bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–04–27
forty-one papers selected by
Catalina Vasilescu, Helmholz Munich
  1. A rare mitochondrial disease with infantile severe metabolic disturbances that improved spontaneously.
  2. Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.
  3. Interpreting the clinical significance of multiple large-scale mitochondrial DNA deletions (MLSMD) in skeletal muscle tissue in the diagnostic evaluation of primary mitochondrial disease.
  4. Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
  5. Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.
  6. Origin and evolution of mitochondrial inner membrane composition.
  7. Mitochondrial transplantation: Triumphs, challenges, and impacts on nuclear genome remodelling.
  8. Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.
  9. Mitochondria and Peroxisome Crosstalk in Peroxisome Biogenesis Disorder 8A Caused by a Rare Variant in PEX16 Gene.
  10. Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis.
  11. TMBIM-2 links neuronal mitochondrial stress to systemic adaptation via calcium signaling.
  12. OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation.
  13. PPARα regulates ER-lipid droplet protein Calsyntenin-3β to promote ketogenesis in hepatocytes.
  14. YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.
  15. 280th ENMC International Workshop: The ERN EURO-NMD mitochondrial diseases working group; diagnostic criteria and outcome measures in primary mitochondrial myopathies. Hoofddorp, the Netherlands, 22-24 November 2024.
  16. TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6.
  17. Impact of Cholesterol on Cardiac Mitochondrial Function.
  18. Mitochondrial DNA signals driving immune responses: Why, How, Where?
  19. Convolutional Neural Network approach to classify mitochondrial morphologies.
  20. Parkinson's gut-microbiota links raise treatment possibilities.
  21. Exosome-Mediated Mitochondrial Regulation: A Promising Therapeutic Tool for Alzheimer's Disease and Parkinson's Disease.
  22. Clinical and Radiological Characterization of TEFM-Associated Neurological Disorder.
  23. Hidden β-γ Dehydrogenation Products in Long-Chain Fatty Acid Oxidation Unveiled by NMR: Implications on Lipid Metabolism.
  24. Age-associated reduction in ER-Mitochondrial contacts impairs mitochondrial lipid metabolism and autophagosome formation in the heart.
  25. SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.
  26. Neuroprotection by Mitochondrial NAD Against Glutamate-Induced Excitotoxicity.
  27. Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.
  28. SIRT1-based therapy targets a gene program involved in mitochondrial turnover in a model of retinal neurodegeneration.
  29. Cardiac dysfunction due to mitochondrial impairment assessed by human iPS cells caused by DNM1L mutations.
  30. Conformational plasticity of mitochondrial VDAC2 controls the kinetics of its interaction with cytosolic proteins.
  31. Mitochondrial calpain-1 truncates ATP synthase beta subunit.
  32. Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells.
  33. Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction.
  34. Compound heterozygous variants of the NARS2 gene in siblings with refractory seizures: two case report and literature review.
  35. Palatal tremor as the clue sign of POLG-related syndrome.
  36. Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration.
  37. Expanding the Allelic and Clinical Heterogeneity of Movement Disorders Linked to Defects of Mitochondrial Adenosine Triphosphate Synthase.
  38. Human de novo mutation rates from a four-generation pedigree reference.
  39. Pain Relief in Mitochondrial Disorders: Use of Spinal Cord Stimulation in a Patient With NARP Syndrome.
  40. Prenatal FBXL4-Associated Mitochondrial DNA Depletion Syndrome-13: A New Case and Review of the Literature.
  41. A protein tunnel that shuttles lipids around the cell.
  1. Pediatr Int. 2025 Jan-Dec;67(1):67(1): e70052
    A rare mitochondrial disease with infantile severe metabolic disturbances that improved spontaneously.
    Mikiko Koizumi, Tae Ikeda, Tomokazu Kimizu, Yasushi Okazaki, Kei Murayama, Yuri Etani.
      
    Keywords:  mitochondrial disease; reversible infantile respiratory chain deficiency
    DOI:  https://doi.org/10.1111/ped.70052
  2. Curr Biol. 2025 Apr 21. pii: S0960-9822(25)00296-9. [Epub ahead of print]35(8): R287-R290
    Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.
    Mohamed A Eldeeb, Michael Shahid, Edward A Fon.
      Dysregulation of mitochondrial protein import induces significant cellular stress. Yet, our understanding of the dialogue between mitochondrial import, the stress it can trigger, and counteracting mechanisms remains incomplete. A recent study unveils how the mitochondrial protease YME1L1 degrades unoccupied mitochondrial translocases during mitochondrial import stress.
