bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–08–03
forty-nine papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Three-donor IVF prevents mitochondrial disease.
  2. ATAD3 duplications bridge mitochondrial diseases and Aicardi-Goutières syndrome.
  3. Therapies for Mitochondrial Disease: Past, Present, and Future.
  4. The genotype/phenotype conundrum of inherited mitochondrial disorders: Insights from a survey of mtDNA mutations associated with Leigh syndrome in complex I.
  5. Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
  6. SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40.
  7. Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations.
  8. ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
  9. Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence.
  10. An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière's disease.
  11. Structural basis for promoter recognition and transcription factor binding and release in human mitochondria.
  12. Mitochondrial protein aggregates recruit key chaperones and are sequestered in a fission/fusion-dependent process.
  13. Oligomer-based functions of mitochondrial porin.
  14. Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.
  15. Csn5 Depletion Reverses Mitochondrial Defects in GCN5-Null Saccharomyces cerevisiae.
  16. Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases.
  17. The Mitochondrial Connection in Parkinson's Disease.
  18. Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.
  19. Causes of and Solutions to Mitochondrial Disorders: A Literature Review.
  20. AI-directed voxel extraction and volume EM identify intrusions as sites of mitochondrial contact.
  21. Pathogenic morphological signatures of perturbations in mitochondrial-related genes revealed by pooled imaging assay.
  22. Harnessing Mitochondrial Transplantation to Target Vascular Inflammation in Cardiovascular Health.
  23. Human mitochondrial RNA polymerase structures reveal transcription start site and slippage mechanism.
  24. Analysis of mitochondrial Complex I activity and ATP hydrolysis capacity of ATP synthase in developing rat brains using frozen tissues.
  25. Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.
  26. 2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction.
  27. In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
  28. Role of Prohibitins as Guardians of mitochondrial homeostasis.
  29. Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
  30. Deep Brain Stimulation in Leigh-Like Syndrome Due to DNM1 Pathogenic Variant.
  31. Cardiolipin acyl chain composition tailors the conformation of mammalian ATP synthase dimers.
  32. Rab14 promotes Parkin mediated mitophagy.
  33. Small Molecule Oxybutynin Rescues Proliferative Capacity of Complex III-Defective Muscle Progenitor Cells.
  34. Protocol for assessing mitochondrial cholesterol transport and protein molten globule state in steroidogenic and nonsteroidogenic systems.
  35. Editorial: Recent advances in mitochondrial dysfunction and therapeutics for neurodegeneration and aging.
  36. Nanotechnological Approaches for Mitochondrial Targeting in Neurodegenerative Diseases.
  37. Perspectives on mitochondrial dysfunction in the regeneration of aging skeletal muscle.
  38. Nitrosative stress affects mitochondrial respiratory chain complex II and complex IV assemblies in Saccharomyces cerevisiae: S-nitrosylation of complex II.
  39. mRNA trafficking directs cell-size-scaling of mitochondria distribution and function.
  40. Effects of pathological mutations on the CHCHD2 monomer structure: A study by AlphaFold3 linked to the generation of conformational ensembles.
  41. Mitochondrial Disorder: Maternally Inherited Diabetes and Deafness.
  42. Comprehensive Insights Into Mitophagy: Mechanisms, Disease Associations, and Therapeutic Implications.
  43. The impact of ERUPR on mitochondrial integrity mediated by PDK4.
  44. Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure.
  45. BAT mitochondria: whitening meets softening.
  46. Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
  47. The profound implications of mitochondrial myopathy on activities of daily living: an observational qualitative study of standardized structured and semi-structured patient interviews.
  48. Multi-omics Analysis Implicates Mitochondrial Complex Assembly Protein COX18 in Mitochondrial Signaling and Tumorigenesis across Cancers.
  49. Mitochondrial dysfunction-mediated metabolic remodeling of TCA cycle promotes Parkinson's disease through inhibition of H3K4me3 demethylation.
  1. Nat Med. 2025 Jul 30.
    Three-donor IVF prevents mitochondrial disease.
    Karen O'Leary.
      
    Keywords:  Genetics; Reproductive techniques ; Technology
    DOI:  https://doi.org/10.1038/d41591-025-00047-3
  2. Dev Med Child Neurol. 2025 Jul 25.
    ATAD3 duplications bridge mitochondrial diseases and Aicardi-Goutières syndrome.
      
    DOI:  https://doi.org/10.1111/dmcn.16446
  3. J Inherit Metab Dis. 2025 Jul;48(4): e70065
    Therapies for Mitochondrial Disease: Past, Present, and Future.
    Megan Ball, Nicole J van Bergen, Alison G Compton, David R Thorburn, Shamima Rahman, John Christodoulou.
      Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA-encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre-molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA-based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.
    Keywords:  clinical trials; gene therapy; mitochondrial disease; small molecule therapy; treatment
    DOI:  https://doi.org/10.1002/jimd.70065
  4. Biochim Biophys Acta Mol Basis Dis. 2025 Jul 25. pii: S0925-4439(25)00344-8. [Epub ahead of print] 167996
    The genotype/phenotype conundrum of inherited mitochondrial disorders: Insights from a survey of mtDNA mutations associated with Leigh syndrome in complex I.
    Zeinab Alsadat Ahmadi, Ulrich Brandt.
      Mitochondrial disorders encompass a broad spectrum of genetic disorders impairing mitochondrial function. Considerable advancements have been made in the diagnosis and clinical management of these primary mitochondrial diseases. However, diagnosis and treatment have remained largely empirical, because the pathogenic mechanisms are still poorly understood by which any of the numerous known mutations lead to a specific phenotype in patients. To make inroads into this central challenge of mitochondrial medicine, we performed a focused survey of a cohort of published cases of Leigh syndrome caused by point mutations in subunits of respiratory chain complex I encoded by the mitochondrial genome. Leigh syndrome is one of the most severe mitochondrial disorders and is characterized by clinical and genetic manifestations predominantly affecting the central nervous system and the brain. We found that even basic correlations between a specific molecular defect and disease severity and progression are often obscured by the heterogeneity of the available diagnostic data. Still, our analysis showed that in order to understand the specific pathogenic impact it entails, for each mutation one has to carefully differentiate which functional domain of complex I is actually affected. It seems evident that much more comprehensive and differentiated studies of representative mutations as well as far more complete and standardized diagnostic data from patients should be obtained. This will be prerequisite for understanding and discriminating pathogenic mechanisms as a way to develop effective rational therapies for Leigh syndrome and other mitochondrial disorders.
    Keywords:  Complex I; Leigh syndrome; Mitochondrial disease; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167996
  5. Commun Biol. 2025 Jul 29. 8(1): 1122
    Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
    Pin-Chao Liao, Tzu-Ying Lin, Catherine A Tsang, Chen-Jing Huang, Katherine Filpo, Istvan Boldogh, Liza A Pon.
      The mitochondria-associated degradation pathway (MAD) mediates removal and elimination of damaged, unfolded mitochondrial proteins by the ubiquitin-proteasome system (UPS). Previous studies revealed that MAD is critical for mitochondrial protein quality control and that MAD function extends beyond mitochondrial outer membrane (MOM) to proteins within the organelle. Here, we reconstitute retrotranslocation of MAD substrates from the mitochondrial matrix across mitochondrial inner and outer membranes in cell-free systems. This retrotranslocation is ATP-dependent but membrane potential-independent. We also identify a role for the TOM complex, the protein import channel in the MOM, in this process. Inhibition of protein translocation across the Tom40p channel reduces the retrotranslocation of MAD substrates. Our studies support the model that the TOM complex is a bidirectional protein channel in the MOM: it mediates retrotranslocation of damaged mitochondrial proteins across the MOM in the MAD pathway for mitochondrial protein quality control in addition to its function in import of proteins into the organelle.
    DOI:  https://doi.org/10.1038/s42003-025-08549-z
  6. Adv Sci (Weinh). 2025 Jul 29. e03408
    SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40.
    Liubing Hu, Jianshuang Li, Haolin Guo, Lei Su, Peina Dong, Juan Huang, Yanyan Liu, Xinjie Liu, Zhenhuan Luo, Wei Xiong, Zhenyu Ju, Qinghua Zhou, Hao Wang, Wenjun Wang.
      SUMOylation, a reversible post-translational modification, regulates various mitochondrial processes, including biogenesis, dynamics, mitophagy, and the mitochondrial unfolded protein response. Although SUMOylation is shown to be triggered by mitochondrial protein import failure in yeast, its impact on mammalian mitochondrial protein import remains unclear. Here, it is demonstrated that SENP6 knockdown-induced SUMOylation causes loss of mitochondrial proteostasis, which impairs mitochondrial morphology and function. Mechanistically, SENP6 knockdown dampens TOM complex assembly by SUMOylating TOM40, thereby hindering the mitochondrial protein import process, including TOM40 precursor, and ultimately disrupts mitochondrial homeostasis. Additionally, it is observed that CCCP treatment resulted in a decrease of SENP6 within mitochondria fraction, accompanied by increased TOM40 SUMOylation in the brains of 3×Tg-Alzheimer's disease (AD) mice or Aβ1-42 peptide-stimulated cells. Collectively, the results suggest that Aβ1-42 accumulation may enhance TOM40 SUMOylation by suppressing SENP6, thereby impairing mitochondrial homeostasis through protein import failure and potentially contributing to the pathological process of AD. This study elucidates the role of TOM40 SUMOylation/deSUMOylation in regulating the mitochondrial import process during mitochondrial stress.
    Keywords:  Mitochondrial protein import; SENP6; SUMOylation; TOM complex; TOM40
    DOI:  https://doi.org/10.1002/advs.202503408
  7. Mol Genet Metab. 2025 Jul 24. pii: S1096-7192(25)00188-X. [Epub ahead of print]146(1-2): 109197
    Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations.
