expression was upregulated in both human and murine MASLD livers, suggesting a compensatory protective response. Furthermore, hepatic overexpression of FDXR restored mitochondrial function, enhanced oxidative capacity, and ameliorated steatosis. These findings identify FDXR as a key regulator linking iron metabolism and mitochondrial integrity in MASLD and highlight its potential as a therapeutic target to prevent disease progression.
    DOI:  https://doi.org/10.21203/rs.3.rs-7014857/v1
  46. bioRxiv. 2025 Aug 31. pii: 2025.08.31.673364. [Epub ahead of print]
    Patterns of Mitochondrial ATP Predict Tissue Folding.
    Bezia Lemma, Megan Rothstein, Pengfei Zhang, Bridget Waas, Marcus Kilwein, Safiya Topiwala, Sherry X Zhang, Anvitha Sudhakar, Katharine Goodwin, Elizabeth R Gavis, Ricardo Mallarino, Andrej Kosmrlj, Celeste M Nelson.
      The construction of complex tissue shapes during embryonic development results from spatial patterns of gene expression and mechanical forces fueled by chemical energy from ATP hydrolysis. We find that chemical energy is similarly patterned during morphogenesis. Specifically, mitochondria are locally enriched at the apical sides of epithelial cells during apical constriction, which is widely used across the animal kingdom to fold epithelial tissues. Timelapse imaging, spatial transcriptomics, and measurements of oxygen consumption rate reveal that mitochondrial density, potential, and ATP increase in epithelial cells prior to actomyosin contraction and tissue folding, which is prevented by inhibiting oxidative phosphorylation. Mitochondrial enrichment and apicobasal patterning are conserved during apical constriction in flies, chicks, and mice, and these subcellular patterns can be used to predict computationally patterns of tissue folding. These findings highlight a spatial dimension of bioenergetics in embryonic development.
    DOI:  https://doi.org/10.1101/2025.08.31.673364
  47. Nat Commun. 2025 Aug 30. 16(1): 8119
    Cardiomyocyte mitochondrial mono-ADP-ribosylation dictates cardiac tolerance to sepsis by configuring bioenergetic reserve in male mice.
    Xiaoqiang Chen, Tianyou Yuan, Danchuan Zheng, Fangfang Li, Hao Xu, Maoqing Ye, Shaowen Liu, Jun Li.
      The metabolic flexibility of tissues determines the degree and reversibility of organ damage during inflammatory challenges. However, effective treatments for myocardial metabolic dysfunction in septic cardiomyopathy (SCM) are unavailable. Nicotinamide adenine dinucleotide-dependent signaling is fundamental to cellular metabolic homeostasis and inflammatory responses. Here, using male mice models, we reveal that both genetic and pharmacological inhibition of mono-ADP-ribosyl hydrolase MacroD1 which is predominantly enriched in cardiomyocytes alleviates myocardial metabolic impairment, inflammation, dysfunction, and the risk of mortality caused by lipopolysaccharide and cecal ligation and puncture. Mechanistically, MacroD1 selectively modulates the activity of mitochondrial complex I (MCI), which is particularly vulnerable at the early stages of sepsis. Inhibition of MacroD1 preserves MCI activity and bioenergetic reserves of cardiomyocytes by enhancing mono-ADP-ribosylation of Ndufb9 protein, thereby mitigating sepsis-induced myocardial pyroptosis and dysfunction. These preclinical results indicate that MacroD1 dictates cardiac tolerance to sepsis by configuring MCI-coupled bioenergetic reserve and cardiomyocyte pyroptosis.
    DOI:  https://doi.org/10.1038/s41467-025-62384-8
  48. Diabet Med. 2025 Aug 31. e70129
    Neonatal diabetes mellitus is a significant feature of COXPD-24 caused by recessive NARS2 variants.
    Russell Donis, Matthew N Wakeling, Nicola Jeffery, Molly Govier, Matthew B Johnson, Samar Sabir Hassan, Mohammed Ahmed Abdullah, Khadiga Yehia Elsayed Eltonbary, Nima Parvaneh, Mahsa M Amoli, Farzaneh Abbasi, Selin Elmaoğulları, Semra Çetinkaya, Kubra Gunes, Meltem Tayfun, Hanieh Yaghootkar, Andrew T Hattersley, Sarah E Flanagan, Elisa De Franco.
       BACKGROUND: Recessive loss-of-function NARS2 variants causing the multi-system disorder Combined oxidative phosphorylation deficiency 24 (COXPD24) have recently been reported in 3 individuals with diabetes diagnosed between 3 days and 14 months of age. In this study, we investigate the presence of NARS2 variants in a large cohort of individuals with early-onset diabetes.
    METHODS: We used genome and targeted next-generation sequencing to screen for rare, coding biallelic NARS2 variants in a cohort of 397 individuals diagnosed with diabetes <24 months of age of unknown genetic cause.
    RESULTS: We identified 8 individuals with homozygous disease-causing missense variants in NARS2 (4 individuals with the p.(Phe216Leu) variant, 3 with p.(Thr180Asn) and one with p.(Val440Leu)). All 8 individuals were diagnosed with insulin-dependent diabetes before 6 months of age (neonatal diabetes, NDM) with the median age at diagnosis being 4 weeks (range: 1 to 20 weeks). 7/8 probands had low birthweight (median Z-score: -2.43, range: -4.17 to 0.86). Neurological features were common, with epilepsy and developmental delay each identified in 7/8 and 6/8 participants, respectively.
    CONCLUSION: Taken together with previously published cases, this study shows that NDM is an important feature of COXPD-24 and highlights a critical role for NARS2 in the insulin-secreting pancreatic β-cell.
    Keywords:  NARS2; mitochondria; mitochondrial disease; mitochondrial dysfunction; monogenic diabetes; neonatal diabetes mellitus; β‐Cells
    DOI:  https://doi.org/10.1111/dme.70129
  49. Front Neurosci. 2025 ;19 1631752
    Impacts of mitochondrial dysfunction on axonal microtubule bundles as a potential mechanism of neurodegeneration.
