bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–07–20
sixty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial DNA: how does it leave mitochondria?
  2. Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells.
  3. Respiratory complex III 2 assembles complex I via toxic intermediate in mitochondrial disease.
  4. Isolation of Mitochondria From Yeast to Estimate Mitochondrial Pools of Inorganic Phosphate.
  5. Mitochondria dysfunction: cause or consequence of physiologic aging?
  6. Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.
  7. Mitochondrial DNA Pathogenic Variant Prevalence in Primary Mitochondrial Disease Patients With African (L) Mitochondrial Genome Haplogroups.
  8. Mitochondrial age-classes expand the heterogeneity of tissue-resident stem cells.
  9. Expanding the Clinical, Pathological, and Molecular Phenotypes of Tetratricopeptide 19 (TTC19) Gene Mutations: A Case Report from India.
  10. A Tunisian POLG mutation expands the clinical spectrum of POLG-related disorders.
  11. Deletion of Skeletal Muscle Mitochondrial Glutamic-Oxaloacetic Transaminase (GOT2) Enhances Oxaloacetate Inhibition of Succinate Dehydrogenase and Alters Substrate Selectivity.
  12. Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders.
  13. Nutrient-Responsive Formation of Mitochondrial-Derived Structures in Caenorhabditis elegans.
  14. MICU proteins facilitate Ca2+-dependent mitochondrial metabolon formation to regulate cellular energetics - independent of MCU.
  15. Organic cation transporter 3 on neuronal mitochondria mediates MPP+-induced mitochondrial dysfunction and neurotoxicity in a TIMM22-dependent manner.
  16. Synergistic Control of Mitochondrial Dynamics and Function by ERAD and Autophagy in Brown Adipocytes.
  17. Reducing the Risks of Mitochondrial Disease in Children.
  18. Specialized high-capacity mitochondria fuel cell invasion.
  19. Mitochondria-Targeting Abasic Site-Reactive Probe (mTAP) Enables the Manipulation of Mitochondrial DNA Levels.
  20. Beyond the Pseudogene: p17/PERMIT as a Mitochondrial Trafficking Protein Linking Aging and Neurodegeneration.
  21. Cardiac pathology in a patient with a novel pathogenic variant c.703del (p.Ile235SerfsTer4) of the TAFAZZIN gene.
  22. Heart is the most susceptible organ in an isogenic background to loss of function mutations in the mitochondrial metallochaperone SCO1.
  23. Mitochondrial Dysfunction in Neurodegenerative Disorders: Role of Prototype Targeted Drug Delivery Solutions.
  24. Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
  25. CRISPRa-Mediated Increase of OPA1 Expression in Dominant Optic Atrophy.
  26. Impact of Mitochondrial A3243G Mutation on Skeletal Muscle Energy Metabolism: Evidence from Human Induced Pluripotent Stem Cell-Derived Skeletal Muscle Cells.
  27. Neuroimaging patterns in patients with mitochondrial leukoencephalopathies.
  28. Advances in Preventing Transmission of Mitochondrial DNA Diseases.
  29. Structures of Chaetomium thermophilum TOM complexes with bound preproteins.
  30. Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease.
  31. Multi-site phosphorylation of BCL2L13 in a TBK1- and AMPK-dependent manner reveals new modes of mitophagy regulation.
  32. Leber's Hereditary Optic Neuropathy.
  33. Genetic mapping of lifespan and mitochondrial stress response in C. elegans.
  34. The Human LRRK2-R1441G Mutation Drives Age-Dependent Oxidative Stress and Mitochondrial Dysfunction in Dopaminergic Neurons.
  35. Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.
  36. NEDD4L induces mitochondrial dysfunction and neurodegeneration by promoting LIPT2 degradation in Huntington's disease.
  37. Neuronal branching in stem cell models of mitochondrial and neurological diseases.
  38. Megakaryocytes as mitochondria factories: potential donors for mitochondria transplantation.
  39. Mitochondrial Hearing Loss: Genetic Variants and Clinical Progression.
  40. Two-Photon FLIM Imaging of Mitochondrial Microenvironment in Apoptosis, Ferroptosis, and Fatty Liver Disease Models Using a Carbazole-Pyridinium Probe.
  41. Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells.
  42. Why and how paternal mitochondrial DNA gets cut out of the inheritance.
  43. mtKO: A dedicated guide RNA library for mitochondria research.
  44. Harnessing tissue-derived mitochondria-rich extracellular vesicles (Ti-mitoEVs) to boost mitochondrial biogenesis for regenerative medicine.
  45. A primary mechanism for efficacy of the ketogenic diet may be energy repletion at the tripartite synapse.
  46. Optogenetics-enabled discovery of integrated stress response modulators.
  47. Building on the momentum of N-of-1 base editor therapies for rare diseases.
  48. Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
  49. Scalable automated reanalysis of genomic data in research and clinical rare disease cohorts.
  50. Choreography of human mitochondrial leaderless mRNA translation initiation.
  51. Hearing the call of mitochondria: Insight into its role in sensorineural hearing loss.
  52. Laminar Shear Stress Increases the Cytosolic Pool of PINK1 in Endothelial Cells and Enhances Mitophagic Sensitivity Toward Dysfunctional Mitochondria.
  53. Smart brain-zapping implants could revolutionize Parkinson's treatment.
  54. BCS1L-Associated Disease: 5'-UTR Variant Shifts the Phenotype Towards Axonal Neuropathy.
  55. Mitochondria-derived peptide MOTS-c restores mitochondrial respiration in type 2 diabetic heart.
  56. Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders.
  57. Atad3 is Essential for Mitochondrial Permeability Transition Pore Opening and Cardiac Ischemia Reperfusion Injury.
  58. ATAD3 duplications bridge mitochondrial diseases and Aicardi-Goutières syndrome.
  59. Amyloid-β protein precursor modulates mitophagy and mitochondrial function through its cellular localization.
  60. UBQLN2 in neurodegenerative disease: mechanistic insights and emerging therapeutic potential.
  1. Trends Cell Biol. 2025 Jul 10. pii: S0962-8924(25)00146-1. [Epub ahead of print]
    Mitochondrial DNA: how does it leave mitochondria?
    Vladimir Gogvadze, Boris Zhivotovsky.
      In recent years, studies have reported the presence of mitochondrial DNA (mtDNA) in the cytosol. However, a certain number of publications on the mechanisms of mtDNA release contain uncertainties. mtDNA is located in the mitochondrial matrix and cannot be released through the same pathways as intermembrane space proteins. This forum article aims to examine the assumptions and elucidate the processes underlying this phenomenon.
    Keywords:  Bcl-2 family proteins; inner mitochondrial membrane; mitochondria; mtDNA; outer mitochondrial membrane
    DOI:  https://doi.org/10.1016/j.tcb.2025.06.005
  2. bioRxiv. 2025 Jun 26. pii: 2025.06.23.660251. [Epub ahead of print]
    Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells.
    Prerona Bora, Mashiat Zaman, Samantha Oviedo, Sergei Kutseikin, Nicole Madrazo, Prakhyat Mathur, Meera Pannikkat, Sophia Krasny, Alan Chu, Kristen A Johnson, Danielle A Grotjahn, Timothy E Shutt, R Luke Wiseman.
      Pathogenic variants in the mitochondrial outer membrane GTPase MFN2 cause the peripheral neuropathy Charcot-Marie-Tooth Type 2A (CMT2A). These mutations disrupt MFN2-dependent regulation of diverse aspects of mitochondrial biology including organelle morphology, motility, mitochondrial-endoplasmic reticulum (ER) contacts (MERCs), and respiratory chain activity. However, no therapies currently exist to mitigate the mitochondrial dysfunction linked to genetic deficiencies in MFN2. Herein, we performed a drug repurposing screen to identify compounds that selectively activate the integrated stress response (ISR) - the predominant stress-responsive signaling pathway responsible for regulating mitochondrial morphology and function. This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. We show that treatment with these compounds promotes adaptive, ISR-dependent remodeling of mitochondrial morphology and protects mitochondria against genetic and chemical insults. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2 -deficient cells. These results demonstrate the potential for pharmacologic HRI activation as a viable strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency.
    DOI:  https://doi.org/10.1101/2025.06.23.660251
  3. bioRxiv. 2025 Jun 18. pii: 2025.06.17.660237. [Epub ahead of print]
    Respiratory complex III 2 assembles complex I via toxic intermediate in mitochondrial disease.
    Maria G Ayala-Hernandez, Anetzy Bermudez Torales, Hannah Camille Tan, Claire B Montgomery, Abhilash Padavannil, Gino Cortopassi, James A Letts.
      Mutations in mitochondrial complex I can cause severe metabolic disease. Although no treatments are available for complex I deficiencies, chronic hypoxia improves lifespan and function in a mouse model of the severe mitochondrial disease Leigh syndrome caused by mutation of complex I subunit NDUFS4. To understand the molecular mechanism of NDUFS4 mutant pathophysiology and hypoxia rescue, we investigated the structure of complex I in respiratory supercomplexes isolated from NDUFS4 mutant mice. We identified complex I assembly intermediates bound to complex III 2 , proving the cooperative assembly model. Further, an accumulated complex I intermediate is structurally consistent with pathological oxygen-dependent reverse electron transfer, revealing unanticipated pathophysiology and hypoxia rescue mechanisms. Thus, the build-up of toxic intermediates and not simply decreases in complex I levels underlie mitochondrial disease.
    DOI:  https://doi.org/10.1101/2025.06.17.660237
  4. Bio Protoc. 2025 Jul 05. 15(13): e5370
    Isolation of Mitochondria From Yeast to Estimate Mitochondrial Pools of Inorganic Phosphate.
    Swagata Adhikary, Vineeth Vengayil, Sunil Laxman.
      Mitochondria are dynamic organelles with essential roles in energetics and metabolism. Several metabolites are common to both the cytosolic and mitochondrial fractions of the cell. The compartmentalization of metabolites within the mitochondria allows specialized uses for mitochondrial metabolism. Inorganic phosphate (Pi) is one such critical metabolite required for ATP synthesis, via glycolysis and mitochondrial oxidative phosphorylation. Estimating total cellular Pi levels cannot distinguish the distribution of Pi pools across different cellular compartments, such as the cytosol and mitochondria, and therefore separate the contributions made toward glycolysis or other cytosolic metabolic processes vs. mitochondrial outputs. Quantifying Pi pools in mitochondria can therefore be very useful toward understanding mitochondrial metabolism and phosphate homeostasis. Here, we describe a protocol for the fairly rapid, efficient isolation of mitochondria from Saccharomyces cerevisiae by immunoprecipitation for quantitative estimation of mitochondrial and cytosolic Pi pools. This method utilizes magnetic beads to capture FLAG-tagged mitochondria (Tom20-FLAG) from homogenized cell lysates. This method provides a valuable tool to investigate changes in mitochondrial phosphate dynamics. Additionally, this protocol can be coupled with LC-MS approaches to quantitatively estimate mitochondrial metabolites and proteins and can be similarly used to assess other metabolite pools that are partitioned between the cytosol and mitochondria. Key features • This protocol describes how to isolate mitochondria from Saccharomyces cerevisiae for quantitative estimation of inorganic phosphate or other metabolites. • Mitochondria are efficiently isolated by immunoprecipitation using magnetic beads, bypassing the need for time-consuming density-based centrifugation. • This method can be integrated into LC-MS-based workflows to quantify mitochondrial metabolites and proteins.
    Keywords:  Differential centrifugation; Immunoprecipitation; Inorganic phosphate; Mitochondria isolation; Saccharomyces cerevisiae
    DOI:  https://doi.org/10.21769/BioProtoc.5370
  5. Genes Dev. 2025 Jul 11.
    Mitochondria dysfunction: cause or consequence of physiologic aging?
    G R Scott Budinger, Navdeep S Chandel.
      Mitochondria are no longer viewed solely as ATP- or metabolite-generating organelles but as key regulators of cellular signaling that shape physiologic aging. Contrary to earlier theories linking aging to mitochondrial DNA mutations and oxidative damage, current evidence shows that these factors do not causally limit physiologic aging. Instead, an evolving literature links age-related loss of mitochondrial signaling and function to important physiologic changes of aging. Moreover, mild inhibition of mitochondrial respiratory function with drugs like metformin promote health span. These findings open new paths for pharmacologically reprogramming mitochondrial signaling to extend healthy aging.
    Keywords:  aging; mitochondria; senescence
    DOI:  https://doi.org/10.1101/gad.353106.125
  6. bioRxiv. 2025 Jun 08. pii: 2025.06.07.658365. [Epub ahead of print]
    Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.
    Karis B D'Alessandro, Enrico Zampese, Jenna L E Blum, Britta Kuusik, Alec Palmiotti, Shawn M Davidson, Colleen R Reczek, D James Surmeier, Navdeep S Chandel.