    Graeme Preston, Neil Jacob, Ibrahim Elsharkawi, Eva Morava, Tamas Kozicz.
      Primary mitochondrial diseases are a heterogeneous group of disorders caused by impaired mitochondrial respiratory chain function due to pathogenic variants in nuclear or mitochondrial DNA. These variants disrupt enzyme activity, membrane integrity, or mitochondrial genome maintenance. Phosphodiesterase type 5 (PDE5) inhibitors have recently emerged as potential modulators of mitochondrial function. Prompted by self-reported symptom improvement in an individual with mitochondrial disease taking tadalafil, we investigated the effects of PDE5 inhibitors in this context. Using high-resolution respirometry, we analyzed mitochondrial function in fibroblasts from six individuals with primary mitochondrial disease following treatment with sildenafil or tadalafil. We hypothesized that PDE5 inhibition would improve mitochondrial respiratory function and alleviate clinical symptoms. Clinical outcomes were also assessed in three individuals receiving off-label tadalafil therapy. Patient-derived fibroblasts showed elevated basal and non-mitochondrial respiration, along with increased glycolytic flux. Treatment with PDE5 inhibitors reduced proton leak-associated OCR, improved coupling efficiency, and normalized metabolic profiles. Off-label tadalafil use was associated with acute, dose-dependent, and sustained symptom improvements in all three individuals, with no adverse effects reported. In MELAS fibroblasts responses varied with m.3243 A > G heteroplasmy levels. These findings suggest PDE5 inhibitors may offer safe, accessible, and personalized therapeutic options for mitochondrial diseases, particularly those involving mitochondrial DNA pathogenic variants.
    Keywords:  Coupling efficiency; Hypermetabolism-like phenotype; Mitochondria; PDE5; Proton leak; Sildenafil; Tadalafil
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109197
  8. Cell Death Discov. 2025 Jul 29. 11(1): 349
    ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
    Mudassar Ali, Anjali, Koyeli Mapa.
      Mitochondria, the double membrane-bound organelles of endosymbiotic origin, are crucial centers for cellular energy production and several essential metabolic pathways. Recent studies reveal that mitochondria become dysfunctional following numerous cellular stresses, and during pathologies, demanding an extensive investigation of mitochondrial turnover mechanisms. Apart from the specific response pathways to tackle different stresses, mitophagy, or degradation of mitochondria by autophagy, is a critical quality control mechanism that clears irreversibly damaged mitochondria. Mitophagy is majorly executed either by receptor-mediated or PINK1-Parkin-dependent pathways. Here, we show that the human orthologue of yeast Vms1, ANKZF1, participates in PINK1-Parkin-mediated mitophagy. We show that ANKZF1 is extensively recruited to damaged mitochondria along with Parkin during mitochondrial proteotoxic stress induced by the expression of a single misfolded/aggregated protein or during uncoupler-induced membrane depolarization. Importantly, ANKZF1 recruitment to damaged mitochondria is significantly enhanced in the presence of Parkin, and ANKZF1 physically interacts with Parkin and LC3 during mitochondrial proteotoxic or depolarization stress. ANKZF1 harbors six putative LC3-interacting regions (LIRs), LIR4 present at residues 333-336, is particularly important for ANKZF1-LC3 interaction. Furthermore, we show that ANKZF1 knockout cells are compromised in clearing stress-damaged mitochondria by mitophagy, indicating an important role of ANKZF1 in mitochondrial turnover during stress. In summary, we show a new role of ANKZF1 in eliminating the stress-damaged mitochondria, reiterating the mito-protective role of Vms1/ANKZF1 during mitochondrial stresses. PINK1/Parkin signaling leads to polyubiquitination of outer mitochondrial membrane (OMM) proteins on stressed mitochondria. ANKZF1 functions as an adaptor protein, binding to polyubiquitinated OMM proteins via UBA domain and autophagosome receptor LC3 via LIR motif.
    DOI:  https://doi.org/10.1038/s41420-025-02638-y
  9. Curr Issues Mol Biol. 2025 Jul 01. pii: 504. [Epub ahead of print]47(7):
    Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence.
    Anna Makridou, Evangelie Sintou, Sofia Chatzianagnosti, Iasonas Dermitzakis, Sofia Gargani, Maria Eleni Manthou, Paschalis Theotokis.
      Mitochondrial dysfunction is a key driver of neurological disorders due to the brain's high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfunction spans a broad clinical spectrum, from early-onset encephalopathies to adult neurodegeneration, with phenotypic and genetic variability necessitating integrated models of mitochondrial neuropathology. Mutations in nuclear or mitochondrial DNA disrupt energy production, induce oxidative stress, impair mitophagy and biogenesis, and lead to neuronal degeneration and apoptosis. This narrative review provides a structured synthesis of current knowledge by classifying mitochondrial-related neurological disorders according to disrupted biochemical pathways, in order to clarify links between genetic mutations, metabolic impairments, and clinical phenotypes. More specifically, a pathway-oriented framework was adopted that organizes disorders based on the primary mitochondrial processes affected: oxidative phosphorylation (OXPHOS), pyruvate metabolism, fatty acid β-oxidation, amino acid metabolism, phospholipid remodeling, multi-system interactions, and neurodegeneration with brain iron accumulation. Genetic, clinical and molecular data were analyzed to elucidate shared and distinct pathophysiological features. A comprehensive table synthesizes genetic causes, inheritance patterns, and neurological manifestations across disorders. This approach offers a conceptual framework that connects molecular findings to clinical practice, supporting more precise diagnostic strategies and the development of targeted therapies. Advances in whole-exome sequencing, pharmacogenomic profiling, mitochondrial gene editing, metabolic reprogramming, and replacement therapy-promise individualized therapeutic approaches, although hurdles including heteroplasmy, tissue specificity, and delivery challenges must be overcome. Ongoing molecular research is essential for translating these advances into improved patient care and quality of life.
    Keywords:  metabolic pathway disruption; mitochondrial diseases; mitochondrial dysfunction in neurodegeneration; mitochondrial genetics; mitochondrial replacement therapy; neurological manifestations; precision medicine
    DOI:  https://doi.org/10.3390/cimb47070504
  10. Cell Rep. 2025 Jul 25. pii: S2211-1247(25)00840-X. [Epub ahead of print]44(8): 116069
    An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière's disease.
    Marcell Harhai, Mads M Foged, Christine Zarges, Juan C Landoni, Sylvain Chollet, Michele Simonelli, Emeline Recazens, Miriam Lisci, Nora Laban, Suliana Manley, Jan Riemer, Jose Antonio Lopez-Escamez, Anna Lysakowski, Alexis A Jourdain.
      Mitochondrial disorders (MDs) are among the most common inborn errors of metabolism, and dysfunction in oxidative phosphorylation (OXPHOS) is a hallmark. Their complex mode of inheritance and diverse clinical presentations render the diagnosis of MDs challenging, and, to date, most lack a cure. Here, we build on previous efforts to identify genes necessary for OXPHOS and report a highly complementary galactose-sensitized CRISPR-Cas9 "growth" screen, presenting an updated inventory of 481 OXPHOS genes, including 157 linked to MDs. We further focus on FAM136A, a gene associated with Ménière's disease, and demonstrate that it supports intermembrane space protein homeostasis and OXPHOS in cell lines, mice, and patients. Our study identifies a mitochondrial basis in familial Ménière's disease, provides a comprehensive resource of OXPHOS-related genes, and sheds light on the pathways involved in MDs, with the potential to guide future diagnostics and treatments for MDs.
    Keywords:  CLPB; CP: Metabolism; FAM136A; HAX1; Ménière; OXPHOS; functional genomics; intermembrane space; mitochondria; mitochondrial disease; proteostasis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116069
  11. Mol Cell. 2025 Jul 22. pii: S1097-2765(25)00545-3. [Epub ahead of print]
    Structural basis for promoter recognition and transcription factor binding and release in human mitochondria.
    Karl Herbine, Ashok R Nayak, Angelica Zamudio-Ochoa, Dmitry Temiakov.
      Transcription in human mitochondria is driven by a core apparatus consisting of a Pol A family RNA polymerase (mtRNAP), the initiation factors TFAM and TFB2M, and the elongation factor TEFM. While earlier structures of initiation and elongation complexes provided valuable snapshots, they represent isolated stages of a highly dynamic and multistep process. Critical aspects of mitochondrial transcription-such as DNA recognition and melting, promoter escape, and the release of initiation factors-remain poorly understood. Here, we present a series of cryoelectron microscopy (cryo-EM) structures that capture the transcription complex as it transitions from the initial open promoter complex to the processive elongation complex through intermediate stages. Our data reveal new, previously unidentified determinants of promoter specificity: the sequential disengagement of mtRNAP from TFAM and the promoter, the release of TFB2M, and the recruitment of TEFM. Together, these findings provide a detailed molecular mechanism underlying transcription in human mitochondria.
    Keywords:  POLRMT; RNA polymerase; TEFM; TFAM; TFB2M; mitochondrial transcription; mtRNAP; promoter; transcription-replication switch
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.016
  12. J Cell Sci. 2025 Jul 30. pii: jcs.263680. [Epub ahead of print]
    Mitochondrial protein aggregates recruit key chaperones and are sequestered in a fission/fusion-dependent process.
    Laura Ruland, Marc Sylvester, Lydia Maus, Hannes Beckert, Wolfgang Voos.