    Scott Murray-Cors, Milli Owens, Yu-Ting Liew, Maureece Day, William Cairns, Andreas Prokop.
      Mitochondrial dysfunction is an important cause for neurodegeneration, often associated with dyshomeostasis of reactive oxygen species, i.e., oxidative stress. However, apart from ATP production, mitochondria have many other functions the aberration of which may impact neurons in very different ways. Oxidative stress can cause the deterioration of axonal microtubule bundles, thus critically affecting the highways for life-sustaining transport and providing a potential path to neurodegeneration. We recently found that aberrant transport of mitochondria can have this effect by causing oxidative stress. We therefore asked which aberrations of mitochondrial physiology might impact microtubules, which of these might explain the observed consequences of aberrant mitochondrial transport, and whether mitochondria-induced microtubule phenotypes are always mediated by oxidative stress. Using one consistent Drosophila primary neuron system, we studied functional loss of 13 different mitochondrial factors known to be detrimental to neurons in vivo. Losses of five factors caused MT damage, namely pyruvate dehydrogenase A, succinate dehydrogenase A, adenine nucleotide translocase, frataxin and superoxide dismutase 2. All involved oxidative stress, hence supported the path from mitochondria via oxidative stress to microtubule deterioration; of these, we discuss superoxide dismutase 2 as potential candidate explaining effects of mitochondrial transport aberration. Six of the remaining factors not causing microtubule damage were important mitochondrial morphogenesis regulators, suggesting efficient protection mechanisms preventing oxidative stress upon mitochondrial contortion.
    Keywords:  Drosophila; microtubules; mitochondria; neurodegeneration; reactive oxygen species
    DOI:  https://doi.org/10.3389/fnins.2025.1631752
  50. Brain Behav. 2025 Sep;15(9): e70822
    PRKN/PINK1 Mutations in a Chinese Patient With Early-Onset Parkinson's Disease.
    Zhongjiao Lu, Ye Sun, Liemei Guo, Mei Xin, Yunlan Du, Ruolian Dai, Gang Chen, Hualong Wang, Gang Wang.
       BACKGROUND: PRKN and PINK1 gene mutations have been associated with Parkinson's disease (PD), particularly early-onset PD (EOPD).
    OBJECTIVES: To describe the clinical and molecular features of a Chinese patient with EOPD who had uncommon PRKN and PINK1 mutations.
    METHODS: The patient's clinical history was reviewed, and whole-exome sequencing was performed to identify genetic mutations. An in vitro mitochondrial stress model was created to study the impact of PRKN deletion on the PINK1-PRKN pathway.
    RESULTS: The patient exhibited a 27-year history of tremors and other motor symptoms, with a notable response to levodopa and subthalamic nucleus deep brain stimulation (STN DBS). Genetic testing revealed an unusual double mutation of PRKN/PINK1, while PRKN deletion blocked the activation of the PINK1-PRKN pathway, disrupting the patient's mitophagy pathway.
    CONCLUSIONS: PRKN/PINK1 mutations may be linked to compromised mitophagy pathways. Genetic screening is significant for EOPD patients, especially those with specific symptoms and ethnic backgrounds.
    DOI:  https://doi.org/10.1002/brb3.70822
  51. Circ Res. 2025 Aug 29. 137(6): 863-865
    Iron Lion ZIPion: ZIP13 Zips Iron to Heart Mitochondria.
    Hualin Fan, Luca Scorrano.
      
    Keywords:  Editorials; iron; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327126
  52. JACC Basic Transl Sci. 2025 Jun 04. pii: S2452-302X(25)00180-9. [Epub ahead of print] 101292
    Novel Peptide Therapeutics Targeting the L-Type Calcium Channel Prevent Hypertrophic Cardiomyopathy by Decreasing Mitochondrial Energetics.
    Teagan S Er, Daniel Reinke, Alice J Francis, Tanya M Solomon, Helena M Viola, Henrietta Cserne Szappanos, Caitlyn M Richworth, Catherine Jenkins, Juan E Camacho Londoño, Padmapriya Ponnuswamy, Ciaran McFarlane, Filip Van Petegem, Livia C Hool.
      Mitochondrial dysfunction is considered to drive the development of hypertrophic cardiomyopathy (HCM). In search of a preventative HCM therapy, we explored the efficacy of amino acid peptide variants that could alter the L-type Ca2+ channel's regulation of mitochondrial energetics. We confirmed that 3 of the 4 variant peptides bound with high affinity to the beta subunit. In vivo treatment of cTnI-G203S and αMHC403/+ mice with the peptide variants prevented the development of HCM and improved contractile function. Here, we describe a novel therapy that uniquely targets the L-type Ca2+ channel to modify mitochondrial function and prevent HCM.
    Keywords:  cTnI-G203S; cardiac; mitochondria; prevention; αMHC(403/+)
    DOI:  https://doi.org/10.1016/j.jacbts.2025.04.006
  53. bioRxiv. 2025 Aug 20. pii: 2025.08.19.671117. [Epub ahead of print]
    Renalase activates mitochondrial leak metabolism in response to cellular stress and to repair damage after injury.
    Xiaojia Guo, Rongmin Chen, Christine Shugrue, Fei-Fei Shang, Rolando Garcia Milian, Haley Moller, Pawel Licznerski, Tian-Min Chen, Richard Kibbey, Ons M'Saad, Yuan Tian, Joerg Bewersdorf, Frank Giordano, Fred S Gorelick, Robert Safirstein, Elizabeth A Jonas, Gary V Desir.
      A variety of mechanisms enhance cell stress response and repair; however, the role of mitochondria in this activity is unclear. Here we show that exogenous renalase (RNLS), an intracellular flavin-dependent NADH oxidase, activates intramitochondrial RNLS activity to promote cell survival. RNLS interacts with the ATP synthase alpha and beta subunits (ATP5α and ATP5β) and opens the ATP synthase c-subunit leak channel to increase complex I and II activities and protein synthesis rate. RNLS causes a selective, sustained, time-dependent increase in cellular protein synthesis without affecting cell proliferation, whereas RNLS deletion or direct inhibition of the mitochondrial leak blocks RNLS-mediated protein synthesis. Functional analysis of newly and differentially synthesized proteins over 24 hours reveals rapid changes in one-carbon metabolism and ribosomal biogenesis pathways as early as one hour after RNLS exposure. Mitochondrial injury is more severe in the RNLS KO kidney after acute stress, related to decreased protein synthesis rate and increased mitophagy. RNLS KO mice exposed to the stress of chronic cardiac pressure overload fail to develop cardiac hypertrophy, the physiological response, and die of heart failure and cardiac rupture. These data highlight the critical role RNLS has in activating mitochondrial leak metabolism to induce selective protein synthesis and protect against acute and chronic stress.