    DOI:  https://doi.org/10.1016/j.cub.2025.03.011
  3. Front Pharmacol. 2025 ;16 1507493
    Interpreting the clinical significance of multiple large-scale mitochondrial DNA deletions (MLSMD) in skeletal muscle tissue in the diagnostic evaluation of primary mitochondrial disease.
    Jing Wang, James T Peterson, Joaquim Diego D Santos, Ada J S Chan, Maria Alejandra Diaz-Miranda, Imon Rahaman, Jean Flickinger, Amy Goldstein, Emily Bogush, Elizabeth M McCormick, Colleen C Muraresku, Vernon E Anderson, Matthew C Dulik, Douglas C Wallace, Rui Xiao, Marni J Falk, Angela N Viaene, Zarazuela Zolkipli-Cunningham.
       Background and Objectives: Improved detection sensitivity from combined Long-Range PCR (LR-PCR), Next-Generation Sequencing (NGS), and droplet digital PCR (ddPCR) to identify multiple large-scale mtDNA deletions (MLSMD) and quantify deletion heteroplasmy have introduced clinical interpretation challenges. We sought to evaluate clinical, biochemical, and histopathological phenotypes of a large clinical cohort harboring MLSMD in muscle to better understand their significance across a range of clinical phenotypes.
    Methods: A single-site retrospective study was performed of 212 diagnostic muscle biopsies obtained from patients referred for Primary Mitochondrial Disease (PMD) evaluation with muscle mitochondrial (mt)DNA sequencing performed at our institution, including electronic medical record (EMR) review of symptoms, biochemical results, and Mitochondrial Myopathy Composite Assessment Tool (MM-COAST) scores.
    Results: MLSMD were identified in 50 of 212 (24%) diagnostic tissue biopsies, and were universally present. in subjects ≥50 years (n = 18/18). In 45 of 50 (90%) subjects with MLSMD, no definitive genetic etiology was identified, despite clinical whole exome sequencing (WES) and/or whole genome sequencing (WGS). MLSMD heteroplasmy levels quantified by ddPCR ranged from 0% to 33%, exceeding 10% heteroplasmy in 5/45 (11%). Subjects with MLSMD (n = 45) were more likely to demonstrate mitochondrial abnormalities on histopathology, upregulation (≥150% of control mean) of one or more electron transport chain (ETC) complex enzyme activities, and reduced citrate synthase indicative of mitochondrial depletion (<60% of control mean) relative to subjects without MLSMD (n = 155). As clinical phenotypes varied across the MLSMD cohort, Bernier diagnostic criteria major/minor symptoms were used to discriminate 13 of 45 subjects with "suspected" PMD having unrevealing WES/WGS results and 32 of 45 subjects scored as "less likely" to have PMD. Relative to the "less likely" cohort, a significantly higher frequency of biochemical and muscle histopathological abnormalities (ragged red and COX negative fibers) were observed in the "suspected" cohort, further supporting a higher index of suspicion for PMD, p < 0.05.
    Discussion: MLSMD in skeletal muscle tissue were a common molecular finding (24%) in our cohort and consistently present in subjects ≥50 years. Among those with genetically undiagnosed MLSMD (n = 45), the "suspected" PMD subset (n = 13/45) represent a promising cohort for novel gene discoveries.
    Keywords:  electron transport chain (ETC) enzymatic activity; mitochondrial DNA (mtDNA); multiple large-scale mitochondrial DNA deletions (MLSMD); primary mitochondrial disease (PMD); ragged blue fibers (RBF); ragged red fibers (RRF)
    DOI:  https://doi.org/10.3389/fphar.2025.1507493
  4. Nat Cell Biol. 2025 Apr 21.
    Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
    Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P Praharaj, Stewart Morley, Bookyong Ko, Mona H Soflaee, Harrison J Tom, Harrison Brown, Hieu S Vu, Shih-Chia Tso, Chad A Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K Allen, Gerta Hoxhaj.
      Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.
    DOI:  https://doi.org/10.1038/s41556-025-01655-4
  5. J Mol Biol. 2025 Apr 21. pii: S0022-2836(25)00227-X. [Epub ahead of print] 169161
    Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.
    Bishal Basak, Erika L F Holzbaur.
      Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson's disease (PD) and Amyotrophic lateral sclerosis(ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.