      The potential proteotoxicity of mitochondrial aggregates in yeast cells is reduced by a sequestration of affected polypeptides into a mitochondrial protein quality control compartment (IMiQ). Based on the expression of an aggregation-prone protein in the mitochondrial matrix, we determined the effect of organelle dynamics on aggregate sequestration. Fusion deficient cells were unable to accumulate the aggregates in the IMiQ, resulting in a stress-sensitive phenotype. In contrast, fission deficient cells could not separate the aggregate from the mitochondrial network. In these mitochondria, the aggregates were neutralized by the formation of a shell formed by mitochondrial chaperones. We also performed quantitative mass spectrometry to analyse the mitochondrial proteome and the extent of co-aggregation of mitochondrial proteins. While only minor changes of the total proteome were detected in response to aggregate accumulation, we found a recruitment of proteins of the respiratory chain complexes and of the protein quality control system (PQC). In particular members of the Hsp70 chaperone family were prominently associated with the aggregate. We conclude that this chaperone-dependent neutralization prevents a major co-aggregation of endogenous mitochondrial proteins.
    Keywords:  Cell biology; Chaperone; Hsp70; Mitochondria; Protein aggregation; Proteostasis; Yeast
    DOI:  https://doi.org/10.1242/jcs.263680
  13. Nat Commun. 2025 Jul 25. 16(1): 6854
    Oligomer-based functions of mitochondrial porin.
    Hironori Takeda, Saori Shinoda, Chiho Goto, Akihisa Tsutsumi, Haruka Sakaue, Chunming Zhang, Takashi Hirashima, Yuta Konishi, Haruka Ono, Yu Yamamori, Kentaro Tomii, Hiroya Shiino, Yasushi Tamura, Solène Zuttion, Bruno Senger, Sylvie Friant, Hubert D Becker, Yuhei Araiso, Nanako Kobayashi, Noriyuki Kodera, Masahide Kikkawa, Toshiya Endo.
      Porin, or the voltage-dependent anion channel (VDAC), is a primary β-barrel channel in the mitochondrial outer membrane. It transports small metabolites and ions through its β-barrel pore and plays key roles in apoptosis and inflammatory response. Here we report the cryo-electron microscopy structure of yeast porin (Por1) in its hexameric form at 3.2 Å resolution. This structure allows us to introduce various mutations at the protomer interfaces, uncovering three critical functions of Por1 assembly beyond transport. Por1 binds unassembled Tom22, a subunit of the mitochondrial protein import gate (the TOM complex), to facilitate protein import into the intermembrane space, maintains proper mitochondrial lipid composition in the outer membrane through lipid scramblase activity, and contributes to the retention and regulated loss of mitochondrial DNA, in cooperation with nucleases identified through screening enabled by the obtained Por1 mutant.
    DOI:  https://doi.org/10.1038/s41467-025-62021-4
  14. Alzheimers Dement. 2025 Aug;21(8): e70519
    Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.
    Huanyao Gao, Kate Jensen, Jarred Nesbitt, Mark Ostroot, Gregory A Cary, Jesse Wiley, Sergey Trushin, Jens O Watzlawik, Wolfdieter Springer, Alexander Galkin, Priyanka Baloni, Cory Funk, Eugenia Trushina.
       INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4-/- mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2.
    METHODS: Cortico-hippocampal tissue from Ndufs4-/- and wild-type mice was subjected to transcriptomic analysis, followed by cross-species comparisons to human late-onset AD and familial AD mouse datasets.
    RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4-/- mice showing greater compensatory adaptations and treatment responses.
    DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest important considerations for personalized therapeutics.
    HIGHLIGHTS: Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks. A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late-onset Alsheimer's disease (AD) patients and familial mouse models of AD. Pharmacological targeting of mtCI mediates neuroprotective signaling. Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria-targeted therapeutics. Mitochondria play a key role in AD development and treatment.
    Keywords:  Alzheimer's disease; Ndufs4 knockout mice; biological domains; mitochondrial complex I; mitochondria‐targeted therapeutics; mitophagy; sex‐specific differences; sex‐specific response; transcriptomic analysis; ubiquitin; weak complex I inhibitors
    DOI:  https://doi.org/10.1002/alz.70519
  15. Int J Mol Sci. 2025 Jul 18. pii: 6916. [Epub ahead of print]26(14):
    Csn5 Depletion Reverses Mitochondrial Defects in GCN5-Null Saccharomyces cerevisiae.
    Angela Cirigliano, Emily Schifano, Alessandra Ricelli, Michele M Bianchi, Elah Pick, Teresa Rinaldi, Arianna Montanari.
      In this study, we investigated the mitochondrial defects resulting from the deletion of GCN5, a lysine-acetyltransferase, in the yeast Saccharomyces cerevisiae. Gcn5 serves as the catalytic subunit of the SAGA acetylation complex and functions as an epigenetic regulator, primarily acetylating N-terminal lysine residues on histones H2B and H3 to modulate gene expression. The loss of GCN5 leads to mitochondrial abnormalities, including defects in mitochondrial morphology, a reduced mitochondrial DNA copy number, and defective mitochondrial inheritance due to the depolarization of actin filaments. These defects collectively trigger the activation of the mitophagy pathway. Interestingly, deleting CSN5, which encodes to Csn5/Rri1 (Csn5), the catalytic subunit of the COP9 signalosome complex, rescues the mitochondrial phenotypes observed in the gcn5Δ strain. Furthermore, these defects are suppressed by exogenous ergosterol supplementation, suggesting a link between the rescue effect mediated by CSN5 deletion and the regulatory role of Csn5 in the ergosterol biosynthetic pathway.
    Keywords:  Saccharomyces cerevisiae; epigenetic regulation; ergosterol; lysine-acetyltransferase; mitochondria; ubiquitin–proteasome pathway
    DOI:  https://doi.org/10.3390/ijms26146916
  16. Neurotherapeutics. 2025 Jul 28. pii: S1878-7479(25)00186-2. [Epub ahead of print] e00708
    Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases.
    Tomohiro Nakamura, Anamika Sharma, Stuart A Lipton.
      Neuronal synaptic activity relies heavily on mitochondrial energy production, as synaptic transmission requires substantial ATP. Accordingly, mitochondrial dysfunction represents a key underlying factor in synaptic loss that strongly correlates with cognitive decline in Alzheimer's disease and other neurocognitive disorders. Increasing evidence suggests that elevated nitro-oxidative stress impairs mitochondrial bioenergetic function, leading to synaptic degeneration. In this review, we highlight the pathophysiological roles of nitric oxide (NO)-dependent posttranslational modifications (PTMs), particularly S-nitrosylation of cysteine residues, and their impact on mitochondrial metabolism. We focus on the pathological S-nitrosylation of tricarboxylic acid cycle enzymes, particularly α-ketoglutarate dehydrogenase, as well as electron transport chain proteins. This aberrant PTM disrupts mitochondrial energy production. Additionally, we discuss the consequences of aberrant protein S-nitrosylation on mitochondrial dynamics and mitophagy, further contributing to mitochondrial dysfunction and synapse loss. Finally, we examine current strategies to ameliorate S-nitrosylation-mediated mitochondrial dysfunction in preclinical models of neurodegenerative diseases and explore future directions for developing neurotherapeutics aimed at restoring mitochondrial metabolism in the context of nitro-oxidative stress.
    Keywords:  Cognitive decline; Protein S-nitrosylation; Synapse loss; TCA cycle; α-Ketoglutarate dehydrogenase
    DOI:  https://doi.org/10.1016/j.neurot.2025.e00708
  17. Cold Spring Harb Perspect Med. 2025 Jul 28. pii: a041891. [Epub ahead of print]
    The Mitochondrial Connection in Parkinson's Disease.
    Eric Schon, Diana Matheoud, Serge Przedborski.
      Mitochondria are highly dynamic organelles with complex structural features that perform several essential cellular functions, including energy production by oxidative phosphorylation, regulation of calcium and lipid homeostasis, and control of programmed cell death. Given their critical role, alterations in mitochondrial biology can lead to neuronal dysfunction and death. Defects in mitochondrial respiration, especially in oxidative energy production, have long been thought to be implicated in the etiology and pathogenesis of Parkinson's disease. However, given the multifaceted roles of mitochondria in health and diseases, the putative role of mitochondria in Parkinson's disease likely extends well beyond defective respiration. As such, mitochondrial dysfunction represents a promising target for disease-modifying therapies in Parkinson's disease and related conditions.
    DOI:  https://doi.org/10.1101/cshperspect.a041891
  18. Blood. 2025 Aug 01. pii: blood.2024028079. [Epub ahead of print]
    Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.
    Abhishek K Singh, Angelo D'Alessandro, Ashley Wellendorf, Daniel Gonzalez-Nieto, Matthew Kofron, Monika Dzieciatkowska, Leo Mejia, Luis Barrio, Marie-Dominique Filippi, Jose A Cancelas.
      Hematopoietic stem cells (HSC) exhibit a distinctive antioxidant profile during steady-state and stress hematopoiesis. HSC and multipotential progenitors (HSC/MPP) are metabolically coupled to bone marrow (BM) mesenchymal stromal cells through mitochondrial transfer, a process dependent on hematopoietic connexin 43 (Cx43) and low AMP-activated protein kinase (AMPK) activity. However, the mechanism by which Cx43 preserves mitochondrial functionality in HSC remains elusive. Here, through integrated transcriptomic, proteomic, metabolomic, phenotypic, and functional analyses of HSC and their isolated mitochondria, we identified that Cx43 is present on inner and outer mitochondrial membranes of HSC/MPP, where it primarily regulates mitochondrial metabolism and ATP synthesis by preserving the mitochondrial cristae, activation of mitochondrial AMPK and 2-oxoglutarate dehydrogenase (OGDH)-a rate liming enzyme in TCA cycle and electron transfer chain. During replicative stress, Cx43 deficient HSC/MPP fail to adapt metabolically, accumulate mitochondrial Ca2+, increase mitochondrial AMPK activity, mitochondrial fission, mitophagy, and production of reactive oxygen species, thereby limiting HSC/MPP regeneration potential. Disruption of hyper mitochondrial fragmentation and mitophagy by Drp1 dominant negative mutant (Drp1K38A) or restoration of mitochondrial function through ex vivo heteroplasmy prevent the harmful effects of Cx43 deficiency on mitochondrial metabolism and restore HSC activity in serial transplantation experiments. Re-expression analysis of Cx43 structure function mutants indicate that Cx43 hemichannels are sufficient to reset HSC mitochondrial metabolism, dynamics, Ca2+ levels, and regeneration capacity. This report defines the cell-autonomous mechanism of action behind the role of Cx43 in HSC activity and opens a venue to translational applications in transplantation.