    HIGHLIGHTS: Renalase interacts with the ATP synthase alpha and beta subunitsRenalase activates mitochondrial leak metabolismRenalase and leak metabolism increase complex I and II activitiesLeak metabolism increases protein synthesis rateRenalase protects against cell stress and organ injury.
    DOI:  https://doi.org/10.1101/2025.08.19.671117
  54. Cell Rep. 2025 Sep 03. pii: S2211-1247(25)01005-8. [Epub ahead of print]44(9): 116234
    Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.
    Shuang Ma, Jianhua Qin, Yao Zhang, Jing Luan, Na Sun, Guoyuan Hou, Jiyuan He, Yang Xiao, Wei Zhang, Minghui Gao.
      Ferroptosis is a regulated necrosis driven by iron-dependent lipid peroxidation. Mitochondria play vital roles in ferroptosis. Mitochondrial dynamics is critical for the health of mitochondria and cells. But how this process regulates ferroptosis is not fully understood. Here, we found that mitochondrial fission is induced during ferroptosis. Disruption of mitochondrial dynamics by impeding the expression of the central players of mitochondrial dynamics control, dynamin-related protein 1 (DRP1) and Mitofusion1/2, or modifying the expression of optic atrophy 1 (OPA1) inhibits ferroptosis. Mechanistically, a defect in mitochondrial dynamics homeostasis increases the ratio of [AMP+ADP]/[ATP], thus activating AMP-activated protein kinase (AMPK), which further phosphorylates nuclear factor erythroid 2-related factor 2 (NRF2) and promotes NRF2 nuclear translocation. Subsequently, NRF2 triggers ferroptosis suppressor 1 (FSP1) upregulation, which renders the cells resistant to ferroptosis. Importantly, mitochondrial fusion promoter M1 can mitigate the chemotoxicity induced by doxorubicin without compromising its anti-cancer efficacy. Collectively, the results of this study demonstrate the crucial role of mitochondrial dynamics in ferroptosis and indicate a potential therapeutic protective approach for chemotoxicity.
    Keywords:  AMPK; CP: Immunology; CP: Metabolism; FSP1; NRF2; chemotoxicity; ferroptosis; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116234
  55. Ophthalmol Retina. 2025 Aug 28. pii: S2468-6530(25)00359-8. [Epub ahead of print]
    Mitochondrial Retinopathy Complicated with Choroidal Neovascularization.
    Kemal Tekin, Mehmet Yasin Teke.
      
    DOI:  https://doi.org/10.1016/j.oret.2025.08.001
  56. Ageing Res Rev. 2025 Sep 03. pii: S1568-1637(25)00238-7. [Epub ahead of print] 102892
    Nuclear mitochondrial DNA transfer revisited: From genomic noise to hallmark of aging.
    Emanuele Marzetti, Rosa Di Lorenzo, Riccardo Calvani, Helio José Coelho-Junior, Vito Pesce, Francesco Landi, Christiaan Leeuwenburgh, Anna Picca.
      Nuclear insertions of mitochondrial DNA (mtDNA) segments (NUMTs) represent an evolutionarily conserved phenomenon originating from the ancient endosymbiotic relationship between mitochondria and host cells. These insertions predominantly localize near intergenic or regulatory regions and are often enriched in tissues with high metabolic activity. Once regarded as inert pseudogenes or genomic artifacts, NUMTs are now recognized as dynamic elements capable of modulating nuclear architecture and cellular function. Advances in whole-genome sequencing have revealed a remarkable diversity of NUMTs across species, including polymorphic variants in humans that suggest ongoing NUMTogenesis. Stress-induced mitochondrial damage promotes mtDNA release and subsequent nuclear integration via non-homologous end joining, a mechanism that may be exacerbated in aging tissues. Studies suggest that NUMTs may intersect with some biological hallmarks of aging. Recently, NUMT accumulation in the brain was shown to correlate with cognitive decline and reduced lifespan, implicating NUMTs in biological aging and associated conditions. Additionally, NUMTs have been observed in oncogenic loci, suggesting potential roles in carcinogenesis. This review synthesizes current evidence on the molecular mechanisms underpinning NUMT generation and explores their intersection with aging biology. We examine how NUMTs may influence mitochondrial-nuclear communication, promote inflammation, and affect telomere dynamics and cellular senescence. We also highlight the relevance of understanding the biological impact of NUMTs across life stages and disease states to inform novel biomarkers and therapeutic strategies.
    Keywords:  DNA repair; biological aging; genomic instability; hallmarks of aging; mitochondrial dysfunction; telomeres
    DOI:  https://doi.org/10.1016/j.arr.2025.102892
  57. Front Cell Neurosci. 2025 ;19 1623747
    SFXN2 contributes mitochondrial dysfunction-induced apoptosis as a substrate of Parkin.
    Shishi Luo, Yechuan He, Yaohui He, Danling Wang.
       Introduction: Mitochondria, situated at the center of intricate signaling networks, play crucial roles in maintaining health and driving disease progression. SFXN2, a recently identified member of the mitochondrial transporter family, is localized to the outer mitochondrial membrane and regulates several critical mitochondrial functions, including iron metabolism, heme biosynthesis, bioenergetics, and redox homeostasis. New evidence also suggests a connection between SFXN2 and mitochondrial dysfunction related human diseases such as Parkinson's disease (PD). Despite growing insights into SFXN2's roles across various mitochondrial functions, its regulation under mitochondrial dysfunction and the resulting biological consequences remains unclear.