      Dysfunction of mitochondrial complex I (MCI) has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Here, we report the effect of expressing MitoLbNOX, a mitochondrial-targeted version of the bacterial enzyme LbNOX, which increases regeneration of NAD+ in the mitochondria to maintain the NAD+/NADH ratio, in dopaminergic neurons with impaired MCI (MCI-Park mice). MitoLbNOX expression did not ameliorate the cellular or behavioral deficits observed in MCI-Park mice, suggesting that alteration of the mitochondrial NAD+/NADH ratio alone is not sufficient to compensate for loss of MCI function in dopaminergic neurons.
    DOI:  https://doi.org/10.1101/2025.06.07.658365
  7. JIMD Rep. 2025 Jul;66(4): e70036
    Mitochondrial DNA Pathogenic Variant Prevalence in Primary Mitochondrial Disease Patients With African (L) Mitochondrial Genome Haplogroups.
    Surita Meldau, Elizabeth M McCormick, Ibrahim George-Sankoh, Gillian T Riordan, Kashief Khan, Laura E MacMullen, Shrinav Dawlat, Dee Blackhurst, Marni J Falk, Joanna L Elson.
      Primary mitochondrial diseases (PMD) are caused by pathogenic variants in over 350 genes, 37 of which are located in mitochondrial DNA (mtDNA). While more than 100 mtDNA variants have confirmed disease associations, there are few reports of mtDNA-related PMD in patients with African heritage, even in well-studied populations. We investigated the frequency of pathogenic mtDNA variants in African L-haplogroups in patients with confirmed PMD from two diagnostic cohorts. Data from genetically confirmed mtDNA-related cases were extracted from existing databases at the National Health Laboratory Service Inherited Metabolic Disease Laboratory in South Africa (SA), and the Children's Hospital of Philadelphia (CHOP) Mitochondrial Medicine Frontier Program (USA). Mitochondrial genome haplogroup context was recorded from existing sequence report data. Stored DNA from the remaining cases was sequenced for mitochondrial genome haplogroup determination. Haplogroup context was obtained for 82 SA and 165 CHOP PMD cases. Sixty-two (47 SA; 15 USA) PMD cases from at least 50 maternal lineages were found to carry L Haplogroups. Unique L sub-haplogroups were identified in 11 (9 SA, 2 USA) families with the m.3243A>G MELAS variant, 6 SA families with the m.11778G>A LHON variant, and 20 (15 SA, 5 USA) cases with single large-scale mtDNA deletions (4 of whom had the 4977 bp common deletion). Several additional well-documented mtDNA pathogenic variants were identified in L-haplogroup context. PMD patient clinical features correlated closely with those described in other haplogroup cohorts. This study demonstrates that common pathogenic mtDNA variants occur in the context of multiple African mtDNA lineages. Disproportionately low diagnostic rates highlight ongoing diagnostic inequalities affecting those on the African continent and African patients globally.
    Keywords:  African American; South Africa; haplogroup L; haplogroup context; primary mitochondrial disease
    DOI:  https://doi.org/10.1002/jmd2.70036
  8. Nat Metab. 2025 Jul 14.
    Mitochondrial age-classes expand the heterogeneity of tissue-resident stem cells.
      
    DOI:  https://doi.org/10.1038/s42255-025-01326-6
  9. Neurol India. 2025 Jan 01. 73(1): 156-159
    Expanding the Clinical, Pathological, and Molecular Phenotypes of Tetratricopeptide 19 (TTC19) Gene Mutations: A Case Report from India.
    M K Farsana, Gautham Arunachal, B N Nandeesh, Karthik Kulanthaivelu, Rohan R Mahale, Hansashree Padmanabha, P S Mathuranath, Pooja Mailankody.
      Tetratricopeptide 19 gene (TTC19) is involved in mitochondrial respiratory chain (MRC) complex III function. Mutations cause developmental delay, Leigh syndrome, and spinocerebellar ataxia. In this report, we highlight the expanding phenotype of TTC19 gene variants. A 28-year-old man with intellectual disability presented with dysarthria, palatal tremors, and cerebellar ataxia of 5 months. After collecting clinical information and blood samples, clinical-exome sequencing was performed. Serum and cerebrospinal fluid lactate levels were elevated. Neuroimaging showed hypertrophic olivary degeneration, and MRC complex III deficiency was found on muscle biopsy. A novel variant of the TTC19 gene was identified, and the patient showed minimal symptomatic improvement with the mitochondrial cocktail. Mitochondrial complex III deficiency has varied ages of onset and multiaxial presentation. This novel variant in TTC19 gene indicated that palatal tremor, hypertrophic olivary degeneration, and axonal neuropathy might be unrecognized manifestations.
    Keywords:  ; Hypertrophic olivary degeneration; mitochondrial complex III deficiency; novel mutation; palatal tremor
    DOI:  https://doi.org/10.4103/neurol-india.Neurol-India-D-24-00143
  10. Mitochondrion. 2025 Jul 11. pii: S1567-7249(25)00068-6. [Epub ahead of print]85 102071
    A Tunisian POLG mutation expands the clinical spectrum of POLG-related disorders.
    Abir Zioudi, Ismail Gouiza, Said Galai, Meriem Hechmi, Hedia Klaa, Zouhour Miladi, Thouraya Ben Younes, Hanene Benrhouma, Ilhem Ben Youssef-Turki, Souheil Omar, Guy Lenaers, Rym Kefi, Neziha Gouider-Khouja, Ichraf Kraoua.
      Mitochondrial Neuro-Gastro-Intestinal Encephalopathy (MNGIE) is a rare and fatal mitochondrial disorder caused by biallelic mutations in the TYMP gene. In rare cases, it can be caused by pathogenic variants in the POLG gene, with a clinical presentation similar to that of TYMP-related MNGIE, except for the absence of leukoencephalopathy. Here we report the cases of six Tunisian patients presenting with a homogeneous clinical MNGIE-like phenotype, characterized by an early infantile onset. Key features included psychomotor delay or regression, peripheral neuropathy, gastrointestinal disturbances, hypotrophy or growth retardation, and elevated cerebrospinal fluid protein levels. All patients originated from the same governorate and carried the same homozygous POLG variant c.2391G > T (p.Met797Ile), which may suggest a founder effect.
    Keywords:  Hyperproteinorachia; MNGIE-like phenotype; Mitochondrial Neuro-Gastro-Intestinal Encephalopathy (MNGIE); Mitochondrial disorders; POLG
    DOI:  https://doi.org/10.1016/j.mito.2025.102071
  11. FASEB J. 2025 Jul 31. 39(14): e70825
    Deletion of Skeletal Muscle Mitochondrial Glutamic-Oxaloacetic Transaminase (GOT2) Enhances Oxaloacetate Inhibition of Succinate Dehydrogenase and Alters Substrate Selectivity.
    Brian D Fink, Ritu Som, Liping Yu, William I Sivitz.
      Oxaloacetate (OAA) is converted to aspartate by mitochondrial glutamic-oxaloacetic transaminase 2 (GOT2) along with the conversion of glutamate to alpha-ketoglutarate (α-KG). Glutamate can also be directly converted to α-KG by glutamate dehydrogenase. In past work, we found that in skeletal muscle mitochondria energized by succinate alone, oxaloacetate accumulates and inhibits succinate dehydrogenase (complex II) in a manner dependent on inner membrane potential (ΔΨ). Here, we tested the hypothesis that deleting GOT2 would increase OAA concentrations, decrease complex II-energized respiration, and alter the selectivity of succinate versus glutamate for energy. Incubating wild-type mitochondria with succinate and glutamate revealed that increments in ADP increased OAA and caused a preferential use of glutamate for energy. Deletion of GOT2 compared to wild-type decreased complex II energized respiration, increased OAA, and decreased consumption of glutamate relative to succinate. OAA accumulation was also associated with decreased conversion of succinate to fumarate and malate. These findings are consistent with GOT2 control of metabolite flow through succinate dehydrogenase via regulation of OAA and consequent inhibition of succinate dehydrogenase. In contrast to respiration energized at complex II, when mitochondria were energized at complex I by pyruvate + malate, respiration did not differ between GOT2KO and WT mitochondria, and oxaloacetate was not detectable. In summary, GOT2 and OAA mediate complex II respiration and mitochondrial energy substrate selectivity.
    Keywords:  glutamic‐oxaloacetic transaminase‐2; mitochondria; mitochondrial complex II; mitochondrial inner membrane potential; oxaloacetate; respiration; skeletal muscle; succinate dehydrogenase
    DOI:  https://doi.org/10.1096/fj.202501071R
  12. bioRxiv. 2025 Jun 25. pii: 2025.06.24.661304. [Epub ahead of print]
    Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders.
    Keaton J Solo, Yuxun Zhang, Sivakama S Bharathi, Bob B Zhang, Adam C Richert, Alexandra V Schmidt, Shakuntala Basu, Clinton Van't Land, Olivia D'Annibale, Timothy C Wood, Jerry Vockley, Eric S Goetzman.
      Long-chain fatty acid oxidation disorders (LC-FAODs) cause energy deficits in heart and skeletal muscle that is only partially corrected by current medium-chain lipid therapies such as triheptanoin. We find that heart and muscle lack medium-chain acyl-CoA synthetases, limiting the capacity for β-oxidation of medium-chain fatty acids. Instead, heart and muscle mitochondria robustly respire on medium-chain acylcarnitines. The mitochondrial matrix enzyme carnitine acetyltransferase (CrAT) efficiently converts orally delivered octanoylcarnitine (C 8 -carnitine) to octanoyl-CoA for energy generation. C 8 -carnitine exhibits twice the oral bioavailability of triheptanoin and distributes to muscle and heart. A single oral dose markedly enhances grip strength, basal locomotion, and treadmill endurance while attenuating lactate and creatine kinase elevations in multiple mouse models of LC-FAODs. Thus, medium-chain acylcarnitines overcome a previously unrecognized metabolic bottleneck in LC-FAOD muscle and may represent an alternative to triglyceride-based therapies for bioenergetic disorders.
    DOI:  https://doi.org/10.1101/2025.06.24.661304
  13. bioRxiv. 2025 Jun 26. pii: 2025.06.24.661357. [Epub ahead of print]
    Nutrient-Responsive Formation of Mitochondrial-Derived Structures in Caenorhabditis elegans.
    Miriam Valera-Alberni, Anne Lanjuin, Silvia Romero-Sanz, Kristopher Burkewitz, Adam L Hughes, William B Mair.
      Mitochondrial morphology is dynamically regulated through remodeling processes essential for maintaining mitochondrial function and ensuring cellular and metabolic homeostasis. While classical models of mitochondrial dynamics center on cycles of fragmentation and elongation, emerging evidence highlights additional membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and mitochondrial-derived compartments (MDCs). These mitochondrial-derived structures, however, have been predominantly characterized in cultured cells and unicellular organisms, leaving their relevance in multicellular systems largely unexplored. Here, we identify a previously uncharacterized class of mitochondrial-derived structures in Caenorhabditis elegans muscle cells that are induced in response to intermittent fasting. We show that these structures appear specifically during the refeeding phase- coinciding with mitochondrial elongation -and are absent during fasting. Consistent with MDCs, the structures, approximately 1 µm in size, are enriched in outer mitochondrial membrane markers such as TOMM-20 aa1-49 and TOMM-70, but notably lack components of the inner mitochondrial membrane. Their formation requires the microtubule-associated MIRO-1/2 proteins, and their size is modulated by the mitochondrial dynamics machinery. Together, our findings reveal a nutritionally regulated mitochondrial remodeling event in C. elegans muscle that may play a role in mitochondrial quality control and adaptation to metabolic cues.
    DOI:  https://doi.org/10.1101/2025.06.24.661357
  14. Res Sq. 2025 Jun 26. pii: rs.3.rs-6346822. [Epub ahead of print]
    MICU proteins facilitate Ca2+-dependent mitochondrial metabolon formation to regulate cellular energetics - independent of MCU.
    John Elrod, Henry Cohen, Benjamin Gottschalk, Carmen Choya-Foces, Adam Chatoff, Anya Wilkinson, Joanne Garbincius, Adyson Johnson, Tyler Stevens, Jordan Howe, Emily Megill, Jennyfer Ngo, Dhanendra Tomar, Nathaniel Snyder, Wolfgang Graier.