    DOI:  https://doi.org/10.1182/blood.2024028079
  19. Int J Mol Sci. 2025 Jul 11. pii: 6645. [Epub ahead of print]26(14):
    Causes of and Solutions to Mitochondrial Disorders: A Literature Review.
    Vera Belousova, Irina Ignatko, Irina Bogomazova, Elena Sosnova, Svetlana Pesegova, Anastasia Samusevich, Evdokiya Zarova, Madina Kardanova, Oxana Skorobogatova, Anna Maltseva.
      Mitochondria are currently of great interest to scientists. The role of mitochondrial DNA (mtDNA) mutations has been proven in the genesis of more than 200 pathologies, which are called mitochondrial disorders. Therefore, the study of mitochondria and mitochondrial DNA is of great interest not only for understanding cell biology but also for the treatment and prevention of many mitochondria-related pathologies. There are two main trends of mitochondrial therapy: mitochondrial replacement therapy (MRT) and mitochondrial transplantation therapy (MTT). Also, there are two main categories of MRT based on the source of mitochondria. The heterologous approach includes the following methods: pronuclear transfer technique (PNT), maternal spindle transfer (MST), Polar body genome transfer (PBT) and germinal vesicle transfer (GVT). An alternative approach is the autologous method. One promising autologous technique was the autologous germline mitochondrial energy transfer (AUGMENT), which involved isolating oogonial precursor cells from the patient, extracting their mitochondria, and then injecting them during ICSI. Transmission of defective mtDNA to the next generation can also be prevented by using these approaches. The development of a healthy child, free from genetic disorders, and the prevention of the occurrence of lethal mitochondrial disorders are the main tasks of this method. However, a number of moral, social, and cultural objections have restricted its exploration, since humanity first encountered the appearance of a three-parent baby. Therefore, this review summarizes the causes of mitochondrial diseases, the various methods involved in MRT and the results of their application. In addition, a new technology, mitochondrial transplantation therapy (MTT), is currently being actively studied. MTT is an innovative approach that involves the introduction of healthy mitochondria into damaged tissues, leading to the replacement of defective mitochondria and the restoration of their function. This technology is being actively studied in animals, but there are also reports of its use in humans. A bibliographic review in PubMed and Web of Science databases and a search for relevant clinical trials and news articles were performed. A total of 81 publications were selected for analysis. Methods of MRT procedures were reviewed, their risks described, and the results of their use presented. Results of animal studies of the MTT procedure and attempts to apply this therapy in humans were reviewed. MRT is an effective way to minimize the risk of transmission of mtDNA-related diseases, but it does not eliminate it completely. There is a need for global legal regulation of MRT. MTT is a new and promising method of treating damaged tissues by injecting the body's own mitochondria. The considered methods are extremely good in theory, but their clinical application in humans and the success of such therapy remain a question for further study.
    Keywords:  mitochondrial DNA; mitochondrial disorders; mitochondrial replacement therapy; mitochondrial transplantation therapy; review; three-parent baby
    DOI:  https://doi.org/10.3390/ijms26146645
  20. J Cell Biol. 2025 Oct 06. pii: e202411138. [Epub ahead of print]224(10):
    AI-directed voxel extraction and volume EM identify intrusions as sites of mitochondrial contact.
    Benjamin S Padman, Runa S J Lindblom, Michael Lazarou.
      Membrane contact sites (MCSs) establish organelle interactomes in cells to enable communication and exchange of materials. Volume EM (vEM) is ideally suited for MCS analyses, but semantic segmentation of large vEM datasets remains challenging. Recent adoption of artificial intelligence (AI) for segmentation has greatly enhanced our analysis capabilities. However, we show that organelle boundaries, which are important for defining MCS, are the least confident predictions made by AI. We outline a segmentation strategy termed AI-directed voxel extraction (AIVE), which refines segmentation results and boundary predictions derived from any AI-based method by combining those results with electron signal values. We demonstrate the precision conferred by AIVE by applying it to the quantitative analysis of organelle interactomes from multiple FIB-SEM datasets. Through AIVE, we discover a previously unknown category of mitochondrial contact that we term the mitochondrial intrusion. We hypothesize that intrusions serve as anchors that stabilize MCS and promote organelle communication.
    DOI:  https://doi.org/10.1083/jcb.202411138
  21. Npj Imaging. 2025 Aug 01. 3(1): 35
    Pathogenic morphological signatures of perturbations in mitochondrial-related genes revealed by pooled imaging assay.
    Colin Kremitzki, Jason Waligorski, Graham Bachman, Lina Mohammed Ali, John Bramley, Maria Vakaki, Vinay Chandrasekaran, Purva Patel, Dhruv Mathur, Paul Hime, Robi Mitra, Jeff Milbrandt, William Buchser.
      Mutations in mitochondrial-related genes underlie numerous neurodegenerative diseases, yet the significance of most variants remains uncertain concerning disease phenotypes. Several thousand genes have been shown to regulate mitochondria in eukaryotic cells, but which of these genes are necessary for proper mitochondrial function and dynamics? We investigated the degree of morphological disruptions in mitochondrial gene-silenced cells to understand the genetic contribution to the expected mitochondrial phenotype and to identify potentially pathogenic variants like pathogenic mutations in MFN2. We analyzed 5835 gRNAs in a high dimensional phenotypic dataset produced by the image-based pooled analysis platform Raft-Seq. Using the MFN2-mutant cell phenotype, we identified several genes, including TMEM11, TIMM8A, NDUFAF4, NDUFAF7, and NDUFS5 (NADH ubiquinone oxidoreductase-related genes), as crucial for normal mitochondrial dynamics in human U2OS cells. Additionally, we found several missense and UTR variants within the genes SLC25A19 and ATAD3A as drivers of mitochondrial aggregation. By examining multiple features instead of a single readout, this analysis was powered to detect genes which had morphological 'signatures' aligned with MFN2-mutant phenotypes. Reanalysis with anomaly detection revealed other critical genes, including APOOL, MCEE, NIT, PHB, and SLC16A7, which perturb mitochondrial network morphology in a manner divergent from MFN2. These studies show causal links between gene knockouts and gene-specific variants into the assembly or maintenance of mitochondrial dynamics and can hopefully lead to a better understanding of mitochondrial related diseases.
    DOI:  https://doi.org/10.1038/s44303-025-00097-9
  22. JACC Basic Transl Sci. 2025 Jul 25. pii: S2452-302X(25)00283-9. [Epub ahead of print]10(8): 101331
    Harnessing Mitochondrial Transplantation to Target Vascular Inflammation in Cardiovascular Health.
    Natalia Matiuto, Brandon Applewhite, Nicola Habash, Ana Martins, Bowen Wang, Bin Jiang.
      Mitochondrial dysfunction is a key contributor to vascular inflammation in many cardiovascular diseases. This review explores mitochondrial transplantation as a promising strategy for addressing mitochondrial dysfunction and vascular inflammation. We discuss mitochondrial dysfunction across different vascular cell types and current clinical management strategies, highlighting the need for novel approaches that directly target mitochondrial health. We also present recent progress in mitochondrial transplantation across cardiac, neurovascular, and peripheral vascular applications in preclinical settings, as well as ongoing clinical trials. Important technical considerations, such as mitochondria sourcing, delivery routes, and storage, are discussed to facilitate future translation. By reinstating mitochondrial health and hence mitigating vascular inflammation, mitochondrial transplantation holds the potential to provide novel, targeted therapies for cardiovascular diseases, ultimately improving patient outcomes, reducing disease progression, and addressing unmet medical needs in vascular health. The translation of this technology into clinical practice could offer significant advances in the treatment of a wide range of cardiovascular conditions.
    Keywords:  endothelial dysfunction; mitochondrial dysfunction; mitochondrial transfer; oxidative stress; vascular inflammation
    DOI:  https://doi.org/10.1016/j.jacbts.2025.101331
  23. Mol Cell. 2025 Jul 22. pii: S1097-2765(25)00581-7. [Epub ahead of print]
    Human mitochondrial RNA polymerase structures reveal transcription start site and slippage mechanism.
    Jiayu Shen, Quinten Goovaerts, Yogeeshwar Ajjugal, Brent De Wijngaert, Kalyan Das, Smita S Patel.
      Transcription of the human mitochondrial DNA is initiated by POLRMT and initiation factors mitochondrial transcription factor A (TFAM) and mitochondrial transcription factor B2 (TFB2M). We present cryo-electron microscopy (cryo-EM) structures of three transcription initiation intermediates (pre-catalytic IC3 [pre-IC3], slipped-IC3, and slipped pre-IC4) catalyzing RNA synthesis by normal and slippage pathways with fully resolved transcription bubbles and RNA transcripts starting from the +1 or -1 position. The structural and biochemical studies reveal mechanisms of promoter melting, start site selection, and slippage synthesis. Promoter melting begins at -4 with base-specific interactions of template -4 and -3 guanines with POLRMT and non-template -1 adenine with TFB2M. The NT-stabilizing loop (K153LDPRSGGVIKPP165) and Y209 of TFB2M and W1026 of POLRMT interact with the non-template strand to guide initiation from the +1 start site. The -1 position is not an alternative start site but supports slippage initiation by base-pairing with a slipped or rebound 2-nt RNA. Cryo-EM resolved additional apo and dimeric complexes whose populations may regulate transcription initiation.