    Methods: The expression levels of SFXN2 protein were analyzed by Western blotting WB. The interaction between SFXN2 and Parkin was examined using co-immunoprecipitation and immunofluorescence assays. Furthermore, the effect of Parkin on SFXN2 ubiquitination was assessed via ubiquitination assay. Finally, RNA sequencing and flow cytometry were employed to investigate that SFXN2 regulates the apoptotic pathway.
    Results: In this study, we identify SFXN2 as a key regulator of mitochondrial homeostasis, demonstrating that its level is tightly regulated via Parkin-mediated ubiquitination and proteasomal degradation. Under conditions of mitochondrial damage, Parkin enhances the degradation of SFXN2, and the reduction of SFXN2 contributes to apoptotic cell death. Functional studies across multiple cell lines, including HEK293, SH-SY5Y, and N2a cells, reveal that the reduction of SFXN2 exacerbates mitochondrial damage-induced apoptosis, whereas overexpression of SFXN2 exhibits an anti apoptotic effect.
    Discussion: Our findings offer new insights into the regulation of SFXN2 in mitochondrial dysfunction through Parkin mediated ubiquitin proteasome system activity, underscoring SFXN2's potential implications in nerodegenerative diseases, particularly PD.
    Keywords:  Parkin; SFXN2; apoptosis; mitochondrial dysfunction; ubiquitination
    DOI:  https://doi.org/10.3389/fncel.2025.1623747
  58. World J Methodol. 2025 Sep 20. 15(3): 102709
    Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance.
    Deepak Parchwani, Ragini Singh, Digisha Patel.
      The mitochondrial DNA copy number (mtDNAcn) plays a vital role in cellular energy metabolism and mitochondrial health. As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation, maintaining an appropriate mtDNAcn level is vital for the overall cellular function. Alterations in mtDNAcn have been linked to various diseases, including neurodegenerative disorders, metabolic conditions, and cancers, making it an important biomarker for understanding the disease pathogenesis. The accurate estimation of mtDNAcn is essential for clinical applications. Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations. Clinically, mtDNAcn serves as a valuable indicator for early diagnosis, disease progression, and treatment response. For instance, in oncology, elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy. In neurodegenerative diseases such as Alzheimer's and Parkinson's, altered mtDNAcn patterns provide insights into disease mechanisms and progression. Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields. As research continues to uncover the implications of mtDNAcn alterations, its potential as a clinical biomarker is likely to expand, thereby enhancing our ability to diagnose and manage complex diseases.
    Keywords:  Aging; Cancer; Mitochondrial DNA; Mitochondrial DNA copy number; Neurodegenerative disease; Quantitative polymerase chain reaction
    DOI:  https://doi.org/10.5662/wjm.v15.i3.102709
  59. Nat Commun. 2025 Aug 30. 16(1): 8126
    Metformin alters mitochondria-related metabolism and enhances human oligodendrocyte function.
    Nina-Lydia Kazakou, Nadine Bestard-Cuche, Laura J Wagstaff, Kellie Horan, Luise Seeker, Sunniva Bøstrand, Rana Fetit, Rebecca Sherrard Smith, Fabio Baldivia Pohl, Bjorn Neumann, Patrick Keeler, Robin J M Franklin, Anna Williams.
      Metformin rejuvenates adult rat oligodendrocyte progenitor cells (OPCs) allowing more efficient differentiation into oligodendrocytes and improved remyelination, and therefore is of interest as a therapeutic in demyelinating diseases such as multiple sclerosis (MS). Here, we test whether metformin has a similar effect in human stem cell derived-OPCs. We assess how well human monoculture, organoid and chimera model culture systems simulate in vivo adult human oligodendrocytes, finding most close resemblance in the chimera model. Metformin increases myelin proteins and/or sheaths in all models even when human cells remain fetal-like. In the chimera model, metformin leads to increased mitochondrial area both in the human transplanted cells and in the mouse axons with associated increase of mitochondrial function/metabolism transcripts. Human oligodendrocytes from MS brain donors treated pre-mortem with metformin also express similar transcripts. Metformin's brain effect is thus not cell-specific, alters metabolism in part through mitochondrial changes and leads to more myelin production. This bodes well for clinical trials testing metformin for neuroprotection.
    DOI:  https://doi.org/10.1038/s41467-025-63279-4
  60. Nature. 2025 Sep 03.
    Genetic suppression features ABHD18 as a Barth syndrome therapeutic target.
    Sanna N Masud, Anchal Srivastava, Patricia Mero, Victoria Saba Echezarreta, Eve Anderson, Lennard van Buren, Jiarun Wei, David Thomson Taylor, Adrian Granda Farias, Nicholas Mikolajewicz, Angela Shaw, Brandon M Murareanu, Michelle Lohbihler, Olivia Sniezek Carney, Simon van Heeringen, Linda Clijsters, Olga Sizova, Jeroen van Ameijde, Freya Nye, Andrea Habsid, Lucy Nedyalkova, Laura McDonald, Craig Simpson, Leanne Wybenga-Groot, Kevin R Brown, Nhi Nho, Radu M Suciu, Katherine Chan, Amy H Y Tong, Frédéric M Vaz, Bastiaan Evers, Robert Lesurf, Tanya Papaz, Lauryl M J Nutter, Stephanie Protze, Maximilian Billmann, Michael Costanzo, Brenda J Andrews, Chad L Myers, Seema Mital, Hilary Vernon, Thijn R Brummelkamp, Charles Boone, Ian C Scott, Micah J Niphakis, Douglas Strathdee, Sebastian M B Nijman, Vincent A Blomen, Jason Moffat.