      Mitochondrial matrix Ca2+ concentration ([matrixCa2+]) is theorized to be an essential regulator of mitochondrial metabolism by positively regulating key mitochondrial dehydrogenases. However, ablation or functional inhibition of the mitochondrial calcium uniporter channel (mtCU) fails to significantly perturb basal metabolism and is largely phenotypically silent in the absence of stress. This begs the question, what are the primary molecular mechanisms regulating calcium-dependent changes in metabolism? The primary function of MICU proteins (MICU1, MICU2, and MICU3) is reported to be gatekeeping of the mtCU and regulating mitochondrial Ca2+ uptake. Here, we demonstrate that MICU proteins function in coordination to impart Ca2+-dependent regulation to FADH2-dependent mitochondrial dehydrogenases through metabolon formation independent of the mtCU and [matrixCa2+]. Our results demonstrate that MICU proteins differentially localize to mitochondrial microdomains and form heterodimers and interactomes in response to intermembrane space Ca2+ binding their respective EF-hand domains. Utilizing an equimolar expression platform coupled with unbiased proteomics we reveal unique interactomes for MICU1/2 versus MICU1/3 heterodimers and demonstrate that MICU proteins control coupling of Mitochondrial Glycerol-3-Phosphate Dehydrogenase with Succinate Dehydrogenase/Complex II and impart Ca2+-dependent changes in activity. We propose that MICU-mediated mitochondrial metabolons are a fundamental system facilitating matching of mitochondrial energy production with cellular demand and is the primary physiological Ca2+ signaling mechanism regulating homeostatic energetics - not mtCU-dependent changes in [matrixCa2+].
    DOI:  https://doi.org/10.21203/rs.3.rs-6346822/v1
  15. BMC Biol. 2025 Jul 15. 23(1): 214
    Organic cation transporter 3 on neuronal mitochondria mediates MPP+-induced mitochondrial dysfunction and neurotoxicity in a TIMM22-dependent manner.
    Ao Guan, Sida Han, Suzhen Liang, Weiwei Shen, Min Guo, Mei Cui.
       BACKGROUND: Mitochondria play crucial roles in cellular metabolism, and metabolite compartmentalization significantly impacts mitochondrial function and disease pathophysiology. MPP+ accumulation in mitochondria, a key factor in MPTP-induced neurodegeneration, leads to mitochondrial dysfunction, such as respiratory chain inhibition, ultimately leading to neuronal death. However, the mechanisms underlying mitochondrial MPP+ accumulation remain poorly understood. Organic cation transporter 3 (OCT3), a passive transporter mediating MPP+ transport, has been observed on the mitochondrial membrane, but it remains unclear whether mitochondrial OCT3 is involved in MPP+ accumulation in mitochondria.
    RESULTS: OCT3 was detected in the mitochondria fraction of SH-SY5Y cells, located on both the inner membrane and outer membrane. Following MPP+ incubation, there was a significant increase in mitochondrial uptake of MPP+, which was mitigated by OCT3 inhibition. Knockdown of the translocase of inner mitochondrial membrane 22 (TIMM22), an important component of the mitochondrial protein import apparatus, successfully reduced OCT3 levels on mitochondria without impairing mitochondrial morphology or mitochondrial membrane potential. TIMM22 knockdown reduced mitochondrial MPP+ uptake, which in turn rescued MPP+-induced mitochondrial fragmentation, complex I inhibition, and mitochondrial membrane potential reduction. Furthermore, TIMM22 knockdown suppressed caspase-9 and caspase-3 activation and reversed the alterations of BAX and BCL-xL induced by mitochondrial MPP+ accumulation.
    CONCLUSIONS: Here we found that OCT3 on neuronal mitochondria serves as an effective MPP+ transporter, crucial for mitochondrial MPP+ uptake and MPP+-induced neurotoxicity. Furthermore, TIMM22 downregulation can selectively reduce mitochondrial OCT3 and reverse MPP+-induced mitochondrial dysfunction and neurotoxicity, highlighting TIMM22 and OCT3 as potential therapeutic targets for MPP+-associated neurodegeneration and diseases.
    Keywords:  MPP+ ; Mitochondria; Neurodegeneration; Organic cation transporter 3; TIMM22
    DOI:  https://doi.org/10.1186/s12915-025-02318-4
  16. bioRxiv. 2025 Jun 15. pii: 2025.06.14.659625. [Epub ahead of print]
    Synergistic Control of Mitochondrial Dynamics and Function by ERAD and Autophagy in Brown Adipocytes.
    Xinxin Chen, Siwen Wang, Mauricio Torres, Sijie Hao, Shengyi Sun, Ling Qi.
      Mitochondrial quality control is essential for maintaining cellular energy homeostasis, particularly in brown adipocytes where dynamic mitochondrial remodeling supports thermogenesis. Although the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy are two major proteostatic systems, how these pathways intersect to regulate mitochondrial integrity in metabolically active tissues remains poorly understood. Here, using adipocyte-specific genetic mouse models combined with high-resolution 2D and 3D ultrastructural imaging technologies, we reveal an unexpected synergy between SEL1L-HRD1 ERAD and autophagy in maintaining mitochondrial structure and function in brown adipocytes. Loss of ERAD alone triggers compensatory autophagy, whereas combined deletion of both pathways (double knockout, DKO) results in severe mitochondrial abnormalities, including the accumulation of hyperfused megamitochondria penetrated by ER tubules, even under basal room temperature conditions. These phenotypes are absent in mice lacking either pathway individually or in SEL1L-IRE1α DKO, highlighting the pathway-specific coordination between ERAD and autophagy. Mechanistically, dual loss of ERAD and autophagy induces ER expansion, excessive ER-mitochondria contact, upregulation of mitochondria-associated membrane (MAM) tethering proteins, impaired calcium transfer, and defective mitochondrial turnover. As a result, DKO adipocytes accumulate dysfunctional mitochondria, exhibit respiratory deficits, and fail to sustain thermogenesis. Collectively, our study uncovers a cooperative and previously unrecognized mechanism of mitochondrial surveillance, emphasizing the critical role of ERAD-autophagy crosstalk in preserving mitochondrial integrity and thermogenic capacity in brown fat.
    One-sentence summary: Our study uncovers a previously unrecognized synergy between SEL1L-HRD1 ERAD and autophagy that is essential for preserving mitochondrial integrity and thermogenic capacity in brown adipocytes, revealing new opportunities for targeting mitochondrial dysfunction in metabolic disease.
    DOI:  https://doi.org/10.1101/2025.06.14.659625
  17. N Engl J Med. 2025 Jul 16.
    Reducing the Risks of Mitochondrial Disease in Children.
    Robin Lovell-Badge.
      
    DOI:  https://doi.org/10.1056/NEJMe2507753
  18. bioRxiv. 2025 May 03. pii: 2025.05.02.651978. [Epub ahead of print]
    Specialized high-capacity mitochondria fuel cell invasion.
    Isabel W Kenny-Ganzert, Lena P Basta, Lianzijun Wang, Qiuyi Chi, Caitlin Su, Katherine S Morton, Joel N Meyer, David R Sherwood.
      Cell invasion through basement membrane (BM) is energetically intensive, and how an invading cell produces high ATP levels to power invasion is understudied. By generating 20 endogenously tagged mitochondrial proteins, we identified a specialized mitochondrial subpopulation within the C. elegans anchor cell (AC) that localizes to the BM breaching site and generates elevated ATP to fuel invasion. These ETC-enriched high-capacity mitochondria are compositionally unique, harboring increased protein import machinery and dense cristae enriched with ETC components. High-capacity mitochondria emerge at the time of AC specification and depend on the AC pro-invasive transcriptional program. Finally, we show that netrin signaling through a Src kinase directs microtubule polarization, which facilitates metaxin adaptor complex dependent ETC-enriched mitochondrial trafficking to the AC invasive front. Our studies reveal that an invasive cell produces high ATP by generating and localizing high-capacity mitochondria. This might be common strategy used by other cells to meet energy demanding processes.
    DOI:  https://doi.org/10.1101/2025.05.02.651978
  19. Angew Chem Int Ed Engl. 2025 Jul 15. e202502470
    Mitochondria-Targeting Abasic Site-Reactive Probe (mTAP) Enables the Manipulation of Mitochondrial DNA Levels.
    Anal Jana, Yu-Hsuan Chen, Linlin Zhao.
      Mitochondrial DNA (mtDNA) encodes essential genes for mitochondrial and cellular functions and acts as a cell signaling molecule in innate immune and inflammatory responses. Defects in mtDNA are implicated in a range of mitochondrial disorders and human diseases. Currently, no chemical strategy exists to prevent mtDNA loss under genotoxic stress. To address this, we developed a mitochondria-targeting probe (mTAP) that selectively reacts with key mtDNA repair intermediates-abasic (AP) sites. We confirmed that mTAP forms oxime conjugates exclusively with mitochondrial AP sites without conjugation with nuclear AP sites. Upon mTAP conjugation, DNA substrates containing AP sites were resistant to cleavage by AP endonuclease (APE1) and mitochondrial extracts. This conjugation significantly reduced the DNA-binding affinity of APE1 without affecting the DNA-binding activity of a mtDNA-packaging factor, mitochondrial transcription factor A (TFAM). Importantly, cellular experiments demonstrated that mTAP treatment alleviated the decrease in mtDNA and transcription product levels induced by mitochondrial AP site damage. Functional assays also demonstrated that mTAP treatment did not compromise mtDNA replication activity or increase the overall mtDNA damage level. These findings highlight the potential of mTAP as a valuable chemical tool to modulate mtDNA levels under genotoxic stress.
    Keywords:  Abasic sites; DNA Repair; DNA damage; Mitochondrial DNA; Nucleic acid modifications
    DOI:  https://doi.org/10.1002/anie.202502470
  20. Aging Cell. 2025 Jul 16. e70175
    Beyond the Pseudogene: p17/PERMIT as a Mitochondrial Trafficking Protein Linking Aging and Neurodegeneration.
    Onder Albayram, Natalia Oleinik, Besim Ogretmen.
      The misclassification of functional genomic loci as pseudogenes has long obscured critical regulators of cellular homeostasis, particularly in aging-related pathways. One such locus, originally annotated as RPL29P31, encodes a 17-kDa protein now redefined as PERMIT (Protein that Mediates ER-Mitochondria Trafficking). Through rigorous experimental validation-including antibody development, gene editing, lipidomics, and translational models-p17/PERMIT has emerged as a previously unrecognized mitochondrial trafficking chaperone. Under aging or injury-induced stress, p17 mediates the ER-to-mitochondria translocation of Ceramide Synthase 1 (CerS1), facilitating localized C18-ceramide synthesis and autophagosome recruitment to initiate mitophagy. Loss of p17 impairs mitochondrial quality control, accelerating neurodegeneration, and sensorimotor decline in both injury and aging models. This Perspective highlights p17 as a paradigm-shifting discovery at the intersection of lipid signaling, mitochondrial biology, and genome reannotation, and calls for a broader reassessment of the "noncoding" genome in aging research. We summarize a rigorous multi-platform validation pipeline-including gene editing, antibody generation, lipidomics, proteomics, and functional rescue assays-that reclassified p17 as a bona fide mitochondrial trafficking protein. Positioned at the intersection of lipid metabolism, organelle dynamics, and genome reannotation, p17 exemplifies a growing class of overlooked proteins emerging from loci historically labeled as pseudogenes, urging a systematic reevaluation of the "noncoding" genome in aging research.
    DOI:  https://doi.org/10.1111/acel.70175
  21. Cardiovasc Pathol. 2025 Jul 10. pii: S1054-8807(25)00034-1. [Epub ahead of print]79 107749
    Cardiac pathology in a patient with a novel pathogenic variant c.703del (p.Ile235SerfsTer4) of the TAFAZZIN gene.
    Marisa Prasanpanich, Majid Husain, Nancy J Halnon, Richard Chang, Neda Zadeh, Jason Knight, Gregory A Fishbein.
       INTRODUCTION: Barth syndrome is a mitochondrial disease caused by loss-of-function mutations in the TAFAZZIN gene located on chromosome Xq28 encoding a transacylase essential for cardiolipin remodeling. Most patients develop dilated cardiomyopathy and progressive heart failure within the first year of life with some requiring cardiac transplantation.
    CASE REPORT: A full-term male infant with an anatomically normal heart presented postnatally with cardiogenic shock necessitating VA-ECMO within the second day of life. WGS revealed a pathogenic c.703del (p.Ile235SerfsTer4) variant in the TAFAZZIN gene. While on the waitlist for cardiac transplantation, he was treated with intravenous Elamipretide, a mitochondrially-targeted tetrapeptide interacting with cardiolipin, without significant side effects, started at three weeks old and continued through transplantation. He underwent a successful orthotopic cardiac transplantation at five months of age. The explanted heart showed dilated left ventricle with hypertrabeculation and was remarkable for endocardial fibroelastosis and diffuse sarcoplasmic vacuolization with coarse granularity. Ultrastructurally, mitochondria displayed megaconia and replacement of cristae by circular, vesicular, cylindrical, and fingerprint-like structures. He continues to do well as an outpatient and remains on subcutaneous Elamipretide.