    Keywords:  POLRMT; TFAM; TFB2M; abortive synthesis; cryo-EM structure; light strand promoter; promoter melting; slippage synthesis; start site selection; transcription initiation
    DOI:  https://doi.org/10.1016/j.molcel.2025.07.002
  24. MicroPubl Biol. 2025 ;2025
    Analysis of mitochondrial Complex I activity and ATP hydrolysis capacity of ATP synthase in developing rat brains using frozen tissues.
    Pamela J Yao, Rachel Munk, Myriam Gorospe, Dimitrios Kapogiannis.
      In a previous study, we analyzed the activity of the mitochondrial respiratory Complex II, Complex IV and ATP synthase in frozen tissues of postnatal rat brains (Yao et al., 2023). In this study, we expand our capability of assessing mitochondrial functions using frozen tissue samples. We optimize protocols for measuring the activity of Complex I, and ATP hydrolysis capacity - known as the reverse action - of ATP synthase. We show that the specific functions of these mitochondrial proteins increase linearly as the brain develops.
    DOI:  https://doi.org/10.17912/micropub.biology.001641
  25. Cell Rep Med. 2025 Jul 16. pii: S2666-3791(25)00321-0. [Epub ahead of print] 102248
    Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.
    Andre Djalalvandi, Keisuke Takeda, Francesca Grespi, Hualin Fan, Tiago Branco Fonseca, Leonardo Nogara, Saman Sharifi, Carlotta Barison, Martina Semenzato, Akiko Omori, Raffaele Cerutti, Davide Steffan, Lorenza Tsansizi, Valeria Balmaceda, Lukas Alan, Camilla Bean, Bert Blaauw, Carlo Viscomi, Luca Scorrano.
      Alterations in mitochondrial ultrastructure and reduced levels of the crista-shaping protein Opa1 are key features of mitochondrial myopathies and aging. We identify and characterize a biological therapy that improves mitochondrial and disuse myopathy models by boosting Opa1 levels. In silico analysis identifies microRNAs (miRNAs) 128-3p and 148/152-3p family as conserved modulators of OPA1 transcription and elevated in various muscle disorders. These miRNAs target the 3' UTR of murine and human OPA1, reducing its mRNA and protein levels, causing mitochondrial fragmentation and crista disorganization. Genetic experiments confirm that their mitochondrial effects rely on 3' UTR binding. In mitochondrial disease patient cells and murine models, elevated OPA1-specific miRNA levels are reduced by antagonistic miRNAs (Opantimirs), which restore mitochondrial ultrastructure, morphology, and function. In vivo, Opantimirs correct mitochondrial ultrastructure and fiber size in muscles of denervated and Cox15-ablated mice, improving strength in the latter. Thus, biopharmacological correction of the mitochondrial ultrastructure can ameliorate mitochondrial myopathies.
    Keywords:  OPA1; antimiRs; cristae remodeling; disuse myopathies; miR-128-3p; miR-148/152-3p family; microRNAs; mitochondrial myopathies; mitochondrial ultrastructure
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102248
  26. Nat Metab. 2025 Aug 01.
    2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction.
    Harshita Kaul, Lea Isermann, Katharina Senft, Milica Popovic, Theodoros Georgomanolis, Linda Baumann, Pujyanathan Sivanesan, Andromachi Pouikli, Hendrik Nolte, Bojana Lucic, Ximena Hildebrandt, Katrin Seidel, Thorsten Gnad, Felix Gaedke, Ulrike Göbel, Franziska Peters, Maksym Cherevatenko, Joo Hyun Park, Astrid Schauss, Nieves Peltzer, Jens Claus Brüning, Jan-Wilhelm Kornfeld, Alexander Pfeifer, Thomas Langer, Marina Lusic, Sara A Wickström, Christian Frezza, Aleksandra Trifunovic.
      Mitochondria have a crucial role in regulating cellular homeostasis in response to intrinsic and extrinsic cues by changing cellular metabolism to meet these challenges. However, the molecular underpinnings of this regulation and the complete spectrum of these physiological outcomes remain largely unexplored. In this study, we elucidate the mechanisms driving the whitening phenotype in brown adipose tissue (BAT) deficient in the mitochondrial matrix protease CLPP. Here we show that CLPP-deficient BAT shows aberrant accumulation of lipid droplets, which occurs independently of defects in oxygen consumption and fatty acid oxidation. Our results indicate that mitochondrial dysfunction due to CLPP deficiency leads to the build-up of the oncometabolite D-2-hydroxyglutarate (D-2HG), which in turn promotes lipid droplet enlargement. We further demonstrate that D-2HG influences gene expression and decreases nuclear stiffness by modifying epigenetic signatures. We propose that lipid accumulation and altered nuclear stiffness regulated through 2HG are stress responses to mitochondrial dysfunction in BAT.
    DOI:  https://doi.org/10.1038/s42255-025-01332-8
  27. Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2511890122
    In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
    Kevin Rose, Eric Herrmann, Eve Kakudji, Javier Lizarrondo, A Yasemin Celebi, Florian Wilfling, Samantha C Lewis, James H Hurley.
      Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in PINK1 and PRKN. Parkin-expressing U2 osteosarcoma (U2OS) cells were treated with the depolarizing agents oligomycin and antimycin A (OA) and subjected to cryo-focused ion beam milling and in situ cryo-electron tomography. Mitochondria were fragmented and devoid of matrix calcium phosphate crystals. Phagophores were visualized, with bridge-like lipid transporter densities connected to mitophagic phagophores. A subpopulation of ATP synthases relocalized from cristae to the inner boundary membrane. The structure of the dome-shaped prohibitin complex, a dodecamer of PHB1-PHB2 dimers, was determined in situ by subtomogram averaging in untreated and treated cells and found to exist in open and closed conformations, with the closed conformation being enriched by OA treatment. These findings provide a set of native snapshots of the manifold nano-structural consequences of mitochondrial depolarization and provide a baseline for future in situ dissection of Parkin-dependent mitophagy.
    Keywords:  autophagy; cryo-ET; mitochondria; mitophagy; prohibitin
    DOI:  https://doi.org/10.1073/pnas.2511890122
  28. Mitochondrion. 2025 Jul 28. pii: S1567-7249(25)00072-8. [Epub ahead of print] 102075
    Role of Prohibitins as Guardians of mitochondrial homeostasis.
    Sabrina Champsi, David A Hood.
      Mitochondria are complex organelles critical to the maintenance of cellular homeostasis. Central to this regulation are Prohibitins (PHBs), a novel set of proteins involved in several mitochondrial quality control pathways, including protein folding, biogenesis, and mitophagy. PHBs mediate various cellular responses including cell survival and myogenesis, suggesting that their roles are intricate and multifaceted. While evidence suggests that PHBs facilitate mitochondrial homeostasis, their exact mechanism of action remains unclear. Elucidating the precise mechanisms driving PHB-mediated adaptations will ultimately enable the development of therapeutic strategies aimed towards the treatment of age-related diseases, characterized by mitochondrial perturbations.
    Keywords:  Aging; Apoptosis; Mitochondria; Mitophagy; Prohibitin
    DOI:  https://doi.org/10.1016/j.mito.2025.102075
  29. Mol Biol Cell. 2025 Jul 30. mbcE25010033
    Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
    Sara Wong, Katherine R Bertram, Sai Sangeetha Balasubramaniam, Nidhi Raghuram, Thomas Knight, J Alan Maschek, James E Cox, Adam L Hughes.
      Lipid saturation is a key determinant of membrane function and organelle health, with changes in saturation triggering adaptive quality control mechanisms to maintain membrane integrity. Among cellular membranes, the mitochondrial outer membrane (OMM) is an important interface for many cellular functions, but how lipid saturation impacts OMM function remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel the OMM by promoting the formation of multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins and lipids from the OMM. These effects depend on the incorporation of UFAs into membrane phospholipids, suggesting that changes in membrane bilayer composition mediate this process. Furthermore, elevated UFAs impair the assembly of the OMM protein translocase (TOM) complex, with unassembled TOM components captured into MDCs. Collectively, these findings suggest that alterations in phospholipid saturation may destabilize OMM protein complexes and trigger an adaptive response to sequester excess membrane proteins through MDC formation.
    DOI:  https://doi.org/10.1091/mbc.E25-01-0033
  30. Tremor Other Hyperkinet Mov (N Y). 2025 ;15 32
    Deep Brain Stimulation in Leigh-Like Syndrome Due to DNM1 Pathogenic Variant.
    Leonel Villa-Villegas, Luz Gabriela Lira-Jaime, Katia Carmina Farías-Moreno, Biagio David González-Ruffino, Alberto Soto-Escageda, Rodrigo Mercado-Pimentel, Carlos Eduardo Piña-Avilés, Carlos Zúñiga-Ramírez.
       Clinical vignette: Leigh syndrome (LS) and Leigh-like syndromes (LLS), now collectively referred to as Leigh Syndrome Spectrum (LSS), encompass a wide range of clinical manifestations, including epilepsy, neurodevelopmental delay, and movement disorders such as ataxia, chorea, and dystonia. Although rare, LSS can present atypical symptoms in certain cases. The primary etiological cause of LSS is genetic, resulting from mitochondrial alterations.
    Clinical dilemma: Hyperkinesias in LSS or other mitochondrial disorders can be disabling, leading to a significant reduction in the patient's quality of life.
    Clinical solution: Globus pallidum deep brain stimulation (GPi-DBS) surgery is an effective treatment for hyperkinesias, such as chorea, and dystonia, caused by mitochondrial defects.