      Cardiolipin (CL) is the signature phospholipid of the inner mitochondrial membrane, where it stabilizes electron transport chain protein complexes1. The final step in CL biosynthesis relates to its remodelling: the exchange of nascent acyl chains with longer, unsaturated chains1. However, the enzyme responsible for cleaving nascent CL (nCL) has remained elusive. Here, we describe ABHD18 as a candidate deacylase in the CL biosynthesis pathway. Accordingly, ABHD18 converts CL into monolysocardiolipin (MLCL) in vitro, and its inactivation in cells and mice results in a shift to nCL in serum and tissues. Notably, ABHD18 deactivation rescues the mitochondrial defects in cells and the morbidity and mortality in mice associated with Barth syndrome. This rare genetic disease is characterized by the build-up of MLCL resulting from inactivating mutations in TAFAZZIN (TAZ), which encodes the final enzyme in the CL-remodelling cascade1. We also identified a selective, covalent, small-molecule inhibitor of ABHD18 that rescues TAZ mutant phenotypes in fibroblasts from human patients and in fish embryos. This study highlights a striking example of genetic suppression of a monogenic disease revealing a canonical enzyme in the CL biosynthesis pathway.
    DOI:  https://doi.org/10.1038/s41586-025-09373-5
  61. Nat Commun. 2025 Aug 30. 16(1): 8115
    A streamlined base editor engineering strategy to reduce bystander editing.
    Izabella Valdez, Ian O'Connor, Divesh Patel, Katherine Gierer, Jan Harrington, Ethan Ellis, Stephen A Caponetti, Robert P Sebra, Hillary C Valley, Kevin Coote, Martin Mense, Samuele G Marro, Tingting Jiang.
      Base editing (BE) can permanently correct over half of known human pathogenic genetic variants without requiring a repair template, thus serving as a promising therapeutic tool to treat a broad spectrum of genetic diseases. However, the broad activity windows of current base editors pose a major challenge to their therapeutic application. Here, we show that integrating a naturally occurring oligonucleotide binding module into the deaminase active center of TadA-8e, a highly active deoxyadenosine deaminase, enhances its editing specificity. When conjugated with a Cas9 nickase or alternative PAM Cas9 variants, the engineered TadA variant-TadA-NW1-consistently achieves robust A-to-G editing efficiencies within an editing window consisting of four nucleotides, substantially narrower than the 10-bp editing window of the TadA-8e-derived ABEs. Moreover, compared to ABE8e, ABE-NW1 shows significantly decreased Cas9-dependent and -independent off-target activity while maintaining similar on-target editing efficiency. Further, TadA-NW1 can be reprogrammed to perform desired cytidine deamination and adenine transversion within a restricted editing window. Finally, in a cystic fibrosis (CF) cell model, ABE-NW1 outperforms existing ABEs in accurately and efficiently correcting the CFTR W1282X variant, one of the most common CF-causing mutations. In all, we engineered a suite of base editors with refined activity windows, enabling more precise base editing. Importantly, this study presents a streamlined genome editor re-engineering strategy to accelerate the development of therapeutic base editing.
    DOI:  https://doi.org/10.1038/s41467-025-63609-6
  62. Hum Mol Genet. 2025 Aug 29. pii: ddaf140. [Epub ahead of print]
    Galactose treatment rescues neuromuscular junction transmission in glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) deficient mice.
    Stephen Henry Holland, Ricardo Carmona-Martinez, Daniel O'Neil, Kelly Ho, Kaela O'Connor, Yoshiteru Azuma, Andreas Roos, Sally Spendiff, Hanns Lochmüller.
      Congenital myasthenic syndromes (CMS) arise from mutations to proteins involved in neuromuscular junction (NMJ) development, maintenance, and neurotransmission. To date, mutations in more than 35 genes have been linked to CMS development. Glutamine fructose-6-phosphate transaminase 1 (GFPT1/Gfpt1) serves as the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), producing the byproduct (UDP-GlcNAc) necessary for protein glycosylation. Gfpt1-deficient models have impaired protein glycosylation, impacting key proteins at the NMJ. The Leloir pathway is a galactose metabolizing pathway which produces UDP-GalNAc as its final product. The enzyme UDP-GalNAc Epimerase (GALE) can also convert excess UDP-GalNAc into UDP-GlcNAc, the byproduct of the HBP. We hypothesized that treatment with galactose both in vitro and in vivo in Gfpt1-deficient models would rescue impaired protein O-GlcNAcylation and reverse the glycosylation status of key NMJ-associated proteins. We show that galactose treatment in vitro activated the Leloir pathway and rescued protein O-GlcNAcylation in Gfpt1-deficient C2C12 myoblasts. In addition, we demonstrated that galactose therapy rescued neuromuscular deficits, improved muscle fatigue and restored NMJ morphology in a skeletal muscle-specific Gfpt1 knockout mouse model. Lastly, we showed that galactose treatment rescued protein O-GlcNAcylation in skeletal muscle, preserving the glycosylation status of the delta (δ) subunit of the acetylcholine receptor (AChRδ). Taken together, we suggest that galactose supplementation can be further explored as a therapy for GFPT1-CMS patients.
    Keywords:  Congenital Myasthenic Syndrome; Galactose; Glutamine-Fructose-6-Phosphate Transaminase 1; Glycosylation; Neuromuscular Junction
    DOI:  https://doi.org/10.1093/hmg/ddaf140
  63. Science. 2025 Aug 28. 389(6763): eadm7066
    Machine learning-based penetrance of genetic variants.
    Iain S Forrest, Ha My T Vy, Ghislain Rocheleau, Daniel M Jordan, Ben O Petrazzini, Girish N Nadkarni, Judy H Cho, Mythily Ganapathi, Kuan-Lin Huang, Wendy K Chung, Ron Do.
      Accurate variant penetrance estimation is crucial for precision medicine. We constructed machine learning (ML) models for 10 diseases using 1,347,298 participants with electronic health records, then applied them to an independent cohort with linked exome data. Resulting probabilities were used to evaluate ML penetrance of 1648 rare variants in 31 autosomal dominant disease-predisposition genes. ML penetrance was variable across variant classes, but highest for pathogenic and loss-of-function variants, and was associated with clinical outcomes and functional data. Compared with conventional case-versus-control approaches, ML penetrance provided refined quantitative estimates and aided the interpretation of variants of uncertain significance and loss-of-function variants by delineating clinical trajectories over time. By leveraging ML and deep phenotyping, we present a scalable approach to accurately quantify disease risk of variants.