    SUMMARY: We describe a case of Barth syndrome harboring a novel pathogenic variant of the TAFAZZIN gene exhibiting dilated cardiomyopathy, hypertrabeculation, endocardial fibroelastosis, and prominent mitochondrial abnormality. Elamipretide was well tolerated.
    Keywords:  Barth syndrome; Elamipretide; Mitochondrial cardiomyopathy
    DOI:  https://doi.org/10.1016/j.carpath.2025.107749
  22. Hum Mol Genet. 2025 Jul 18. pii: ddaf123. [Epub ahead of print]
    Heart is the most susceptible organ in an isogenic background to loss of function mutations in the mitochondrial metallochaperone SCO1.
    Sampurna Ghosh, Kimberly A Jett, Zakery N Baker, Aren Boulet, Amzad Hossain, Stanley A Moore, Martina Ralle, Binbing Ling, Paul A Cobine, Scot C Leary.
      SCO1 is a nuclear-encoded protein with roles in cytochrome c oxidase (COX) assembly and the regulation of copper homeostasis. It remains unclear, however, why mutations in this ubiquitously expressed gene product cause distinct, tissue-specific forms of disease that primarily affect heart, liver or brain function. To gain a better understanding of the clinical heterogeneity observed across SCO1 pedigrees, we deleted Sco1 in the murine brain and observed a severe COX deficiency in the absence of altered tissue copper content that was tied to early, neonatal lethality. We therefore transitioned to whole body knockin mice expressing allelic variants of SCO1 that are pathogenic in humans to more accurately reflect the patient condition and avoid the lethality associated with tissue-specific Sco1 knockout. Sco1M277V mice exhibited the most severe COX deficiency in their brain, modeling the pathophysiological consequences of the p.Met294Val variant in humans and supporting the idea that the primary role of SCO1 in this tissue is to promote COX assembly. Phenotyping of Sco1G115S, Sco1P157L and Sco1M277V mice nonetheless emphasized that the heart generally displayed the most severe, combined COX and copper deficiency, with Sco1G115S and Sco1P157L hearts developing a dilated cardiomyopathy that was accompanied by significant depletion of their mitochondrial copper pool. Taken together, our findings suggest that in an isogenic context the heart is the most susceptible organ to loss of SCO1 function, and that single nucleotide polymorphisms at modifier loci in an outbred population likely contribute to the clinical heterogeneity observed across SCO1 pedigrees.
    Keywords:  Cytochrome c oxidase; SCO1; copper; mitochondrial disease
    DOI:  https://doi.org/10.1093/hmg/ddaf123
  23. Curr Drug Saf. 2025 Jul 11.
    Mitochondrial Dysfunction in Neurodegenerative Disorders: Role of Prototype Targeted Drug Delivery Solutions.
    Dilpreet Singh.
      Mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Targeted drug delivery to mitochondria represents a promising therapeutic strategy to mitigate neuronal degeneration and preserve mitochondrial function in these devastating conditions. This review provides a comprehensive overview of recent advances in targeted drug delivery solutions for mitochondrial dysfunction in neurodegenerative disorders. The mechanisms underlying mitochondrial dysfunction in AD, PD, HD, and ALS are explored, highlighting the specific challenges and opportunities for therapeutic intervention. Emerging drug delivery technologies are discussed, including mitochondriaresponsive systems, nanoparticles, peptides, and viral vectors, designed to deliver therapeutic agents directly to mitochondria along with suitable case studies. Furthermore, preclinical and clinical studies evaluating the efficacy and safety of mitochondria-targeted therapeutics are reviewed, and future directions and challenges in the field are outlined. By elucidating the intersection of mitochondrial biology and drug delivery, this review aims to inspire further research and innovation toward effective treatments for neurodegenerative diseases.
    Keywords:  Mitochondrial dysfunction; drug delivery; effective treatment; research; targeted therapy.
    DOI:  https://doi.org/10.2174/0115748863375490250626163609
  24. bioRxiv. 2025 Jun 18. pii: 2025.06.18.660458. [Epub ahead of print]
    Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
    Rebecca Cornell, Ava Handley, Roger Pocock.
      Animals integrate environmental and internal cues to maintain homeostasis and health. The mitochondrial stress response is an essential cytoprotective mechanism, and priming its activation provides a survival advantage. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signalling from carbon dioxide sensing neurons to govern a non-canonical mitochondrial stress response in the intestine. This stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. GCY-9 loss disrupts pathogen avoidance, leading to indiscriminate feeding. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset risks associated with this behaviour. Thus, environmental sensing by peripheral neurons can pre-emptively enhance systemic mitochondrial function in response to metabolic uncertainty.
    One-Sentence Summary: Protecting mitochondria by integrating environmental signals.
    DOI:  https://doi.org/10.1101/2025.06.18.660458
  25. Int J Mol Sci. 2025 Jul 02. pii: 6364. [Epub ahead of print]26(13):
    CRISPRa-Mediated Increase of OPA1 Expression in Dominant Optic Atrophy.
    Giada Becchi, Michael Whitehead, Joshua P Harvey, Paul E Sladen, Mohammed Dushti, J Paul Chapple, Patrick Yu-Wai-Man, Michael E Cheetham.
      Dominant Optic Atrophy (DOA) is the most common inherited optic neuropathy and presents as gradual visual loss caused by the loss of retinal ganglion cells (RGCs). Over 60% of DOA cases are caused by pathogenic variants in the OPA1 gene, which encodes a mitochondrial GTPase essential in mitochondrial fusion. Currently, there are no treatments for DOA. Here, we tested the therapeutic potential of an approach to DOA using CRISPR activation (CRISPRa). Homology directed repair was used to introduce a common OPA1 pathogenic variant (c.2708_2711TTAGdel) into HEK293T cells as an in vitro model of DOA. Heterozygous c.2708_2711TTAGdel cells had reduced levels of OPA1 mRNA transcript, OPA1 protein, and mitochondrial network alterations. The effect of inactivated Cas9 fused to an activator (dCas9-VPR) was tested with a range of guide RNAs (gRNA) targeted to the promotor region of OPA1. gRNA3 and dCas9-VPR increased OPA1 expression at the RNA and protein level towards control levels. Importantly, the correct ratio of OPA1 isoform transcripts was maintained by CRISPRa. CRISPRa-treated cells showed an improvement in mitochondrial networks compared to untreated cells, indicating partial rescue of a disease-associated phenotype. Collectively, these data support the potential application of CRISPRa as a therapeutic intervention in DOA.
    Keywords:  CRISPR; CRISPR activation; OPA1; alternative splicing; gene editing; gene expression; mitochondria; mitochondrial fusion; optic atrophy; retinal ganglion cell
    DOI:  https://doi.org/10.3390/ijms26136364
  26. Stem Cells Dev. 2025 Jul 16.
    Impact of Mitochondrial A3243G Mutation on Skeletal Muscle Energy Metabolism: Evidence from Human Induced Pluripotent Stem Cell-Derived Skeletal Muscle Cells.
    Ritsuko Oikawa, Kenichi Yokota, Junji Fujikura, Tomoya Uchimura, Kazutoshi Miyashita, Kaori Hayashi, Hidetoshi Sakurai, Masakatsu Sone.
      The study of skeletal muscle disorders in patients with mitochondrial diseases is crucial for gaining insights into disease physiology; however, their molecular mechanisms have not been fully elucidated. We previously established human-induced pluripotent stem (iPS) cells in two patients with the mitochondrial DNA (mtDNA) A3243G mutation and isolated iPS cell clones with either undetectable or high levels of mutations. In the present study, we established skeletal muscle cells from iPS cells with mutation-high and mutation-undetectable clones and comparatively analyzed their mitochondrial functions. Fluorescence immunostaining, fusion index, and qRT-PCR revealed no differences in the morphology, differentiation efficiency, or expression levels of skeletal muscle markers between the mutation-high and mutation-undetectable clones. However, the basal oxygen consumption rate, an indicator of mitochondrial respiration, and adenosine triphosphate (ATP) production were reduced in the mutation-high clones of patients 1 and 2. In addition, the extracellular acidification rate, an indicator of glycolytic activity, was reduced in mutation-high clones of patient 2, who exhibited a more severe clinical phenotype. In the mutation-high clones of both patients, mitochondrial Complex I activity and mtDNA copy number were also reduced, whereas the expression levels of peroxisome proliferator-activated receptor gamma coactivator 1α and glucose transporter type 4 were upregulated, indicating compensation for ATP deficiency. These findings reveal the effects of mitochondrial disorders on energy metabolism in skeletal muscles and provide novel insights into skeletal muscle dysfunction in patients with mitochondrial diseases.
    Keywords:  induced pluripotent stem cells; mitochondria; mitochondrial disease; oxygen consumption rate; skeletal muscle
    DOI:  https://doi.org/10.1177/15473287251359330
  27. J Neurol Sci. 2025 Jul 09. pii: S0022-510X(25)00222-9. [Epub ahead of print]476 123605
    Neuroimaging patterns in patients with mitochondrial leukoencephalopathies.
    Sonal Sharma, James Peterson, Cesar Augusto Alves, Rui Xiao, Amy Goldstein.
       BACKGROUND AND OBJECTIVES: Leukoencephalopathies are characterized by white matter (WM) abnormalities and include various primary mitochondrial diseases (MD) that impact mitochondrial function across all neuroglial cells. Understanding these associations is vital for effective clinical management.
    METHODS: We performed a retrospective analysis of patients with genetically confirmed MD who exhibited white matter abnormalities at a pediatric academic medical center. Data were obtained through medical record reviews, collecting information on demographics, genetic etiology, features of WM involvement, and other areas such as the basal ganglia, cortex, cerebellum, and spine on MRI. Biomarkers like CSF protein and plasma lactate levels were also recorded. Statistical analysis was conducted using R version 4.4.1 to assess significance of specific MRI features in relation to nuclear vs. mitochondrial DNA.
    RESULTS: Among 192 MD patients, 142 had available neuroimaging. Of these, 43 (30 %) patients with a median age of 15.5 months exhibited WM involvement, with 53.4 % being female. The most common findings were periventricular (32 %), diffuse (42 %), and multifocal (17 %) WM lesions, with corpus callosum involvement in 51 % of cases. Distinct patterns observed included cystic changes (19 %), diffusion restriction (42 %), and white matter volume loss (40 %). Genetic analysis revealed a diverse range of mutations affecting mtDNA (30 %) and nDNA (70 %) genes.
    DISCUSSION: Our study highlights specific neuroimaging patterns associated with leukoencephalopathies in MD. For example, periventricular involvement in MTRFR mutations and diffuse abnormalities in FBXL4 mutations reflect the variability of WM manifestations. These findings can help clinicians identify the genetic etiology in this patient cohort.
    Keywords:  Leukoencephalopathies; Neuroimaging; Primary mitochondrial disease; White matter changes
    DOI:  https://doi.org/10.1016/j.jns.2025.123605
  28. N Engl J Med. 2025 Jul 16.
    Advances in Preventing Transmission of Mitochondrial DNA Diseases.
    Julie Steffann.
      
    DOI:  https://doi.org/10.1056/NEJMe2507755
  29. Proc Natl Acad Sci U S A. 2025 Jul 22. 122(29): e2507279122
    Structures of Chaetomium thermophilum TOM complexes with bound preproteins.
    Ahmed-Noor A Agip, Pamela Ornelas, Tzu-Jing Yang, Ermanno Uboldi, Sabine Häder, Melanie A McDowell, Werner Kühlbrandt.
      Mitochondria import most of their proteins from the cytoplasm through the TOM complex. Preproteins containing targeting signals are recognized by the TOM receptor subunits and translocated by Tom40 across the outer mitochondrial membrane. We present four structures of the preprotein-bound and preprotein-free TOM core and holo complexes from the thermophilic fungus Chaetomium thermophilum, obtained by single-particle electron cryomicroscopy. Our structures reveal the symmetric arrangement of two copies of the Tom20 receptor subunit in the TOM holo complex. Several different conformations of Tom20 within the TOM holo complex highlight the dynamic nature of the receptor. The structure of preprotein-bound Tom20 provides insight into the early stages of protein translocation.
    Keywords:  TOM complex; cryoEM; mitochondrial translocation; preproteins
    DOI:  https://doi.org/10.1073/pnas.2507279122
  30. N Engl J Med. 2025 Jul 16.
    Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease.
    Louise A Hyslop, Emma L Blakely, Magomet Aushev, Jordan Marley, Yuko Takeda, Angela Pyle, Eilis Moody, Catherine Feeney, Jan Dutton, Carol Shaw, Sarah J Smith, Kate Craig, Charlotte L Alston, Lisa Lister, Karina Endacott, Samantha Byerley, Helen McDermott, Kathryn Wilson, Lynne Botham, Beth Matthew, Nilendran Prathalingam, Matthew Prior, Alison Murdoch, Douglass M Turnbull, Gavin Hudson, Meenakshi Choudhary, Robert W Taylor, Rekha N Pillai, Jane A Stewart, Robert McFarland, Mary Herbert.