    Gap in knowledge: Pathogenic DNM1-related mitochondrial disorders with Leigh syndrome phenotype may show long-term improvement of hyperkinetic movements after GPi-DBS.
    Keywords:  Deep brain stimulation; Dynamin 1; Hyperkinesias; Leigh Syndrome; Leigh-like syndrome; Mitofusin 2
    DOI:  https://doi.org/10.5334/tohm.1017
  31. Commun Chem. 2025 Jul 30. 8(1): 220
    Cardiolipin acyl chain composition tailors the conformation of mammalian ATP synthase dimers.
    M Makowski, V G Almendro-Vedia, I López-Montero.
      The interplay between ATP synthase dimers and the four-tailed lipid cardiolipin (CL) shapes mitochondrial cristae structure and function. In the mitochondrial disorder Barth syndrome (BTHS), cristae membranes accumulate a less unsaturated, three-tailed form of cardiolipin (MLCL). These cristae become structurally and functionally compromised through mechanisms poorly understood. We have studied through molecular dynamics simulations how BTHS lipid composition affects the conformation of the ATP synthase dimer. The wedge-shaped transmembrane region of the ATP synthase dimer attracts cardiolipins through shape complementarity. MLCL showed decreased affinity for the dimer interface than CLs of the healthy model. A more heterogeneous lipid environment with a higher elastic strain promoted a dimer conformation that would stabilize wider intracrista spaces, and hence, less efficient OXPHOS reactions in BTHS. Our results provide clues on the role played by the CL acyl chain composition in the architecture and function of mitochondria in health and BTHS.
    DOI:  https://doi.org/10.1038/s42004-025-01611-1
  32. Mol Biol Cell. 2025 Jul 30. mbcE25060271
    Rab14 promotes Parkin mediated mitophagy.
    Samina Momtaz, Marco Padilla-Rodriguez, Paola Cruz Flores, Natalia Rulli, Nam Yong Lee, Jean M Wilson.
      Mitochondrial degradation by mitophagy is essential to maintain cell metabolism; dysregulation can result in the accumulation of damaged mitochondria. While the Rab family of small GTPase proteins are involved with vesicular trafficking in the endocytic and biosynthetic pathways, Rab-GTPases also have a role in mitochondrial integrity. However, a role for Rab14, a trans-Golgi network (TGN)-endosomal Rab-GTPase in mitophagy has not been described. In cells knocked down for Rab14, mitochondria acquire an elongated morphology and increased levels of mitochondrial proteins, whereas overexpression of Rab14 decreased these proteins. Furthermore, mito-Keima assays show increased mitophagy upon Rab14 overexpression. Rab14-induced mitophagy is dependent on Parkin expression, as well as TBK1 and PI3K activity, placing it in the Parkin-dependent mitophagy pathway. 3D-reconstruction shows contact site formation between Rab14 and mitochondria, and inhibition of the TGN kinase PI(4)KIIIβ decreases Rab14-mitochondria contact sites and prevents Rab14-mediated mitophagy, suggesting that TGN-derived Rab14 vesicles mediate mitophagy. These results suggest that Rab14 promotes mitophagy and plays an essential role in modulating cellular metabolism. [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-06-0271
  33. Am J Physiol Cell Physiol. 2025 Jul 31.
    Small Molecule Oxybutynin Rescues Proliferative Capacity of Complex III-Defective Muscle Progenitor Cells.
    Yue Qu, Kaydine Edwards, Muying Li, Matthew Williams, Yang Liu, Pei-Yin Tsai, Chloe Cheng, Jamie E Blum, Noel Acor, Tenzin Oshoe, Claire Walter, Venkatesh Thirumalaikumar, Anna E Thalacker-Mercer, Aleksandra Skirycz, Joeva Barrow.
      Mitochondrial disease encompasses a group of genetically inherited disorders hallmarked by an inability of the respiratory chain to produce sufficient ATP. These disorders present with multisystemic pathologies that predominantly impact highly energetic tissues such as skeletal muscle. There is no cure or effective treatment for mitochondrial disease. We have discovered a small molecule known as oxybutynin that can bypass Complex III mitochondrial dysfunction in primary murine and human skeletal muscle progenitor cells (MPCs). Oxybutynin administration improves MPC proliferative capacity, enhances cellular glycolytic function, and improves myotube formation. Mechanistically, results from our isothermal shift assay indicates that oxybutynin interacts with a suite of proteins involved in mRNA processing which then trigger the upregulation biological pathways to circumvent CIII mitochondrial dysfunction. Taken together, we provide evidence for the small molecule oxybutynin as a potential therapeutic candidate for the future treatment of CIII mitochondrial dysfunction.
    Keywords:  Complex III; Mitochondrial Disease; Muscle Progenitor Cells; Oxybutynin; Uqcrfs1
    DOI:  https://doi.org/10.1152/ajpcell.00141.2025
  34. STAR Protoc. 2025 Jul 25. pii: S2666-1667(25)00377-6. [Epub ahead of print]6(3): 103971
    Protocol for assessing mitochondrial cholesterol transport and protein molten globule state in steroidogenic and nonsteroidogenic systems.
    Himangshu S Bose, Mahuya Bose, Randy M Whittal.
      Steroid hormones are essential for the survival of all mammals for carbohydrate metabolism, stress management, and sexual reproduction. Here, we present a protocol for assessing mitochondrial cholesterol transport and protein molten globule state via measurement of pregnenolone or progesterone synthesis in steroidogenic and nonsteroidogenic cellular systems. We describe steps for cell culture, transfection, and measurement of steroidogenic activity from nonsteroidogenic cells. We then detail procedures for metabolic conversion. For complete details on the use and execution of this protocol, please refer to Bose,1 Bose et al.,2 Pawlak et al.,3 and Prasad et al.4.
    Keywords:  Cell Biology; Health Sciences; Mass Spectrometry; Metabolism; Molecular Biology; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2025.103971
  35. Front Cell Neurosci. 2025 ;19 1650938
    Editorial: Recent advances in mitochondrial dysfunction and therapeutics for neurodegeneration and aging.
    Monokesh K Sen, Keagan Dunville, Nicole Miles, Michelle Newbery, Neville S Ng, Lezanne Ooi.
      
    Keywords:  Alzheimer's disease; Parkinson's disease; mitochondria; motor neuron disease; neurodegeneration
    DOI:  https://doi.org/10.3389/fncel.2025.1650938
  36. Curr Top Med Chem. 2025 Jul 28.
    Nanotechnological Approaches for Mitochondrial Targeting in Neurodegenerative Diseases.
    Ahmet Doğan Ergin.
       OBJECTIVES: Mitochondria are dynamic organelles essential for energy metabolism and cellular homeostasis, playing critical roles in ATP production, calcium regulation, redox balance, and apoptosis. However, mitochondrial dysfunction is a central factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Given the essential role of mitochondria in neuronal survival, targeted therapeutic strategies that restore mitochondrial function have gained significant attention. This review explores the latest advances in mitochondrial-targeted therapies and their potential applications in neurodegenerative diseases.
    METHODS: A comprehensive literature review was conducted on mitochondrial-targeted therapeutic strategies, with a focus on nanotechnology-based drug delivery systems. The analysis includes various nanoparticle-based approaches, such as liposomes, DQAsomes, and polymeric nanoparticles, which have demonstrated high biocompatibility, controlled drug release, and enhanced mitochondrial targeting efficiency. Additionally, mitochondria-penetrating peptides and delocalized lipophilic cations (DLCs) are discussed for their role in improving drug localization within mitochondria and overcoming biological barriers, including the blood-brain barrier (BBB).
    RESULTS: Recent research shows the potential of mitochondrial-targeted antioxidants, peptides, and biocompatible nanocarriers in arranging mitochondrial dysfunction and protecting neurons from oxidative damage. Various nanoparticle-based drug delivery systems have demonstrated the ability to selectively target mitochondria, improving drug bioavailability, therapeutic efficacy, and neuroprotective outcomes in neurodegenerative diseases.
    CONCLUSION: Mitochondria-targeted therapies provide promising avenues for disease-modifying treatments aimed at preserving neuronal integrity and delaying disease progression. The unique properties of nanoparticles, such as their ability to enhance drug stability, facilitate controlled release, and achieve precise mitochondrial localization, make them valuable tools for neurodegenerative disease therapy. Future research should focus on optimizing delivery systems, validating clinical applicability, and exploring interdisciplinary approaches to accelerate translation into effective treatments.
    Keywords:  Alzheimer's disease; Nanoparticle; dqasome; mitochondria targeting; mitochondrial dysfunction.; neurological
    DOI:  https://doi.org/10.2174/0115680266397447250723073446
  37. Cell Mol Biol Lett. 2025 Jul 28. 30(1): 94
    Perspectives on mitochondrial dysfunction in the regeneration of aging skeletal muscle.
    Kai Wang, Mailin Gan, Yuhang Lei, Tianci Liao, Jiaxin Li, Lili Niu, Ye Zhao, Lei Chen, Yan Wang, Li Zhu, Linyuan Shen.
      As the global population trends toward aging, the number of individuals suffering from age-related debilitating diseases is increasing. With advancing age, skeletal muscle undergoes progressive oxidative stress infiltration, coupled with detrimental factors such as impaired protein synthesis and mitochondrial DNA (mtDNA) mutations, culminating in mitochondrial dysfunction. Muscle stem cells (MuSCs), essential for skeletal muscle regeneration, also experience functional decline during this process, leading to irreversible damage to muscle integrity in older adults. A critical contributing factor is the loss of mitochondrial metabolism and function in MuSCs within skeletal muscle. The mitochondrial quality control system plays a pivotal role as a modulator, counteracting aging-associated abnormalities in energy metabolism and redox imbalance. Mitochondria meet functional demands through processes such as fission, fusion, and mitophagy. The significance of mitochondrial morphology and dynamics in the mechanisms of muscle regeneration has been consistently emphasized. In this review, we provide a comprehensive summary of recent advances in understanding the mechanisms of aging-related mitochondrial dysfunction and its role in hindering skeletal muscle regeneration. Additionally, we present novel insights into therapeutic approaches for treating aging-related myopathies.