    DOI:  https://doi.org/10.1126/science.adm7066
  64. BMC Genomics. 2025 Aug 30. 26(1): 787
    MitoCOMON: whole mitochondrial DNA sequencing by primer design and long overlapping amplicon assembly.
    Yoshikazu Furuta, Manami Kakita, Hidenori Tanaka.
       BACKGROUND: Mitochondrial DNA sequences are used for inter- and intra-specific comparison analysis in ecological studies. Instead of using short regions as marker sequences, analyzing longer regions, such as whole mitochondrial DNA sequences, can improve the accuracy of such studies by increasing the likelihood of detecting species or specific sequences. However, current methods for sequencing whole mitochondrial DNA require primer design for each target species or long fragments of genomic DNA as a PCR template. We developed a method and accompanying tool for PCR-based long-read sequencing of whole mitochondrial DNA, named MitoCOMON, which is applicable to wide-target taxonomic clades and partially digested template DNA.
    RESULTS: PCR amplification of whole mitochondrial DNA as four fragments facilitates the successful assembly of the whole mitochondrial DNA sequence, even when a sample is a mixture of multiple species or partially degraded. The tool that we developed consists of two modules that can design a primer set for species in a target taxonomic clade and assemble the whole mitochondrial DNA sequence from amplicons which were amplified using the designed primer set. Primer sets were designed for mammal and bird species, which showed a high success rate for whole mitochondrial DNA sequencing with high sequence accuracy. Multiple whole mitochondrial DNA sequences were also assembled from samples mixed with the genomic DNA of several species without forming chimeric sequences. In addition to the accuracy, some assembled sequences also retained a long duplication at the D-loop region, suggesting that the method addresses large rearrangements. Compared with a method that amplifies the whole mitochondrial DNA as a single amplicon, our method was effective for partially degraded samples.
    CONCLUSIONS: Our method and accompanying tool, named MitoCOMON, enables an easier acquisition of whole mitochondrial DNA sequences from samples with some DNA degradation without designing species-specific primers. This approach can enhance the accessibility of mitochondrial genomic data and is expected to improve the resolution of ecological analyses, including accurate species identification and individual-level discrimination.
    Keywords:   De Novo assembly; Long reads; Structural variation; Whole mitochondrial DNA sequencing
    DOI:  https://doi.org/10.1186/s12864-025-12010-0
  65. Clin Genet. 2025 Sep 02.
    Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients.
    Pegah Beheshti, Fahimeh Akbarian, Emran Esmaeilzadeh, Hamid Galehdari, Mehdi Khorrami, Sadeq Vallian, Alireza Abdi, Özge Güngör, Rasim Tuncel, Ayca Aykut, Özgul Ekmekci, Haluk Akın, Asude Durmaz, Atefeh Sohanforooshan Moghaddam, Niloofar Chamanrou, Fatemeh Karimi, Arezu Kazemi, Mahvash Habibi, Mohammad Amin Tabatabaiefar, Hamid Reza Khorram Khorshid, Farshid Parvini, Uluç Yiş, Ipek Polat, Leila Youssefian, Hassan Vahidnezhad, Morteza Heidari, Payam Sarraf, Ehsan Ghayoor Karimiani, Reza Maroofian, Sajjad Biglari.
      Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive, multisystem disorder caused by biallelic loss-of-function (LOF) variants in MICU1, the calcium-sensing gatekeeper of the mitochondrial calcium uniporter. We clinically and genetically characterized seven affected individuals from six Iranian-Turkish consanguineous families and combined these data with 54 previously published cases (total of 62). The targeted neuromuscular assessment, along with muscle biopsy and exome sequencing, identified six pathogenic MICU1 variants, including c.355C>T; p.Arg119*, c.493 + 1G>A, c.508C>T; p.Gln170*, c.547C>T; p.Gln183*, c.1226C>G; p.Ser409*, and c.553C>T; p.Arg185*. Notably, we report one adult-onset patient whose symptoms began at age 29 and progressed more rapidly than those in childhood-onset cases. A separate pedigree contained monozygotic twins who exhibited an indistinguishable clinical course, emphasizing the consistency of the genotype-driven phenotype. Across the combined cohort, the mean age at onset was 5.9 ± 7.3 years (median = 3 years); 61.5% presented before age 5, while 9.5% manifested after 15 years. Deep phenotyping of 61 patients from different ethnic backgrounds revealed that common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%). Functional studies targeting MCU modulation may provide future therapeutic options.
    Keywords:   MICU1 ; MPXPS; exome sequencing; genotype–phenotype correlation; myopathy with extrapyramidal signs
    DOI:  https://doi.org/10.1111/cge.70062
  66. Hum Gene Ther. 2025 Sep 01.
    Advancements in Nonviral Gene Editing Strategies for Rare Diseases.
    Jimena Pérez-Maroto, Laura Sepp-Lorenzino, Diego Castaño-Esteban, Daniela Palacios, Begoña Sot.
      Rare diseases are serious and often chronic conditions that affect a small number of individuals. However, with over 7,000 rare diseases identified, their cumulative global numbers and impact are substantial. A considerable proportion of these conditions is caused by genetic abnormalities. Among these, monogenic disorders are of particular relevance, as they are caused by mutations in specific genes. The development of gene therapy, and more specifically, gene editing, offers innovative approaches to treat these rare diseases. A significant challenge associated with the implementation of such strategies concerns the delivery of gene editing tools. Nonviral vectors based on nanomaterials have demonstrated considerable potential as promising alternatives to viral vectors, thereby overcoming their disadvantages. The biocompatibility and tunability of nanoparticles, along with their potential capacity to target diverse tissues, positions them as a promising therapeutic approach for the treatment of a wide range of organ-specific rare diseases. Here, we review current progress in the development and evaluation of novel nanomedicine strategies for gene editing in rare diseases, highlighting new gene editing approaches, delivery systems, and potential targets.
    Keywords:  CRISPR-Cas9; gene editing; nanoparticles; nonviral vectors; rare diseases
    DOI:  https://doi.org/10.1177/10430342251372056
  67. FEBS J. 2025 Sep 02.
    Synthetic trap-peptides identify a TOM complex phosphatase - PP2A dephosphorylates Tom6.