       BACKGROUND: Children born to women who carry pathogenic variants in mitochondrial DNA (mtDNA) are at risk for a range of clinical syndromes collectively known as mtDNA disease. Mitochondrial donation by pronuclear transfer involves transplantation of nuclear genome from a fertilized egg from the affected woman to an enucleated fertilized egg donated by an unaffected woman. Thus, pronuclear transfer offers affected women the potential to have a genetically related child with a reduced risk of mtDNA disease.
    METHODS: We offered mitochondrial donation (by pronuclear transfer) or preimplantation genetic testing (PGT) to a series of women with pathogenic mtDNA variants who sought to reduce the transmission of these variants to their children. Patients with heteroplasmy (variants present in a proportion of copies of mtDNA) were offered PGT, and patients with homoplasmy (variants present in all copies of mtDNA) or elevated heteroplasmy were offered pronuclear transfer.
    RESULTS: Clinical pregnancies were confirmed in 8 of 22 patients (36%) and 16 of 39 patients (41%) who underwent an intracytoplasmic sperm injection procedure for pronuclear transfer or for PGT, respectively. Pronuclear transfer resulted in 8 live births and 1 ongoing pregnancy. PGT resulted in 18 live births. Heteroplasmy levels in the blood of the 8 infants whose mothers underwent pronuclear transfer ranged from undetectable to 16%. Levels of the maternal pathogenic mtDNA variant were 95 to 100% lower in 6 newborns and 77 to 88% lower in 2 newborns than in the corresponding enucleated zygotes. Heteroplasmy levels were known for 10 of the 18 infants whose mothers underwent PGT and ranged from undetectable to 7%.
    CONCLUSIONS: We found that mitochondrial donation through pronuclear transfer was compatible with human embryo viability. An integrated program involving pronuclear transfer and PGT was effective in reducing the transmission of homoplasmic and heteroplasmic pathogenic mtDNA variants. (Funded by NHS England and others.).
    DOI:  https://doi.org/10.1056/NEJMoa2415539
  31. bioRxiv. 2025 Jul 11. pii: 2025.07.10.663832. [Epub ahead of print]
    Multi-site phosphorylation of BCL2L13 in a TBK1- and AMPK-dependent manner reveals new modes of mitophagy regulation.
    Hoda Ahmed, Mack B Reynolds, Gary Kasof, Gerald S Shadel, Reuben Shaw.
      Mitophagy is a selective autophagic process that eliminates damaged mitochondria via lysosomal degradation, playing a crucial role in maintaining cellular metabolic balance. Mitophagy can occur through two pathways: ubiquitin-dependent and ubiquitin-independent. Recently, we and others have shown that, upon mitochondrial stress, AMP-activated protein kinase (AMPK) contributes to Parkin-mediated, ubiquitin-dependent mitophagy. The ubiquitin-independent pathway involves multiple outer mitochondrial membrane (OMM) "mitophagy receptors" that contain LC3-interacting region (LIR) motifs, including BNIP3, NIX/ BNIP3L, FUNDC1, and BCL2L13. LIR motifs bind Atg8/LC3 family proteins, facilitating the recruitment of the autophagosome membrane to target damaged mitochondria for degradation. The kinase Unc-51 Like autophagy activating kinase 1 (ULK1) phosphorylates the serine preceding the LIR motif in BNIP3, NIX, and FUNDC1, enhancing their binding to LC3 and promoting mitophagy. However, while BCL2L13 has been identified as a ULK1 binding partner, its regulation by phosphorylation remains unclear. We utilized mass spectrometry (MS) to map phosphorylation sites in BCL2L13 following mitochondrial stress and developed phospho-specific antibodies against two sites, Ser261 and Ser275, which were induced after exposure to the mitochondrial uncoupler, CCCP. Endogenous BCL2L13 Ser261 and Ser275 were both phosphorylated in an AMPK-dependent manner in cells and tissues. As neither site matches the established AMPK substrate consensus motif, we sought to identify which kinases directly mediate their phosphorylation downstream of AMPK. Surprisingly, genetic studies revealed that ULK1 is not regulating either site, but instead, TBK1 is controlling Ser275. This work reveals that BCL2L13 is unique amongst mitophagy receptors in being activated by mitochondrial stress and innate immune stimuli in an AMPK- and TBK1-dependent manner.
    DOI:  https://doi.org/10.1101/2025.07.10.663832
  32. Med Arch. 2025 ;79(3): 241-248
    Leber's Hereditary Optic Neuropathy.
    Allen Popovic-Beganovic, Vladislav Dzinic.
       Background: Leber's hereditary optic neuropathy (LHON) is the most common maternally inherited disease linked to mitochondrial DNA (mtDNA). The patients present with subacute asymmetric bilateral vision loss. It is a rare disease that typically affects young adults-men more than women-and is a relatively common cause of blindness. The majority (more than 95%) of patients have one of three mtDNA point mutations: m.14484T→C, m.3460G→A, or m.11778G→ A.The hallmark of hereditary optic neuropathies determined by mitochondrial dysfunction is the vulnerability and degeneration of retinal ganglion cells (RGC). Due to its low prevalence in the population (1:50,000), this diagnosis is often overlooked, misdiagnosed, and mismanaged, which may exacerbate symptoms.
    Objective: The aim of the paper is to present the complexity and challenge of making the correct diagnosis in patients with progressive vision loss.
    Case report: A 42-year-old patient, female, complains of a bilateral decrease in visual acuity after surgery performed under general anaesthesia. The visual acuity value at the first ophthalmological examination was 0.8 bilaterally and could not be corrected. The OCT finding was within the ''reference values'', while the visual field finding showed non-specific changes. Further examinations by a neurologist and psychiatrist do not lead to a correct diagnosis. After a long time, genetic testing reveals a genetic mutation and a diagnosis of LHON is made.
    Conclusion: Although still uncommon, the presentation of LHON in middle-aged women is possible and should be considered as one of the differential diagnoses in a patient when painless vision loss occurs.
    Keywords:  Leber’s hereditary optic neuropathy; depression; glaucoma; multiple sclerosis; retinal ganglion cell layer
    DOI:  https://doi.org/10.5455/medarh.2025.79.241-248
  33. bioRxiv. 2025 Jun 26. pii: 2025.06.26.661693. [Epub ahead of print]
    Genetic mapping of lifespan and mitochondrial stress response in C. elegans.
    Xiaoxu Li, Weisha Li, Arwen W Gao, Yunyun Zhu, Elena Katsyuba, Katherine A Overmyer, Terytty Yang Li, Ziwen Wang, Luc Legon, Lucie Plantade, Laurent Mouchiroud, Matteo Cornaglia, Hao Li, Riekelt H Houtkooper, Joshua J Coon, Johan Auwerx.
      The mitochondrial unfolded protein response (UPR mt ) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPR mt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPR mt modulator, fipp-1 / FIP1L1 , which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, underscoring its translational relevance. Overall, our findings demonstrate a novel UPR mt modulator across species and provide insights into potential translational research.
    DOI:  https://doi.org/10.1101/2025.06.26.661693
  34. bioRxiv. 2025 Jun 17. pii: 2025.06.16.660029. [Epub ahead of print]
    The Human LRRK2-R1441G Mutation Drives Age-Dependent Oxidative Stress and Mitochondrial Dysfunction in Dopaminergic Neurons.
    Yuanxin Chen, Lianteng Zhi, Shiquan Cui, Huaixin Wang, Chenbo Zeng, Hui Zhang.
      Mitochondrial dysfunction and oxidative stress are central to Parkinson's disease (PD) pathogenesis, particularly affecting substantia nigra pars compacta (SNc) dopamine (DA) neurons. Here, we investigate how the R1441G mutation in leucine-rich repeat kinase 2 (LRRK2), a key genetic contributor to familial and sporadic PD, impacts mitochondrial function in midbrain DA neurons. Using a BAC transgenic mouse model overexpressing human LRRK2-R1441G, we crossed these mice with TH-mito-roGFP mice, enabling mitochondria-targeted redox imaging in DA neurons. The two-photon imaging of acute brain slices from 3-, 6-, and 10-month-old mice revealed a progressive elevated oxidative stress in SNc DA neurons and their striatal projections, accompanied with reduced respiratory complex activity and decline in mitochondrial health. Spatial transcriptomics via GeoMx Digital Spatial Profiler identified molecular changes linked to dysregulated mitochondrial uncoupling protein function and calcium homeostasis. These findings demonstrate age-dependent mitochondrial dysfunction in LRRK2-mutant SNc DA neurons, highlighting calcium channels and uncoupling proteins as potential therapeutic targets to slow PD progression.
    DOI:  https://doi.org/10.1101/2025.06.16.660029
  35. Nat Chem Biol. 2025 Jul 15.
    Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.
    Guinevere L Grice, Eleanor Minogue, Hudson W Coates, Mekdes Debela, Richard J Stopforth, Niek Wit, Zongyu Li, Joseph P Crowley, Arthur Kaser, Nicole Kaneider-Kaser, P Robin Antrobus, Marcia C Haigis, Randall S Johnson, James A Nathan.
      Glutarate is an intermediate of amino acid catabolism and an important metabolite for reprogramming T cell immunity. Glutarate exerts its effects either by directly inhibiting metabolite-dependent enzymes or through conjugation to substrates. Intriguingly, glutarylation can occur on protein and nonprotein substrates, but our understanding of these distinct glutaryl modifications is in its infancy. Here we uncover ABHD11 as a noncanonical deglutarylating enzyme critical for maintaining the tricarboxylic acid (TCA) cycle. Mechanistically, we find ABHD11 removes glutaryl adducts from lipoate-an essential fatty acid modification required for the TCA cycle. Loss of ABHD11 results in the accumulation of glutaryl-lipoyl adducts that drive an adaptive program, involving 2-oxoglutarate accumulation, that rewires mitochondrial metabolism. Functionally, this role of ABHD11 influences the metabolic programming of human CD8+ T cells. Therefore, our findings reveal lipoyl glutarylation as a reversible modification that regulates the TCA cycle.
    DOI:  https://doi.org/10.1038/s41589-025-01965-6
  36. Proc Natl Acad Sci U S A. 2025 Jul 22. 122(29): e2503342122
    NEDD4L induces mitochondrial dysfunction and neurodegeneration by promoting LIPT2 degradation in Huntington's disease.
    Pan Fan, Yaqing Liu, Chunyue Liu, Hao Yao, Shibo Xu, Yueqing Jiang, Yang Wu, Yan Liu, Xing Guo.
      Impairment of mitochondrial protein stability is associated with neurodegeneration in Huntington's disease (HD). However, the E3 ligase responsible for maintaining mitochondrial protein homeostasis in HD remains poorly understood. In this study, we demonstrate that NEDD4L protein levels are elevated in human striatal organoids (hSOs) derived from induced pluripotent stem cells of patients as well as in a mouse model of HD. Overexpression of NEDD4L leads to degeneration and cell death of medium spiny neurons (MSNs), along with a reduction in motor activities. Conversely, deletion of NEDD4L restores abnormal MSN morphology, corrects deficits in calcium signaling, alleviates neurodegeneration in HD-hSOs, and improves motor dysfunction observed in YAC128 mice. Mechanistically, NEDD4L disrupts mitochondrial function by binding to lipoyl(octanoyl) transferase 2 (LIPT2) and promoting its degradation through ubiquitination and lysosomal pathways. This process impairs lipoic acid biosynthesis and the lipoylation of E2 subunits of alpha-ketoglutarate dehydrogenase (α-KGDH E2). Furthermore, either overexpressing LIPT2 or administering lipoic acid mitigates neurodegeneration and rectifies deficits in motor coordination activity. These findings unveil a molecular mechanism underlying the regulation of lipoic acid metabolism and underscore the potential therapeutic role of protein lipoylation in the treatment of HD.
    Keywords:  Huntington’s disease; LIPT2; NEDD4L; neurodegeneration; ubiquitin
    DOI:  https://doi.org/10.1073/pnas.2503342122
  37. Stem Cells. 2025 Jul 16. pii: sxaf050. [Epub ahead of print]
    Neuronal branching in stem cell models of mitochondrial and neurological diseases.
    Selene Lickfett, Carmen Menacho, Sidney Cambridge, Alessandro Prigione.