    Keywords:  Aging; Mitochondrial dynamics; Mitophagy; Oxidative stress; Skeletal muscle regeneration
    DOI:  https://doi.org/10.1186/s11658-025-00771-1
  38. Biochim Biophys Acta Gen Subj. 2025 Jul 30. pii: S0304-4165(25)00090-X. [Epub ahead of print] 130845
    Nitrosative stress affects mitochondrial respiratory chain complex II and complex IV assemblies in Saccharomyces cerevisiae: S-nitrosylation of complex II.
    Sanchita Biswas, Ayantika Sengupta, Shubhojit Das, Chirandeep Dey, Rajib Sengupta, Alok Ghosh, Sanjay Ghosh.
      The elevated level of nitric oxide (NO) and reactive nitrogen species (RNS) induce nitrosative stress in cells and inhibit mitochondrial respiration. Reports showed that RNS rapidly inactivate complex I, followed by inhibition of complex II, III and IV in isolated mitochondria. However, the mechanism(s) by which NO and RNS inhibit these complexes still unclear. In this study facultative anaerobic yeast Saccharomyces cerevisiae has been used for investigating mitochondrial respiratory dysfunction under nitrosative stress, as four out of five mitochondrial oxidative pHosphorylation complexes i.e. complexes II, III, IV and V are structurally conserved from yeast to human. Using microbiological growth assays, we showed that S. cerevisiae wild type W3O3 cells treated with graded concentration of sodium nitroprusside (SNP) and S-Nitrosoglutathione (GSNO) induce nitrosative stress, and cell growth was severely compromised under the respiratory proficient rich glycerol-ethanol media. Both the whole cell and the mitochondrial oxygen consumption rates were also significantly compromised under nitrosative stress. Surprisingly, mitochondrial respiratory chain complex II succinate dehydrogenase (SDH) of S. cerevisiae was found S-nitrosylated and therefore inactivated under nitrosative stress. Endogenous RNS produced by S-nitrosoglutathione reductase mutant cells of S. cerevisiae also showed increased S-nitrosylation of SDH. Complex III and IV activities were irreversibly inhibited in S. cerevisiae under nitrosative stress. Interestingly, protein tyrosine nitration was also enhanced in mitochondria in a dose dependent manner upon SNP treatment. Reduced expressions of both Sdh2 (succinate dehydrogenase subunit-2) and Cox2 (mitochondrial complex IV subunit) were observed at the transcription and translation level in S. cerevisiae under nitrosative stress. Blue Native-PAGE followed by Western blotting analysis, further revealed significantly reduced native complex II and the complex III and IV containing super-complexes assemblies in consequences of nitrosative stress in S. cerevisiae. Henceforth, the present in vivo study provides for the first-time novel information on the modification of mitochondrial complexes under nitrosative stress which in turn regulates the mitochondrial respiratory chain complexes assembly in S. cerevisiae.
    Keywords:  Mitochondrial respiratory chain complex; Nitrosative stress; S-nitrosylation; Saccharomyces cerevisiae; Succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.bbagen.2025.130845
  39. Nat Commun. 2025 Jul 31. 16(1): 7029
    mRNA trafficking directs cell-size-scaling of mitochondria distribution and function.
    Joshua J Bradbury, Georgia E Hulmes, Ranjith Viswanathan, Guilherme Costa, Holly E Lovegrove, Shane P Herbert.
      The subcellular positioning of organelles is critical to their function and is dynamically adapted to changes in cell morphology. Yet, how cells sense shifts in their dimensions and redistribute organelles accordingly remains unclear. Here we reveal that cell-size-scaling of mitochondria distribution and function is directed by polarised trafficking of mRNAs. We identify a 29 bp 3'UTR motif in mRNA encoding TRAK2, a key determinant of mitochondria retrograde transport, that promotes cell-size-dependent targeting of TRAK2 mRNA to distal sites of cell protrusions. Cell-size-scaled mRNA polarisation in turn scales mitochondria distribution by defining the precise site of TRAK2-MIRO1 retrograde transport complex assembly. Consequently, 3'UTR motif excision perturbs size-regulated transport and eradicates scaling of mitochondria positioning, triggering distal accumulation of mitochondria and progressive hypermotility as cells increase size. Together, our results reveal an RNA-driven mechanistic basis for the cell-size-scaling of organelle distribution and function that is critical to homeostatic control of motile cell behaviour.
    DOI:  https://doi.org/10.1038/s41467-025-61940-6
  40. Comput Biol Med. 2025 Jul 25. pii: S0010-4825(25)01161-8. [Epub ahead of print]196(Pt B): 110810
    Effects of pathological mutations on the CHCHD2 monomer structure: A study by AlphaFold3 linked to the generation of conformational ensembles.
    Zeyneb Azra Özmen, Fatma Nilsu Çaylı, Vladimir N Uversky, Junga Alexa Woo, David E Kang, Orkid Coskuner-Weber.
      CHCHD2 is a mitochondrial protein linked to neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and frontotemporal dementia (FTD). To investigate the structural effects of disease-associated mutations, we analyzed 19 pathogenic variants using AlphaFold3 and conformational ensemble modeling with AFflecto. While the radius of gyration and end-to-end distances remained largely unchanged, mutations significantly altered secondary structure elements and contact maps, particularly in local folding. Intrinsic disorder and LLPS analyses revealed that mutations modulate the protein's droplet-forming capacity and interaction flexibility. These changes may impact protein-protein interactions, phase behavior, and mitochondrial function. Our findings indicate that pathogenic CHCHD2 mutations cause subtle but functionally relevant structural perturbations rather than global destabilization. This study underscores the importance of ensemble-based modeling in understanding mutation-induced dysfunction in intrinsically disordered proteins involved in neurodegeneration.
    Keywords:  AlphaFold3; CHCHD2; Conformational ensembles; Genetic mutations; IDRs; Neurodegenerative diseases; Structure-function relationship
    DOI:  https://doi.org/10.1016/j.compbiomed.2025.110810
  41. Adv Exp Med Biol. 2025 ;1467 177-180
    Mitochondrial Disorder: Maternally Inherited Diabetes and Deafness.
    Fabiha Ahmed, Stephen H Tsang, Alicia R P Aycinena, Tarun Sharma.
      Patients with maternally inherited diabetes and deafness (MIDD) have insulin-dependent diabetes with relatively low BMI; usually the onset of the diabetes is during the third or fourth decade of life and it is associated with progressive neurosensory deafness.
    Keywords:  MIDD; Mitochondrial disorder; Mitochondrial inherited diabetes and deafness
    DOI:  https://doi.org/10.1007/978-3-031-72230-1_31
  42. J Cell Biochem. 2025 Jul;126(7): e70056
    Comprehensive Insights Into Mitophagy: Mechanisms, Disease Associations, and Therapeutic Implications.
    Min Tang, Ikram Outissint, Yijing Chen, Xun Gong.
      Mitophagy, a selective autophagic process, is critical for maintaining mitochondrial quality and cellular homeostasis. It plays a dual role, facilitating cell survival by removing damaged mitochondria or contributing to programmed cell death in certain conditions. Dysregulation of mitophagy is implicated in various diseases, including neurodegenerative disorders, metabolic syndromes, cardiovascular diseases, and cancers. This review examines the key regulatory mechanisms of mitophagy, focusing on pathways such as the PINK1-Parkin, BNIP3/NIX, and FUNDC1 pathways, alongside emerging modulators. Notably, mitophagy is frequently associated with various cell death pathways, such as apoptosis, necroptosis, ferroptosis, and pyroptosis. Primarily, mitophagy functions as a protective mechanism rather than a direct trigger of cell death. It may be connected to cell death when its capacity is overwhelmed rather than actively promoting the process. For instance, impaired mitophagy exacerbates neurodegeneration in Parkinson's and Alzheimer's diseases, while its activation protects against ischemic injury in cardiovascular diseases. In cancer, mitophagy is paradoxical, as it either inhibits tumor growth or promotes survival under stress. Therapeutic interventions targeting mitophagy, including small-molecule modulators, show promise in preclinical studies; however, they require further clinical validation. Advancements in imaging techniques, single-cell omics, and high-throughput screenings are anticipated to deepen our understanding of mitophagy dynamics and therapeutic potential. This review highlights mitophagy as a pivotal target for treating diseases associated with mitochondrial dysfunction, providing insights into innovative therapeutic strategies.
    Keywords:  cell death pathways; metabolic syndromes; mitophagy; neurodegenerative disorders; therapeutic strategies
    DOI:  https://doi.org/10.1002/jcb.70056
  43. Cell Death Dis. 2025 Jul 29. 16(1): 573
    The impact of ERUPR on mitochondrial integrity mediated by PDK4.
    Priyanka Mallick, Sebabrata Maity, Rupsha Mondal, Trina Roy, Puyam Milan Meitei, Shashank Saxena, Bhavani Shankar Sahu, Oishee Chakrabarti, Saikat Chakrabarti.