    Laura Scheinost, Christina Ludwig, Nico Höfflin, Asli Aras Taskin, Adinarayana Marada, F-Nora Vögtle, Chris Meisinger, Maja Köhn.
      The identification of phosphatases that dephosphorylate specific sites in proteins remains a major challenge, particularly for the major class of serine/threonine-specific phosphatases, which function as holoenzymes. Here, we report the development of synthetic trap-peptides to identify phosphatases that bind to Tom6, a subunit of the mitochondrial translocase of the outer membrane (TOM) complex. The TOM complex is regulated by reversible phosphorylation, and although responsible kinases have been identified, the corresponding phosphatases so far remain unknown. Here, the trap-peptides enriched phosphoserine/threonine-specific protein phosphatases 2A (PP2A) and 4 (PP4) as full holoenzymes from yeast cytosolic fractions. We observed that their interaction with Tom6 was mediated through their regulatory subunits Cdc55reg and Psy2reg, respectively, and that PP2A was able to dephosphorylate Ser16 of Tom6 in vitro. In summary, synthetic trap-peptides facilitate the identification of complete holoenzymes that bind to the target sequence and reveal PP2A as the first TOM phosphatase.
    Keywords:  PP2A; PP4; TOM complex; Tom6 Phosphatase substrates
    DOI:  https://doi.org/10.1111/febs.70246
  68. Cell Metab. 2025 Aug 26. pii: S1550-4131(25)00359-6. [Epub ahead of print]
    Mitochondrial dysfunction reveals H2S-mediated synaptic sulfhydration as a potential mechanism for autism-associated social defects.
    Panpan Xian, Mengmeng Wang, Rougang Xie, Hongyu Ma, Weian Zheng, Junjun Kang, Yujiang Chen, Hanze Liu, Songqi Dong, Haiying Liu, Wenle Zhang, Honghui Mao, Fang Wang, Ning Yang, Jun Yu, Ningxia Zhao, Yazhou Wang, Shengxi Wu.
      Clinical studies have identified multiple mitochondrial disturbances in the peripheral tissues of patients with autism. However, how neuronal metabolism contributes to the autism-associated phenotype remains unclear. In this study, we focused on the anterior cingulate cortex (ACC) and reported hydrogen sulfide (H2S) elevation as a common outcome to mitochondrial dysfunction in Shank3b-/- and Fmr1-/y neurons. Cystathionine β-synthase overexpression in ACC impaired synaptic transmission and social function in wild-type mice, while its knockdown effectively rescued synaptic and social defects in both autism mouse models. Dramatic changes in synaptic protein sulfhydration were observed in Shank3b-/- ACC, with over-sulfhydration of mGluR5 validated in both models. Ablating mGluR5 sulfhydration partially alleviated social deficits in both strains. Furthermore, sulfur amino acid restriction ameliorated social dysfunction in Shank3b-/- and Fmr1-/y mice and synaptic defects in corresponding human neurons. Our data indicate that excessive H2S and synaptic protein sulfhydration may serve as potential mechanisms underlying the autism-associated social dysfunction.
    Keywords:  H(2)S; autism spectrum disorder; mGluR5; social dysfunction; sulfhydration
    DOI:  https://doi.org/10.1016/j.cmet.2025.08.003
  69. Eur J Med Genet. 2025 Sep 02. pii: S1769-7212(25)00050-3. [Epub ahead of print] 105043
    Diagnostic yield of whole exome sequencing in a cohort of 825 patients.
    Peter Førster Andersen, Jakob Ek, Helena Gásdal Karstensen, Mads Bak, Sabine Grønborg, Hanne Buciek Hove, Birgitte Diness, Tina Duelund Hjortshøj, Trine Bjørg Hammer, Christina Høi-Hansen, Bitten Schönewolf Greulich, Anne-Marie Bisgaard, Morten Duno, Elsebet Østergaard.
      Genetic testing plays a significant role in rare disease diagnostics. The most widespread technology for genetic testing of patients is next generation sequencing or second-generation sequencing, including whole exome sequencing (WES). Our laboratory performed diagnostic WES on 1660 samples representing 825 index patients aged 0-84 years between 2014 and 2020. The cohort is comprised of consecutive patients with a rare disease referred for diagnostic WES with analysis of all known disease genes. The main referrals were paediatric, clinical genetic and adult neurology departments. Patients' symptoms were translated to terms in the Human Phenotype Ontology (HPO) system and each symptom assigned to a single top-level HPO term. Variants were classified according to ACMG-AMP guidelines. The diagnostic yield in this cohort was 33.7% with 278 patients receiving a genetic diagnosis. Patients with complex phenotypes with involvement of several organ systems were more likely to receive a genetic diagnosis. Higher diagnostic yields were seen for phenotypes including growth abnormalities, abnormalities of the ear or of the musculoskeletal system as well.
    Keywords:  Diagnostic Yield; Human; Medical Genetics; Whole Exome Sequencing
    DOI:  https://doi.org/10.1016/j.ejmg.2025.105043
  70. J Cell Sci. 2025 Sep 01. pii: jcs.264376. [Epub ahead of print]
    Histone deacetylase 7 mediates lipopolysaccharide-inducible mitochondrial fission in macrophages.
    Rishika Abrol, Syeda Farhana Afroz, James E B Curson, Karoline D Raven, Kaustav Das Gupta, Kimberley S Gunther, Alun Jones, Robert C Reid, Zherui Xiong, Jennifer H Gunter, Jessica A Engel, Christian R Engwerda, Antje Blumenthal, David P Fairlie, Robert G Parton, Steven Zuryn, Ronan Kapetanovic, Divya Ramnath, Matthew J Sweet.