    Keywords:  PINK1; Parkin; autophagosomes; lysosomes; mitochondria; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1016/j.jmb.2025.169161
  6. J Cell Sci. 2025 May 01. pii: jcs263780. [Epub ahead of print]138(9):
    Origin and evolution of mitochondrial inner membrane composition.
    Kailash Venkatraman, Nicolas-Frédéric Lipp, Itay Budin.
      Unique membrane architectures and lipid building blocks underlie the metabolic and non-metabolic functions of mitochondria. During eukaryogenesis, mitochondria likely arose from an alphaproteobacterial symbiont of an Asgard archaea-related host cell. Subsequently, mitochondria evolved inner membrane folds known as cristae alongside a specialized lipid composition supported by metabolic and transport machinery. Advancements in phylogenetic methods and genomic and metagenomic data have suggested potential origins for cristae-shaping protein complexes, such as the mitochondrial contact site and cristae-organizing system (MICOS). MICOS protein homologs function in the formation of cristae-like intracytoplasmic membranes (ICMs) in diverse extant alphaproteobacteria. The machinery responsible for synthesizing key mitochondrial phospholipids - which cooperate with cristae-shaping proteins to establish inner membrane architecture - could have also evolved from a bacterial ancestor, but its origins have been less explored. In this Review, we examine the current understanding of mitochondrial membrane evolution, highlighting distinctions between prokaryotic and eukaryotic mitochondrial-specific proteins and lipids and their differing roles in shaping cristae and ICM architecture, and propose a model explaining the concurrent specialization of the mitochondrial lipidome and inner membrane structure in eukaryogenesis. We discuss how advancements across a range of disciplines are shedding light on how multiple membrane components co-evolved to support the central functions of eukaryotic mitochondria.
    Keywords:  Cardiolipin; Cristae; Curvature; Evolution; Mitochondria; Phospholipids
    DOI:  https://doi.org/10.1242/jcs.263780
  7. Mitochondrion. 2025 Apr 18. pii: S1567-7249(25)00039-X. [Epub ahead of print] 102042
    Mitochondrial transplantation: Triumphs, challenges, and impacts on nuclear genome remodelling.
    Elly H Shin, Quinn Le, Rachel Barboza, Amanda Morin, Shiva M Singh, Christina A Castellani.
      Mitochondria are membrane-bound organelles of eukaryotic cells that play crucial roles in cell functioning and homeostasis, including ATP generation for cellular energy. Mitochondrial function is associated with several complex diseases and disorders, including cardiovascular, cardiometabolic, neurodegenerative diseases and some cancers. The risk for these diseases and disorders is often associated with mitochondrial dysfunction, particularly the quantitative and qualitative features of the mitochondrial genome. Emerging results implicate mito-nuclear crosstalk as the mechanism by which mtDNA variation affects complex disease outcomes. Experimental approaches are emerging for the targeting of mitochondria as a potential therapeutic for several of these diseases, particularly in the form of mitochondrial transplantation. Current approaches to mitochondrial transplantation generally involve isolating healthy mitochondria from donor cells and introducing them to diseased recipients towards amelioration of mitochondrial dysfunction. Using such a protocol, several reports have shown recovery of mitochondrial function and improved disease outcomes post-mitochondrial transplantation, highlighting its potential as a therapeutic method for several complex, severe and debilitating diseases. Additionally, the mitochondrial genome can be modified prior to transplantation to target disease-associated site-specific mutations and to reduce the ratio of mutant-to-WT alleles. These promising results may underlie the potential impact of mitochondrial transplantation on mito-nuclear genome interactions in the setting of the disease. Further, we recommend that mitochondrial transplantation experimentation include an assessment of potential impacts on remodelling of the nuclear genome, particularly the nuclear epigenome and transcriptome. Herein, we review these and other triumphs and challenges of mitochondrial transplantation as a potential novel therapeutic for mitochondria-associated diseases.
    Keywords:  Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial transplantation; Nuclear epigenome; Nuclear transcriptome
    DOI:  https://doi.org/10.1016/j.mito.2025.102042
  8. Sci Rep. 2025 Apr 21. 15(1): 13811
    Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.
    Emi Matsumoto, Taeko Sasaki, Tetsuya Higashiyama, Narie Sasaki.