      ER and mitochondrial stress are often interconnected and considered major contributors to aging as well as neurodegeneration. Coordinated induction of ERUPR and mitoUPR has been observed in diabetes and pulmonary disorders. However, in the context of aging and neurodegeneration, regulation of this intra-organellar crosstalk has remained relatively elusive. Here, we demonstrate that pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial protein, accumulates at the ER-mitochondrial contact sites (MAMs) during ER stress. Classically, PDK4 is known to phosphorylate PDHA1 (pyruvate dehydrogenase E1 subunit alpha 1) and plays a significant role in regulating the oxidative phosphorylation-driven ATP production. In this study, we propose a non-canonical kinase-independent function of PDK4; we show that it acts as a connecting link between ERUPR and mitoUPR, with significance in aging and Alzheimer's disease (AD) associated neurodegeneration. Transcriptomics analyses show increased PDK4 levels upon drug-induced ER stress. We detect elevated PDK4 levels in lysates from human AD patient and mouse models as well as in ex vivo AD models. Additionally, exogenous expression of PDK4 was found to refine ER-mitochondria communication, significantly altering mitochondrial morphology and function. Further, we also observe defective autophagic clearance of mitochondria under such conditions. It is prudent to suggest that elevated PDK4 levels could be one of the key factors connecting ERUPR with mitoUPR, a phenotypic contributor in aging and in AD-like neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41419-025-07743-5
  44. Nat Commun. 2025 Jul 28. 16(1): 6923
    Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure.
    Andrew Roe, Catríona M Dowling, Cian D'Arcy, Daniel Alencar Rodrigues, Yu Wang, Matthew Hiller, Carl Keogh, Kate E R Hollinshead, Massimiliano Garre, Brenton Cavanagh, Kieran Wynne, Tianyan Liu, Zhixing Chen, Emma Kerr, Marie McIlroy, Jochen H M Prehn, Ingmar Schoen, Tríona Ní Chonghaile.
      Fumarate hydratase (FH), a key node of mitochondrial metabolism, is also a tumour suppressor. Despite its prominent roles in tumourigenesis and inflammation, its regulation remains poorly understood. Herein, we show that histone deacetylase 6 (HDAC6) regulates FH activity. In triple-negative breast cancer cells, HDAC6 inhibition or knockdown results in alterations to mitochondrial cristae structure, as detected by live-cell super-resolution STED nanoscopy and electron microscopy, along with the release of mitochondrial DNA. Mass-spectrometry immunoprecipitation reveals multiple mitochondrial HDAC6-interactors, with FH emerging as a top hit. Super-resolution 3D-STORM shows HDAC6 interactions with FH in mitochondrial networks, which increases after perturbation of HDAC6 activity with BAS-2. Treatment with BAS-2 leads to fumarate accumulation by 13C glucose labelling, along with downstream succination of proteins and cell death. Together, these results identify HDAC6 inhibition as a regulator of endogenous FH activity in tumour cells, and highlight it as a promising candidate for indirectly targeting tumour metabolism.
    DOI:  https://doi.org/10.1038/s41467-025-61897-6
  45. Nat Metab. 2025 Aug 01.
    BAT mitochondria: whitening meets softening.
    Mateus Prates Mori, Oswaldo A Lozoya, Janine H Santos.
      
    DOI:  https://doi.org/10.1038/s42255-025-01319-5
  46. Commun Med (Lond). 2025 Jul 31. 5(1): 323
    Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    Fangfang Zhang, Tatjana Dorn, Barbara Gnutti, Yair Anikster, Sarah Kuebler, Rebecca Ahrens-Nicklas, Rachel Gosselin, Shamima Rahman, Ronen Durst, Enrica Zanuttigh, Miriam A Güra, Christine M Poch, Anna B Meier, Karl-Ludwig Laugwitz, Hans-Joachim Schüller, Ana C Messias, Ody C Sibon, Dario Finazzi, Alyssa Rippert, Dong Li, Kristen Truxal, Deipanjan Nandi, Brent C Lampert, Mildrid Yeo, Alice Gardham, Batel Nissan, Smadar Horowitz Cederboim, Alessandra Moretti, Arcangela Iuso.
       BACKGROUND: PPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in PPCS, which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway. To date, only six patients worldwide have been identified.
    METHODS: Whole-exome sequencing was performed to identify pathogenic PPCS variants in affected individuals. Protein stability was assessed by Western blotting. CoA levels were quantified using a microplate-based assay in patient-derived fibroblasts, cardiac progenitor cells, and cardiomyocytes. Functional evaluation of cardiac cells and engineered heart patches was conducted to investigate contractile performance and arrhythmogenicity. Pantethine was tested as a potential therapeutic agent both in vitro and through long-term clinical follow-up in patients.
    RESULTS: Causative PPCS variants are identified in six individuals with DCM and variable associated features, including neuromuscular and neurological symptoms. Identified variants lead to reduced PPCS protein stability and decreased cellular CoA levels. Cardiac cells exhibit impaired contractility and arrhythmias, which are partially rescued by pantethine treatment. Clinically, patients receiving pantethine show sustained improvement over time.
    CONCLUSIONS: Our study expands the genetic and clinical spectrum of PPCS deficiency disorder, identifying six new cases with diverse phenotypes. Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells. Pantethine treatment shows promise in partially rescuing DCM phenotypes, both in vitro and in patients. However, complete reversal may require early intervention. These findings underscore the importance of timely diagnosis and treatment in PPCS DD. Future research should focus on optimizing pantethine supplementation and exploring additional therapies to enhance CoA levels and cardiac function in affected individuals.
    DOI:  https://doi.org/10.1038/s43856-025-01017-z
  47. Ther Adv Chronic Dis. 2025 ;16 20406223251344763
    The profound implications of mitochondrial myopathy on activities of daily living: an observational qualitative study of standardized structured and semi-structured patient interviews.
    Elizabeth M McCormick, James T Peterson, Joaquim Diego D Santos, Jean Flickinger, Rui Xiao, Richard Haas, Zarazuela Zolkipli-Cunningham.
       Background: The impact of Mitochondrial Myopathy (MM) symptoms on functional ability across activities of daily living (ADLs) has not been fully characterized, nor is it understood how MM patients define their key symptoms. Furthermore, it is unclear what MM individuals perceive as a clinically meaningful improvement.
    Objective: We sought to characterize how MM patients feel about their symptoms in the key MM domains of muscle weakness, muscle fatigue, exercise intolerance, imbalance, and peripheral neuropathy; as well as their functional ability.
    Design: We conducted a single-center, observational, qualitative study that involved standardized structured and semi-structured patient interviews.
    Methods: Most interview questions were open-ended, allowing individuals to provide personalized narratives that were transcribed in real time. A total of 33 individuals with MM were interviewed either in-person or remotely. Interview transcripts underwent thematic analysis in accordance with grounded theory. Data was presented using a mixed-methods approach.
    Results: Subjects provided extensive narratives that demonstrated the substantial and widespread impact of MM across many aspects of MM patient lives, including the impact of each MM domain of muscle weakness, muscle fatigue, exercise intolerance, imbalance, and peripheral neuropathy on ADLs; the need to adapt to preserve independence and quality of life (QOL); impaired self-perception, participation in social activities, hobbies, and relationships; and change in circumstances over time.
    Conclusion: These meaningful insights highlight the critical and emergent need for approved drug treatment(s) in this profoundly burdened patient population. Our results will serve as a comprehensive resource to inform the physician, patient, industry and advocacy communities on outcome measure selection and clinical trial design; and to help inform regulatory agencies in the United States Food and Drug Administration (FDA) drug approval process for MM.
    Keywords:  Mitochondrial Myopathy (MM); activities of daily living (ADLs); adaptation; dexterity; exercise intolerance; imbalance; impact; muscle fatigue; muscle weakness
    DOI:  https://doi.org/10.1177/20406223251344763
  48. Cell Biochem Biophys. 2025 Aug 01.
    Multi-omics Analysis Implicates Mitochondrial Complex Assembly Protein COX18 in Mitochondrial Signaling and Tumorigenesis across Cancers.
    Devyani Goswami, Sayak Ghosh, Rittick Dutta, Debapriya Ghatak, Debapriya Ranjit, Rudranil De.
      
    Keywords:   COX18 ; Cancer; Gene-drug interactions; Mitochondria; Prognosis; Tumor micro-environment
    DOI:  https://doi.org/10.1007/s12013-025-01857-5
  49. Cell Death Discov. 2025 Jul 29. 11(1): 351
    Mitochondrial dysfunction-mediated metabolic remodeling of TCA cycle promotes Parkinson's disease through inhibition of H3K4me3 demethylation.
    Xiaoyuan Zhang, Fali Zhang, Yue Zeng, Aiying Li, Jiamao Yan, Pei Li, Kexin Qin, Teng Zhang, Jiaojiao Huang, Minghui Zhao, Massimo De Felici, Yang Zhou, Wei Shen.
      Parkinson's disease (PD), a neurodegenerative disorder caused by complex factors, is usually associated to mitochondrial dysfunctions but the links between such disorder and PD remain object of research. Here, we report that impaired mitochondrial quality control (MQC) system is a molecular basis of the mitochondrial dysfunction in PD and that tricarboxylic acid cycle (TCA cycle) disorder is the main feature of such mitochondrial dysfunction. Multi-omics analysis revealed that MDH2, OGDHL and IDH3G enzymes are bottlenecks in the enzymatic reactions of the TCA cycle in PD. Mechanistically, the abnormal α-KG/fumarate ratio caused by the TCA cycle bottleneck inhibits histone H3K4me3 demethylation and further enhances the expression of alpha-synuclein (SNCA), which may promote PD at an early stage. On these bases, we proposed a number of PD therapeutic strategies targeting mitochondria and histone methylation modifications, which proved to be effective in in vitro or in vivo models, especially citrate supplementation, in restoring normal TCA cycle enzymatic reactions. Taken together, our work highlights the non-negligible regulatory role of "mitochondrial-nuclear" communication in PD and provides important insights for the development of PD therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41420-025-02651-1
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