      Histone deacetylase 7 (HDAC7) drives several immunometabolism-related processes in macrophages including lipopolysaccharide (LPS)-inducible glycolysis and inflammatory mediator production. Using an advanced biotin ligase TurboID system in human macrophages, we report 104 candidate HDAC7 interaction partners that may contribute to its immunometabolic functions. One such protein is the mitochondrial fission-promoting GTPase dynamin-related protein 1 (DRP1), which associates with HDAC7 in cells. Using gain- and loss-of-function genetic approaches, we show that HDAC7 promotes LPS-inducible mitochondrial fission in macrophages, as well as DRP1-dependent metabolic and inflammatory responses. HDAC7 enzymatic activity was dispensable for LPS-inducible fission, as previously reported for LPS-inducible glycolysis. However, a pharmacological inhibitor of HDAC7 attenuated fission in primary human and mouse macrophages, implicating its acetyl-lysine docking function in this response. HDAC7 thus drives inducible mitochondrial fission in macrophages. Small molecules targeting the acetyl-lysine docking function of HDAC7 may have applications in preventing pathological processes driven by dysregulated mitochondrial fission.
    Keywords:  Dynamin-related protein 1; Glycolysis; Histone deacetylase; Immunometabolism; Lysine deacetylase; Macrophages; Mitochondrial dynamics; Mitochondrial fission; Post-translational modification; Toll-like receptor
    DOI:  https://doi.org/10.1242/jcs.264376
  71. Nature. 2025 Sep 03.
    Spatial joint profiling of DNA methylome and transcriptome in tissues.
    Chin Nien Lee, Hongxiang Fu, Angelysia Cardilla, Wanding Zhou, Yanxiang Deng.
      The spatial resolution of omics analyses is fundamental to understanding tissue biology1-3. The capacity to spatially profile DNA methylation, which is a canonical epigenetic mark extensively implicated in transcriptional regulation4,5, is lacking. Here we introduce a method for whole-genome spatial co-profiling of DNA methylation and the transcriptome of the same tissue section at near single-cell resolution. Applying this technology to mouse embryogenesis and the postnatal mouse brain resulted in rich DNA-RNA bimodal tissue maps. These maps revealed the spatial context of known methylation biology and its interplay with gene expression. The concordance and distinction in spatial patterns of the two modalities highlighted a synergistic molecular definition of cell identity in spatial programming of mammalian development and brain function. By integrating spatial maps of mouse embryos at two different developmental stages, we reconstructed the dynamics that underlie mammalian embryogenesis for both the epigenome and transcriptome, revealing details of sequence-, cell-type- and region-specific methylation-mediated transcriptional regulation. This method extends the scope of spatial omics to include DNA cytosine methylation, enabling a more comprehensive understanding of tissue biology across development and disease.
    DOI:  https://doi.org/10.1038/s41586-025-09478-x
  72. Drug Discov Today. 2025 Aug 30. pii: S1359-6446(25)00175-8. [Epub ahead of print] 104462
    Addressing global regulatory challenges in rare disease drug development.
    Enrico Costa, Vijayalekshmi Ajith, Ahmed F Al Khaldi, Antonella Isgrò, Kerry J Lee, Riccardo Luigetti, Anna M G Pasmooij, Violeta Stoyanova-Beninska, Eveline Trachsel, Julienne Vaillancourt, Steffen Thirstrup.
      Despite progress in rare disease treatment, many conditions still lack therapeutic options. In addition to specific legislation promoting research and investment, regulators have supported early dialogs with stakeholders, optimized processes and expedited the approval of medicines in areas with unmet medical needs, such as rare diseases. However, several challenges persist, particularly in generating robust evidence. The introduced flexibility must be balanced with uncertainty management. Our analysis identifies several priorities: establishing a common global regulatory language; recognizing and validating surrogate endpoints; involving patients in defining meaningful outcomes; and leveraging digital health technologies and decentralized clinical trials. These tools offer opportunities to improve evidence generation and access, supporting more efficient and inclusive development processes where traditional approaches can be limited or unfeasible.
    Keywords:  Rare diseases; expedited pathways; medicines regulation; orphan drugs; unmet medical needs
    DOI:  https://doi.org/10.1016/j.drudis.2025.104462
  73. Mol Genet Metab. 2025 Aug 24. pii: S1096-7192(25)00218-5. [Epub ahead of print]146(1-2): 109227
    TPI deficiency: A case report and review of the literature.
    Aaron Williams, Monika Weisz-Hubshman, Vittoria Rossi, Emily Bland, Elizabeth Mizerik, Xi Luo, Paul R Hillman, Kathleen Shields, Fernando Scaglia.
      Triosephosphate isomerase (TPI) is a ubiquitously expressed enzyme encoded by the TPI1 gene. It catalyzes the interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in the fifth step of glycolysis. TPI deficiency (TPI Df; MIM# 615512) is an autosomal recessive disorder due to biallelic pathogenic variants in TPI1. In keeping with other glycolytic enzymopathies, severe hemolytic anemia is a common finding. Additionally, many individuals with TPI Df develop neuromuscular symptoms, which is unusual for a glycolytic enzymopathy. There appears to be a genotype-phenotype correlation between a TPI1 p.Glu105Asp/null genotype and a severe life-limiting neuromuscular phenotype. Tpi1-deficient mice with a p.Glu105Asp/null genotype recapitulate the life-limiting neuromuscular phenotype seen in humans, but the exact pathomechanism remains unclear. Here we describe a 2-month-old male proband who presented with failure to thrive, respiratory failure, seizures, and severe hemolytic anemia, who passed away at 3 months of age. Trio whole genome sequencing showed compound heterozygous variants with the common p.Glu105Asp variant in trans to a newly described likely pathogenic splice site c.324 + 1G > C variant, predicted to cause nonsense mediated decay. Here we review our case as well as the literature to hypothesize a mechanism by which TPI Df due to a p.Glu105Asp/null genotype causes severe disease. Given the overall fatal nature of this condition, novel therapeutic approaches are urgently needed. Currently, treatments are experimental. Ketogenic diet and triheptanoin were effective in treating seizures in a TPI mutant Drosophila, known as TPIsugarkill, although clinical data in humans is lacking. Additionally, bone marrow transplant has been shown to improve the hematologic phenotype in mice and has been done in an isolated number of patients. While there are no proven therapies available at this time, we hope this review will lead the discussion to consider future therapeutic options.
    Keywords:  Hemolytic anemia; Neurodegeneration; Seizures; Triosephosphate isomerase (TPI) deficiency
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109227
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