      Neuronal branching, the extension and arborization of neurites, is critical for establishing and maintaining functional neural circuits. Emerging evidence suggests that mitochondria play an important role in regulating this process. In this review, we explore how the use of human induced pluripotent stem cell (iPSC)-derived neuronal models in two dimensions (2D) and three dimensions (3D) could help uncover possible mechanisms linking mitochondrial function and dysfunction to neuronal branching capacity. We highlight examples of iPSC-based models of mitochondrial and neurological diseases where aberrant neurite growth has been observed and discuss the potential therapeutic implications. Additionally, we review current methodologies for assessing neurite outgrowth in 2D and 3D neuronal models, addressing their strengths and limitations. Insights gained from these models emphasize the significance of mitochondrial health in neuronal branching and demonstrate the potential of iPSC-derived neurons and brain organoids for studying disrupted neuronal morphology. Harnessing these human stem cell models to devise phenotypic drug discovery platforms can eventually pave the way for innovative therapeutic interventions, particularly in the context of disorders with poorly understood genetic mechanisms and limited therapeutic options.
    Keywords:  iPSCs; mitochondria; mitochondrial diseases; neurodegeneration; neuronal branching; neurons
    DOI:  https://doi.org/10.1093/stmcls/sxaf050
  38. Curr Opin Hematol. 2025 Jul 15.
    Megakaryocytes as mitochondria factories: potential donors for mitochondria transplantation.
    Émilie Mercure, Martin Pelletier, Éric Boilard.
       PURPOSE OF REVIEW: There is an increasing recognition that mitochondria are dynamic regulators of cell fate. Mitochondria transplantation has emerged as a promising therapeutic strategy for conditions ranging from metabolic disorders to neurodegenerative diseases. Thus, there is a growing need for scalable mitochondrial sources for transplantation. We highlight megakaryocytes, best known for their role in platelet production, as a novel and versatile candidate source for mitochondria transplantation.
    RECENT FINDINGS: Megakaryocytes are naturally equipped to package and deliver functional mitochondria when producing platelets. Furthermore, MKs can share their mitochondria with neighboring cells in the bone marrow. Given the abundance of mitochondria in megakaryocytes, they may represent an ideal source of mitochondria for transplantation. A better understanding of the role of mitochondria in megakaryocyte heterogeneity and metabolic functions may help harness megakaryocytes for therapeutic transplantation applications.
    SUMMARY: Megakaryocyte-derived mitochondria transplantation offers a promising avenue for treating metabolic disorders, leveraging existing mechanisms. Future research should address limitations in megakaryocyte biogenesis and heterogeneity, and optimize delivery systems to maximize therapeutic efficacy.
    Keywords:  cell therapy; megakaryocytes; mitochondria transplantation
    DOI:  https://doi.org/10.1097/MOH.0000000000000889
  39. Cureus. 2025 Jun;17(6): e85825
    Mitochondrial Hearing Loss: Genetic Variants and Clinical Progression.
    Toru Miwa, Kousuke Hashimoto, Toshiyuki Seto, Hirokazu Sakamoto.
      Mitochondrial diseases can affect multiple organ systems including the auditory pathway, leading to sensorineural hearing loss (SNHL). Although several mitochondrial DNA (mtDNA) mutations are linked to progressive hearing impairment, the underlying mechanisms and clinical course of mitochondrial hearing loss remain incompletely understood. In the present study, we analyzed the frequency and progression of mitochondrial mutations in 15 patients diagnosed with unexplained SNHL who underwent genetic testing at our institution. The most common mutations were m.3243A>G and m.1555A>G. Both are of particular interest due to their relatively high prevalence among mitochondrial mutations and strong clinical implications-m.3243A>G is linked to mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and diabetes, while m.1555A>G is associated with aminoglycoside-induced and non-syndromic hearing loss. Hearing loss associated with m.3243A>G is generally progressive, although the rate of deterioration varies among individuals. In contrast, the m.1555A>G cases remained stable throughout the follow-up period. No significant correlation was observed between the heteroplasmy levels and hearing deterioration, although a weak negative association was observed. Despite significant hearing impairment, hearing aids are underutilized by a considerable proportion of patients. These findings provide new insights into the phenotypic variability of mitochondrial hearing loss and underscore the need for longitudinal studies to assess its natural progression and potential therapeutic interventions.
    Keywords:  heteroplasmy; m.3243a>g and m.1555a>g; mitochondrial dna mutations; phenotypic variability; sensorineural hearing loss
    DOI:  https://doi.org/10.7759/cureus.85825
  40. Anal Chem. 2025 Jul 14.
    Two-Photon FLIM Imaging of Mitochondrial Microenvironment in Apoptosis, Ferroptosis, and Fatty Liver Disease Models Using a Carbazole-Pyridinium Probe.
    Tong Zhu, Shang Wan, Hong Wang, Zhihui Feng, Xin Yang, Linge Wang, Bin Song, Xiaohe Tian, Wenwu Ling.
      Mitochondria are dynamic organelles whose microenvironmental state is tightly linked to cell death pathways and metabolic disease progression. However, directly visualizing mitochondrial microenvironment dynamics (e.g., viscosity changes) in living systems remains challenging. Here, we report an innovative two-photon fluorescent probe with a donor-π-acceptor architecture - featuring a hexyl-carbazole donor and a pyridinium acceptor - that exhibits bright near-infrared two-photon fluorescence. The probe's design enables robust mitochondrial targeting and high-performance two-photon excitation in the NIR region. By employing two-photon fluorescence lifetime imaging microscopy (TP-FLIM), we achieve quantitative, real-time and high-resolution mapping of mitochondrial functional status in live cells and tissues. Using this TP-FLIM approach, the probe sensitively tracks dynamic mitochondrial alterations under stress. In cultured cells undergoing apoptosis or ferroptosis, it reports distinct microenvironmental changes associated with mitochondrial stress and remodeling - for instance, revealing increased mitochondrial viscosity during apoptotic condensation and compaction of the organelle during ferroptotic cell death. In a nonalcoholic fatty liver disease (NAFLD) mouse model, longitudinal imaging with the probe visualizes progressive mitochondrial dysfunction and remodeling across different disease stages, reflecting the mounting stress on hepatic mitochondria as NAFLD advances. Overall, this D-π-A based two-photon FLIM probe provides a powerful biosensing tool for functional imaging of mitochondria, highlighting dynamic mitochondrial remodeling and microenvironment changes in cell death and disease contexts with high spatiotemporal resolution.
    DOI:  https://doi.org/10.1021/acs.analchem.5c01996
  41. Nat Metab. 2025 Jul 14.
    Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells.
    Simon Andersson, Hien Bui, Arto Viitanen, Daniel Borshagovski, Ella Salminen, Sami Kilpinen, Angelika Gebhart, Emilia Kuuluvainen, Swetha Gopalakrishnan, Nina Peltokangas, Martyn James, Kaia Achim, Eija Jokitalo, Petri Auvinen, Ville Hietakangas, Pekka Katajisto.
      Cellular metabolism is a key regulator of cell fate1, raising the possibility that the recently discovered metabolic heterogeneity between newly synthesized and chronologically old organelles may affect stem cell fate in tissues2,3. In the small intestine, intestinal stem cells (ISCs)4 produce metabolically distinct progeny5, including their Paneth cell (PC) niche6. Here we show that asymmetric cell division of mouse ISCs generates a subset enriched for old mitochondria (ISCmito-O), which are metabolically distinct, and form organoids independently of niche because of their ability to recreate the PC niche. ISCmito-O mitochondria produce more α-ketoglutarate, driving ten-eleven translocation-mediated epigenetic changes that promote PC formation. In vivo α-ketoglutarate supplementation enhanced PC turnover and niche renewal, aiding recovery from chemotherapy-induced damage in aged mice. Our results reveal a subpopulation of ISCs whose old mitochondria metabolically regulate cell fate, and provide proof of principle for metabolically promoted replacement of specific aged cell types in vivo.
    DOI:  https://doi.org/10.1038/s42255-025-01325-7
  42. Curr Opin Genet Dev. 2025 Jul 16. pii: S0959-437X(25)00073-5. [Epub ahead of print]94 102381
    Why and how paternal mitochondrial DNA gets cut out of the inheritance.
    Mayu Shimomura, Thomas R Hurd.
      Mitochondrial DNA (mtDNA) is inherited maternally across animals, yet the evolutionary rationale behind this unusual mode of inheritance remains a longstanding mystery. Understanding the processes that prevent the transmission of paternal mtDNA and thus ensure maternal-only inheritance is crucial to uncovering the evolutionary significance of this widespread phenomenon. Historically, research has focused on mechanisms that act within eggs to destroy sperm mitochondria via autophagy and the ubiquitin-proteasome degradation system. However, recent discoveries across multiple animal species, including humans, reveal a surprising twist: paternal mtDNA is actively degraded within mitochondria independently of and prior to the complete breakdown of the organelle itself, often even prior to fertilization. Only a few studies have begun to illuminate the molecular machinery responsible for this early mtDNA elimination. In this review, we explore the emerging landscape of paternal mtDNA elimination mechanisms across species, highlighting newly discovered pathways, evolutionary implications, and open questions that are furthering our understanding of mitochondrial inheritance.
    DOI:  https://doi.org/10.1016/j.gde.2025.102381
  43. Proc Natl Acad Sci U S A. 2025 Jul 22. 122(29): e2502285122
    mtKO: A dedicated guide RNA library for mitochondria research.
    Karambir Kaur, Javeria Zaheer, Fengchao Lang, Diego Luis Ribeiro, Meili Zhang, Hua Song, Wei Zhang, Raj Chari, Hussam Alkaissi, Chunzhang Yang.
      Mitochondria are multifunctional organelles central to both physiological and pathological processes. In malignant cancer cells, mitochondrial reprogramming establishes the metabolic foundation to meet cellular demands, which is particularly important in tumor cells with existing metabolic perturbations. To identify key mitochondrial pathways supporting cancer development, we developed mitochondria Knockout (mtKO), a robust and unbiased CRISPR screening platform to pinpoint critical mitochondria-associated pathways. The mtKO screen revealed that the mitochondrial antioxidant enzyme SOD2 is essential for cells harboring IDH1 mutations. Mechanistically, SOD2 activity determines the disease manifestation of IDH1-mutated cancers, through maintaining redox homeostasis and mitochondrial fitness. This study introduces a powerful functional genomic tool to identify mitochondrial-centered pathways and reveals the selective mitochondrial vulnerability in Krebs cycle-deficient cancers for future therapeutic intervention.
    Keywords:  CRISPR screen; IDH1; SOD2; metabolism; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2502285122
  44. Sci Adv. 2025 Jul 18. 11(29): eadt1318
    Harnessing tissue-derived mitochondria-rich extracellular vesicles (Ti-mitoEVs) to boost mitochondrial biogenesis for regenerative medicine.
    Peng Lou, Xiyue Zhou, Yimeng Zhang, Yijing Xie, Yizhuo Wang, Chengshi Wang, Shuyun Liu, Meihua Wan, Yanrong Lu, Jingping Liu.
      Mitochondrial damage is a critical pathological factor in various forms of tissue injury, and specific therapies with high biosafety are desirable. Inspired by the natural role of extracellular vesicles (EVs) in regulating mitochondrial metabolism, we report that healthy tissue-derived mitochondria-rich EVs (Ti-mitoEVs) can boost mitochondrial biogenesis for regenerative medicine. Ti-mitoEVs that contain abundant functional mitochondria can be highly efficiently isolated from muscles via an optimized method. In vitro, Ti-mitoEV treatment increased mitochondrial biogenesis and reduced mitochondrial damage in recipient cells, and these effects occurred at least partly via mitochondrial genome transfer. In vivo, Ti-mitoEV treatment attenuated diverse types of tissue injury (e.g., muscle and kidney) by rescuing mitochondrial injury and its associated inflammation. As natural nanovesicles, the therapeutic potency of mitoEVs can be further improved by integrating them with other engineering methods. This study highlights the promising role of Ti-mitoEVs in boosting mitochondrial biogenesis, positioning them as potential therapies for treating various types of tissue injury characterized by mitochondrial damage.
    DOI:  https://doi.org/10.1126/sciadv.adt1318
  45. J Neural Eng. 2025 Jul 14.
    A primary mechanism for efficacy of the ketogenic diet may be energy repletion at the tripartite synapse.
    Shubhada N Joshi, Aditya Joshi, Narendra D Joshi.
       OBJECTIVE: The ketogenic diet is a well-known treatment for epilepsy. Despite decades of research, it is not yet known how the diet accomplishes its anti-seizure efficacy. One of the earliest proposed mechanisms was that the ketogenic diet is able to replenish cellular energy stores in the brain. Although several mechanisms have been suggested for how energy depletion may contribute to seizure generation and epileptogenesis, how the dynamics of energy depletion actually leads to abnormal electrical activity is not known.
Approach: In this work, we investigated the behavior of the tripartite synapse using a recently developed neurochemical model, which was modified to include ketone chemistry. We ran transient, non-steady-state simulations mimicking normoglycemia and ketosis for metabolic conditions known to be clinically treated with the ketogenic diet, as well as a condition for which the ketogenic diet was not effective clinically. 
Main Results: We found that reduction in glucose, as well as pathological decreases in the activity of glucose transporter 1, pyruvate dehydrogenase complex, monocarboxylate transporter 1 (MCT1), and mitochondrial complex I, all led to functioning of the tripartite synapse in a rapid burst-firing mode suggestive of epileptiform activity. This was rescued by the addition of the ketone D-β-hydroxybutyrate in the glucose deficit, glucose transporter 1 deficiency, and pyruvate dehydrogenase complex deficiency, but not in MCT1 deficiency or mitochondrial complex I deficiency.
Significance: We demonstrated that replenishment of cellular energy stores is a feasible mechanism for the efficacy of the ketogenic diet. Although we do not rule out other proposed mechanisms, our work suggests that cellular energy repletion may be the primary action of the ketogenic diet. Further study of the contribution of energy deficits to seizure onset and even epileptogenesis may yield novel therapies for epilepsy in the future.&#xD.
    Keywords:  ATP; cell metabolism; energy metabolism; epilepsy; ketogenic diet; ketone
    DOI:  https://doi.org/10.1088/1741-2552/adef7f
  46. Cell. 2025 Jul 03. pii: S0092-8674(25)00690-7. [Epub ahead of print]
    Optogenetics-enabled discovery of integrated stress response modulators.
    Felix Wong, Alicia Li, Satotaka Omori, Ryan S Lach, Jose Nunez, Yunke Ren, Sean P Brown, Vipul Singhal, Brent R Lyda, Taivan Batjargal, Ethan Dickson, Jose Roberto Rodrigues Reyes, Juan Manual Uruena Vargas, Shalaka Wahane, Hahn Kim, James J Collins, Maxwell Z Wilson.
      The integrated stress response (ISR) is a conserved stress response that maintains homeostasis in eukaryotic cells. Modulating the ISR holds therapeutic potential for diseases including viral infection, cancer, and neurodegeneration, but few known compounds can do so without toxicity. Here, we present an optogenetic platform for the discovery of compounds that selectively modulate the ISR. Optogenetic clustering of PKR induces ISR-mediated cell death, enabling the high-throughput screening of 370,830 compounds. We identify compounds that potentiate cell death without cytotoxicity across diverse cell types and stressors. Mechanistic studies reveal that these compounds upregulate activating transcription factor 4 (ATF4), sensitizing cells to stress and apoptosis, and identify GCN2 as a molecular target. Additionally, these compounds exhibit antiviral activity, and one compound reduced viral titers in a mouse model of herpesvirus infection. Structure-activity and toxicology studies highlight opportunities to optimize therapeutic efficacy. This work demonstrates an optogenetic approach to drug discovery and introduces ISR potentiators with therapeutic potential.
    Keywords:  antiviral; drug discovery; endoplasmic reticulum stress; integrated stress response; optogenetics; phenotypic screening; proteostasis; small molecules; synthetic biology; unfolded protein response
    DOI:  https://doi.org/10.1016/j.cell.2025.06.024
  47. Nat Rev Drug Discov. 2025 Jul 15.
    Building on the momentum of N-of-1 base editor therapies for rare diseases.
    Katie Kingwell.
      
    DOI:  https://doi.org/10.1038/d41573-025-00119-6
  48. bioRxiv. 2025 Jun 20. pii: 2025.06.16.659985. [Epub ahead of print]
    Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
    Joy Omini, Inga Krassovskaya, Taiwo Dele-Osibanjo, Connor Pedersen, Toshihiro Obata.
      The tricarboxylic acid (TCA) cycle enzymes, malate dehydrogenase (MDH1) and citrate synthase (CIT1), form a multienzyme complex called 'metabolon' that channels intermediate, oxaloacetate, between the reaction centers of the enzymes. Since the MDH1-CIT1 metabolon enhances the pathway reactions in vitro, it is postulated to regulate the TCA cycle flux through dynamic assembly in response to cellular metabolic demands. Here, we demonstrated that yeast mitochondrial MDH1 and CIT1 dissociated when aerobic respiration was suppressed by the Crabtree effect and associated when the pathway flux was enhanced by acetate. Pharmacological TCA cycle inhibitions dissociated the complex, while electron transport chain inhibition enhanced the interaction. The multienzyme complex assembly was related to the mitochondrial matrix acidification and oxidation, as well as cellular levels of malate, fumarate, and citrate. These factors significantly affected the MDH1-CIT1 complex affinity in vitro. Especially the buffer pH significantly changed the MDH1-CIT1 affinity within the pH range between 6.0 and 7.0, which is observed in the mitochondrial matrix under physiological conditions. These results show a dynamic association and dissociation of a metabolon in the mitochondria and its relationship with pathway flux, supporting the metabolon's role in metabolic regulation. Multiple factors, including pH and metabolite availabilities, possibly regulate MDH1-CIT1 interaction.
    DOI:  https://doi.org/10.1101/2025.06.16.659985
  49. medRxiv. 2025 May 21. pii: 2025.05.19.25327921. [Epub ahead of print]
    Scalable automated reanalysis of genomic data in research and clinical rare disease cohorts.
    Matthew J Welland, K D Ahlquist, Paul De Fazio, Christina Austin-Tse, Lynn Pais, Laura Wedd, Samantha Bryen, Rocio Rius, Michael Franklin, Caitlin Morrison, Giles Hall, Laura Gauthier, Alex Bloemendal, David I Francis, Andrew J Mallett, Amali Mallawaarachchi, Paul J Lockhart, Richard Leventer, Ingrid E Scheffer, Katherine B Howell, Karin S Kassahn, Hamish S Scott, Julie McGaughran, John Christodoulou, David R Thorburn, Bryony A Thompson, Chirag V Patel, Greg Smith, Anne O'Donnell-Luria, Simon Sadedin, Heidi L Rehm, Sebastian Lunke, Jeremiah Wander, Kaitlin E Samocha, Cas Simons, Daniel G MacArthur, Zornitza Stark.
      Reanalysis of genomic data in rare disease is highly effective in increasing diagnostic yields but remains limited by manual approaches. Automation and optimization for high specificity will be necessary to ensure scalability, adoption and sustainability of iterative reanalysis. We developed a publicly available automated tool, Talos, and validated its performance using data from 1,089 individuals with rare genetic disease. Trio-based analysis identified 86% of known in-scope diagnoses, returning one variant per case on average. Variant burden reduced to one variant per 200 cases on iterative monthly reanalysis cycles. Application to an unselected cohort of 4,735 undiagnosed individuals identified 248 diagnoses (5.2% yield): 73 (29%) due to new gene-disease relationships, 56 (23%) due to new variant-level evidence, and 119 (48%) due to improved filtering and analysis strategies. Our automated, iterative reanalysis model, applied to thousands of rare disease patients, demonstrates the feasibility of delivering frequent, systematic reanalysis at scale.
    DOI:  https://doi.org/10.1101/2025.05.19.25327921
  50. bioRxiv. 2025 Jul 10. pii: 2025.07.10.662049. [Epub ahead of print]
    Choreography of human mitochondrial leaderless mRNA translation initiation.
    Shuangjie Shen, Yinghua Xu, Daniel L Kober, Jinfan Wang.
      It remains unclear how human mitochondrial ribosomal subunits assemble into an elongation-competent 55S particle on mRNAs devoid of 5' leader sequences. Here, we reconstituted and directly tracked human mitochondrial translation initiation using real-time single-molecule fluorescence spectroscopy. Corroborated with cryo-EM structural analysis, we show that the initiation factor mtIF2 and initiator fMet-tRNA Met are loaded to the 28S subunit to drive mRNAs binding via 5' start codon recognition. This enables sequential loading of the two ribosomal subunits onto the leaderless mRNA to initiate. In parallel, a preassembled 55S monosome can also be loaded with mtIF2 and fMet-tRNA Met to initiate on the mRNA. Both initiation pathways yield active complexes to enter translation elongation, which is gated by mtIF2. The monosome loading pathway can initiate promiscuously with non-formylated Met-tRNA Met , thus its usage may under tight regulation in cells, e.g. by mtIF3. Our work provides a dynamic framework for the distinct human mitochondrial translation initiation.
    DOI:  https://doi.org/10.1101/2025.07.10.662049
  51. Neurobiol Dis. 2025 Jul 11. pii: S0969-9961(25)00246-3. [Epub ahead of print]213 107030
    Hearing the call of mitochondria: Insight into its role in sensorineural hearing loss.
    Haojia He, Zhuoxue Han, Shuai Cheng, You Zhou.
      Sensorineural hearing loss (SNHL) is a prevalent and complex auditory disorder with a multifactorial pathogenesis, in which mitochondrial dysfunction plays a pivotal role. Mitochondria are abundantly localized in critical structures of the inner ear, where they not only provide the substantial energy required for auditory transduction but also regulate key cellular processes. Growing evidence suggests that mitochondrial impairment, characterized by excessive reactive oxygen species (ROS) generation, dysregulated inflammatory responses, disrupted apoptosis, and mitochondrial DNA (mtDNA) mutations, is closely linked to the onset and progression of SNHL. Recent advances in mitochondria-targeted therapeutic strategies, such as antioxidant delivery, promotion of mitochondrial biogenesis, and mitochondrial gene therapy, have shown promising preclinical results. However, significant challenges remain in translating these approaches into clinical practice, particularly in terms of targeted delivery, long-term efficacy, and potential side effects. This comprehensive review systematically examines the molecular mechanisms underlying mitochondrial involvement in SNHL pathogenesis, evaluates recent progress in mitochondria-targeted interventions, and discusses current limitations and future directions in this rapidly evolving field. By integrating current knowledge and identifying key research gaps, this review aims to provide a solid theoretical foundation and fresh perspectives for the development of effective therapeutic strategies for SNHL.
    Keywords:  Mitochondria; Mitophagy; Oxidative stress; Sensorineural hearing loss; Therapy
    DOI:  https://doi.org/10.1016/j.nbd.2025.107030
  52. bioRxiv. 2025 Jun 26. pii: 2025.06.21.660867. [Epub ahead of print]
    Laminar Shear Stress Increases the Cytosolic Pool of PINK1 in Endothelial Cells and Enhances Mitophagic Sensitivity Toward Dysfunctional Mitochondria.
    Soon-Gook Hong, Junchul Shin, Jason Saredy, Soo Young Choi, Hong Wang, Joon-Young Park.
      Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) is an essential molecule in mitophagy process in mammalian cells. Mutation or deficiency of PINK1 has been closely related to several disease conditions. The purpose of this study was to determine PINK1 expression levels and subcellular localization under exercise-mimic laminar shear stress (LSS) condition in human aortic endothelial cells (HAECs) or in exercising mice, and its implication on endothelial homeostasis and cardiovascular disease (CVD) prevention. First, LSS significantly elevated both full-length PINK1 (FL-PINK1) mRNA and protein expressions in ECs. Mitochondrial fractionation assays and confocal microscopic analysis showed reduced FL-PINK1 accumulation on mitochondria with an increase in a cytosolic pool of FL-PINK1 under LSS. Mitophagy flux, determined by a mtKeima probe, decreased with intact mitochondrial morphology and membrane potential under LSS, suggesting that elevated cytosolic PINK1 is not utilized for immediate mitophagy inductions. However, increased cytosolic PINK1 seems to elevate mitophagic sensitivity toward dysfunctional mitochondria in pathological conditions. LSS-preconditioned ECs showed lower angiotensin II (AngII)-induced mtDNA lesions and displayed rapid Parkin recruitment and mitophagy induction in response to mitochondrial uncoupler (CCCP) treatment. Exercise-preconditioned mice, a physiological LSS-enhanced model, showed elevated PINK1 expression in ECs of the thoracic aorta compared to sedentary control. In addition, exercise enhanced AngII-induced mitophagy induction in ECs and reduced AngII-induced mtDNA lesion formation in the mouse aorta. Taken together, LSS increases a cytosolic pool of FL-PINK1, which may elevate the mitophagic sensitivity toward dysfunctional mitochondria in ECs.
    DOI:  https://doi.org/10.1101/2025.06.21.660867
  53. Nature. 2025 Jul;643(8072): 625-627
    Smart brain-zapping implants could revolutionize Parkinson's treatment.
    Sally Adee.
      
    Keywords:  Brain; Neuroscience; Parkinson's disease
    DOI:  https://doi.org/10.1038/d41586-025-02196-4
  54. Ann Clin Transl Neurol. 2025 Jul 14.
    BCS1L-Associated Disease: 5'-UTR Variant Shifts the Phenotype Towards Axonal Neuropathy.
    Rotem Orbach, Nunziata Maio, Russell J Butterfield, A Reghan Foley, Sarah Silverstein, Yan Li, Katherine Chao, Tanya J Lehky, Abigail Potticary, Tracey A Rouault, Sandra Donkervoort, Carsten G Bönnemann.
       OBJECTIVES: To investigate the consequences of a pathogenic missense variant (c.838C>T; p.L280F) and a 5'-UTR regulatory variant (c.-122G>T) in BCS1L on disease pathogenesis and to understand how regulatory variants influence disease severity and clinical presentation.
    METHODS: Deep phenotyping, research-based whole genome sequencing, biochemical characterization of identified variants, and studies in patient-derived fibroblast cultures were applied to uncover the underlying genetic cause and molecular defects in siblings with a genetically uncharacterized complex neurologic condition.
    RESULTS: Genome sequencing identified a paternally inherited missense variant (c.838C>T; p.L280F) and a maternally inherited 5'-UTR variant (c.-122G>T) in BCS1L in two affected siblings. Although the missense variant disrupts complex III assembly, the 5'-UTR variant allows residual wild-type BCS1L expression, likely mitigating disease severity. Biochemical studies in patient-derived fibroblasts confirmed the pathogenicity of both variants and demonstrated a moderate in vitro response to a coenzyme Q10 analog.
    INTERPRETATION: This study expands the clinical spectrum of BCS1L-related disorders to include a comparatively milder phenotype with central and peripheral nervous system involvement. Our findings demonstrate that the 5'-UTR variant modulates disease severity by enabling residual wild-type BCS1L expression, partially mitigating the pathogenic effects of the missense variant. These insights underscore the importance of evaluating both protein coding and regulatory variants in mitochondrial disease diagnostics and pathogenesis.
    Keywords:  5′‐UTR; BCS1L; complex III; motor neuropathy; oxidative phosphorylation
    DOI:  https://doi.org/10.1002/acn3.70108
  55. Front Physiol. 2025 ;16 1602271
    Mitochondria-derived peptide MOTS-c restores mitochondrial respiration in type 2 diabetic heart.
    Toan Pham, Andrew Taberner, Anthony Hickey, June-Chiew Han.
       Introduction: Type 2 diabetes (T2D) is a global epidemic, and heart failure is the primary cause of premature death among T2D patients. Mitochondrial dysfunction has been linked to decreased contractile performance in diabetic heart, partly due to a disturbance in the mitochondrial capacity to supply adequate metabolic energy to contractile proteins. MOTS-c, a newly discovered mitochondrial-derived peptide, has shown promise as a therapeutic for restoring energy homeostasis and muscle function in metabolic diseases. However, whether MOTS-c therapy improves T2D heart function by increasing mitochondrial bioenergetic function remains unknown.
    Methods: Here we studied the mitochondrial bioenergetic function of heart tissues isolated from a rat model mimicking type 2 diabetes induced by a high-fat diet and low-dose streptozotocin. Treated diabetic group received MOTS-c (15 mg/kg) daily injection for 3 weeks. We employed high-resolution respirometric and fluorometric techniques to simultaneously assess mitochondrial ATP production and hydrolysis capacity, reactive oxygen species (ROS) production, and oxygen flux in cardiac tissue homogenates.
    Results: We found that untreated T2D rats had hyperglycemia, poor glucose control, and left ventricular hypertrophy relative to controls. T2D mitochondria showed decreased oxygen flux at the oxidative phosphorylation (OXP) while ROS production, ATP production and hydrolysis rates remained unchanged. Diabetic rats treated with MOTS-c showed decreased fasting glucose levels, improved glucose homeostasis, and decreased degree of cardiac hypertrophy. At the subcellular level, MOTS-c treated mitochondria showed increased OXPHOS respiration and ROS levels and decreased ATP hydrolysis rate during anoxic conditions.
    Discussion: These findings demonstrate beneficial effects of MOTS-c treatment on glucose homeostasis and suggest a useful therapeutic option for diabetic-related cardiomyopathy and mitochondrial dysfunction.
    Keywords:  ATP; MOTS-c; diabetic heart; mitochondrial respiration; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphys.2025.1602271
  56. medRxiv. 2025 Jul 08. pii: 2025.07.08.25330848. [Epub ahead of print]
    Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders.
    Undiagnosed Diseases Network
      ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. Functional evaluation in C. elegans revealed that all variants tested were damaging to gene function via a dominant negative genetic mechanism. Biochemical and proteomics studies showed a marked reduction in complex V abundance and activity in proband-derived blood cells and fibroblasts. Mitochondrial physiology studies in fibroblasts revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP levels indicative of uncoupled oxidative phosphorylation as a pathophysiologic mechanism. Our findings contrast functionally and clinically with the previously reported ATP5F1A variant, p.Arg207His, suggesting a distinct pathological mechanism. This study therefore expands the phenotypic and genotypic spectrum of ATP5F1A -associated conditions and highlights how functional studies can provide understanding of the genetic, molecular, and cellular mechanisms of ATP5F1A variants of uncertain significance. With 12 heterozygous individuals now reported, ATP5F1A is the most frequent nuclear genome cause of complex V deficiency.
    DOI:  https://doi.org/10.1101/2025.07.08.25330848
  57. bioRxiv. 2025 Jun 17. pii: 2025.06.13.658955. [Epub ahead of print]
    Atad3 is Essential for Mitochondrial Permeability Transition Pore Opening and Cardiac Ischemia Reperfusion Injury.
    Dexter Robichaux, Sual J Lopez, Arielys Mendoza, Daniel Ramirez, Suh-Chin J Lin, Jeffery D Molkentin, Pablo M Peixoto, Jason Karch.
      The molecular identity of the mitochondrial permeability transition pore (mPTP) has remained elusive since the discovery of its existence over 75 years ago. Despite the numerous candidate proteins proposed, none have withstood genetic ablation, leaving them relegated to auxiliary regulatory roles. To date, no essential mPTP component has been identified. Here, we establish ATAD3 as the first essential component of the mPTP. Genetic deletion of Atad3 in cardiomyocytes and hepatocytes renders heart and liver mitochondria incapable of undergoing Ca 2+ -induced mPTP-dependent swelling. Moreover, these mitochondria exhibit the highest Ca 2+ retention capacity ever reported following genetic perturbation of the mPTP. Furthermore, patch-clamp recordings of recombinant ATAD3a in liposomes reveal intrinsic channel activity. Given the established role of mPTP-dependent necrosis in driving ischemia/reperfusion (I/R) injury, we show that cardiac-specific Atad3 deletion markedly reduces infarct size following I/R, with no additive protection from cyclosporine A. Together, these findings establish ATAD3 as an core, putative pore-forming component essential for mPTP opening and mPTP-dependent necrosis, resolving a long-standing mystery in mitochondrial biology.
    DOI:  https://doi.org/10.1101/2025.06.13.658955
  58. Dev Med Child Neurol. 2025 Jul 15.
    ATAD3 duplications bridge mitochondrial diseases and Aicardi-Goutières syndrome.
    ATAD3 Study Group
      A recurrent 68-kb heterozygous duplication of the ATAD3 locus has been implicated in a mitochondrial disorder characterized by prenatal or neonatal onset and rapidly fatal course with cardiomyopathy, hyperlactataemia, cataract, and encephalopathy. We analysed the clinical, neuroimaging, and molecular spectrum associated with duplication of the ATAD3 gene cluster in nine patients (four males, five females; age range: 3 days-3 years, median: 11 days, mean: 7.8 months, SD: 1 year 1 month). Five patients presented with prenatal signs (intrauterine growth restriction in four of nine and cardiac abnormalities in three of nine) leading to medical termination of pregnancy in one case. All live-born children presented with neonatal hypotonia, frequently associated with cardiomyopathy (five of eight), cataract or corneal opacities (five of eight), and hyperlactataemia (six of eight). Two patients carrying distinct duplications exhibited a long survival (>2 years) and presented with major progressive brain atrophy with epileptic encephalopathy. We documented elevated cerebrospinal fluid neopterin in one and increased cerebrospinal fluid alpha-interferon activity in the other. Brain magnetic resonance imaging showed white matter T2 hyperintensity (seven of seven) and temporal cystic leukoencephalopathy (five of seven). Nuclear magnetic resonance spectroscopy showed a lactate peak in five of five patients; brain computed tomography showed basal ganglia calcifications in two of three patients. In this study, we expand the clinical spectrum of ATAD3 duplications, including prolonged survival and severe neurological involvement with neuroimaging similarities to Aicardi-Goutières syndrome and more broadly interferonopathy. We suggest a putative common mechanism that involves mitochondrial nucleic acid leakage and interferon response.
    DOI:  https://doi.org/10.1111/dmcn.16414
  59. J Alzheimers Dis. 2025 Jul 17. 13872877251360243
    Amyloid-β protein precursor modulates mitophagy and mitochondrial function through its cellular localization.
    Taylor A Strope, Benjamin Troutwine, Brittany M Hauger, Keith P Smith, Russell H Swerdlow, Heather M Wilkins.
      BackgroundAmyloid-β (Aβ) is generated from amyloid-β protein precursor (AβPP) via secretase enzymes. While AβPP processing and its localization are well understood, the function of AβPP is largely unknown. AβPP has been shown to localize to mitochondria, but the consequence of this is not understood.ObjectiveWe examined the consequences of modulating mitochondrial AβPP content on mitochondrial function.MethodsWe measured mitochondrial AβPP localization in postmortem human brain from non-demented and AD subjects. To understand the effects of mitochondrial localization of AβPP on mitochondria, we leveraged AβPP constructs with increased (D23A) or decreased (3 M) mitochondrial localization compared to a wild-type (WT) construct. We measured mitochondrial function including dynamics and mitophagy.ResultsWe observed increased AβPP mitochondrial localization in postmortem brain of sporadic AD subjects. Increased or decreased mitochondrial AβPP content led to reduced electron transport chain (ETC) activities, reduced ATP levels, increased mitochondrial superoxide production, hyperpolarized mitochondrial membrane potential, and increased mitochondrial calcium content. Reduced mitochondrial AβPP content reduced mitophagy flux, while increased mitochondrial AβPP content increased mitophagy flux. Increased or decreased mitochondrial AβPP content reduced mitochondrial biogenesis. We identified interactions between AβPP and mitophagy/autophagy proteins. We next examined if a specific motif in AβPP was responsible for alterations in mitochondrial function and mitophagy. Mitophagy flux was inhibited with expression of ΔCT AβPP, suggesting a role for the C-terminus of AβPP in mitophagy induction.ConclusionsOverall, these findings highlight a critical role of AβPP in mitochondrial physiology. Alterations to AβPP mitochondrial content can lead to mitochondrial dysfunction.
    Keywords:  Alzheimer's disease; amyloid-β; amyloid-β protein precursor; mitochondria; mitophagy
    DOI:  https://doi.org/10.1177/13872877251360243
  60. Biochem Soc Trans. 2025 Jul 14. pii: BST20253053. [Epub ahead of print]
    UBQLN2 in neurodegenerative disease: mechanistic insights and emerging therapeutic potential.
    Autumn M Matthews, Alexandra M Whiteley.
      Ubiquilins (UBQLNs) regulate cellular protein turnover by shuttling proteins, or 'clients', to the proteasome or autophagy pathways for degradation. Of the five different UBQLN genes in humans, UBQLN2 is the most highly expressed in the nervous system and muscle tissue and has been linked to multiple neurodegenerative diseases. In particular, point mutations of UBQLN2 cause an X-linked, dominant form of amyotrophic lateral sclerosis (ALS), ALS with frontotemporal dementia (ALS/FTD), or FTD. Failed protein degradation is a hallmark of many neurodegenerative diseases, including ALS and FTD; however, it is not clear exactly how ALS/FTD-associated UBQLN2 mutations contribute to pathogenesis. Recent studies have revealed the complexity of UBQLN2 biology and allow deeper understanding as to how UBQLN2 dysfunction may contribute to neurodegenerative disease. UBQLN2 is necessary for mitochondrial protein degradation and for regulating mitochondrial turnover, both of which are essential for motor neurons and have been implicated in the pathogenesis of ALS. Stress granule (SG) formation and regulation are also affected by UBQLN2 mutations, and their dysregulation may contribute to the toxic protein aggregation and SG changes observed in neurodegenerative disease. Finally, there are compelling links connecting UBQLN2 dysfunction with changes to downstream neuronal morphology, function, and behavior. This review will detail the emerging consensus on how UBQLN2 protects against neurodegenerative disease and will provide insights into potential therapeutic approaches.
    Keywords:  ALS; PEG10; Ubiquilin 2; mitochondria; neurodegenerative disease; protein degradation; stress granules
    DOI:  https://doi.org/10.1042/BST20253053
This page is being maintained by Thomas Krichel. It was last updated on 2025‒07‒20 at 9:52.