      Mitochondrial DNA (mtDNA) is organized with proteins into mitochondrial nucleoid (mt-nucleoid). The mt-nucleoid is a unit for the maintenance and function of mtDNA. The regulator of chromosome condensation 1-like protein (RCC1L) performs various functions in mitochondria, including translation, but its involvement in regulating mt-nucleoid maintenance is unknown. Herein, we found that human RCC1L was required to maintain mt-nucleoids and mtDNA. Human RCC1L has three splicing isoforms: RCC1LV1, RCC1LV2, and RCC1LV3. Knockout (KO) cells lacking all RCC1L isoforms, which were lethal without pyruvate and uridine, exhibited a decrease in mt-nucleoids and mtDNA, along with swollen and fragmented mitochondria. Among the three RCC1L isoforms, only RCC1LV1 recovered all phenotypes observed in RCC1L KO cells. As the treatment of wild-type cells with chloramphenicol, a mitochondrial translation inhibitor, did not lead to the decrease in mt-nucleoids accompanied by mtDNA depletion, the decrease in mt-nucleoids and mtDNA in RCC1L KO cells was not solely attributed to impaired mitochondrial translation. Using conditional RCC1L KO cells, we observed a rapid decrease in mt-nucleoids and mtDNA during a specific period following RCC1L loss. Our findings indicate that RCC1L regulates the maintenance of mt-nucleoids and mtDNA besides its role in mitochondrial translational regulation.
    Keywords:  Mitochondrial DNA; Mitochondrial nucleoid; RCC1L
    DOI:  https://doi.org/10.1038/s41598-025-98397-y
  9. Clin Genet. 2025 Apr 24.
    Mitochondria and Peroxisome Crosstalk in Peroxisome Biogenesis Disorder 8A Caused by a Rare Variant in PEX16 Gene.
    Mohamad Wehbe, Rudy N Zalzal, Riyad El-Khoury, Lama Charafeddine, Pascale E Karam.
      Peroxisome biogenesis disorder 8A is a rare autosomal recessive disorder caused by mutations in the PEX16 gene. We report the clinical, biochemical, and molecular features of a patient harboring the homozygous NM_004813.4: c.526C>T, p.(Arg176*) mutation in PEX16 associated with mitochondrial dysfunction. This newborn presented with microcephaly, encephalopathy, hypotonia, failure to thrive, hepatomegaly, and abnormal retinal pigmentation. He had elevated plasma very long-chain fatty acids. Skeletal muscle biopsy revealed significant mitochondrial depletion with deficiencies of the respiratory chain Complexes I-IV, with significant reductions in cytochrome c oxidase and citrate synthase activity. The peroxisome biogenesis disorder 8A was confirmed by whole genome sequencing. This is the first case delineating the association of mitochondrial dysfunction with peroxisome biogenesis disorder 8A caused by the above mutation. Further studies are needed to elucidate the underlying pathophysiological mechanisms of mitochondria and peroxisome crosstalk.
    Keywords:   PEX16 ; Zellweger; mitochondria; peroxisome disorders
    DOI:  https://doi.org/10.1111/cge.14753
  10. Mol Genet Metab. 2025 Apr 18. pii: S1096-7192(25)00104-0. [Epub ahead of print]145(2): 109113
    Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis.
    Hiroyuki Iijima, Atsuko Imai-Okazaki, Yoshihito Kishita, Ayumu Sugiura, Masaru Shimura, Kei Murayama, Yasushi Okazaki, Akira Ohtake.
      BOLA3 is one of the proteins involved in the assembly and transport of [4Fe-4S] clusters, which are incorporated into mitochondrial respiratory chain complexes I and II, aconitase, and lipoic acid synthetase. Pathogenic variants in the BOLA3 gene cause a rare condition known as multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, characterized by life-threatening lactic acidosis, nonketotic hyperglycinemia, and hypertrophic cardiomyopathy. The aim of this study was to elucidate the biochemical characteristics of patients with BOLA3 variants and to clarify the role of BOLA3 protein in humans. The characteristics, clinical course, and biochemical data of eight Japanese patients with BOLA3 pathogenic variants were collected. In addition, metabolomic analyses were performed using capillary electrophoresis time-of-flight mass spectrometry, blue native polyacrylamide gel electrophoresis (BN-PAGE)/Western blot analysis of mitochondrial respiratory chain complexes, and in-gel enzyme staining of mitochondrial respiratory chain complexes of fibroblasts from all eight patients. Metabolomic data were compared between the eight patients with BOLA3 variants and three control samples using Welch's t-test. In the metabolomic analysis, levels of lactic acid, pyruvic acid, alanine, tricarboxylic acid (TCA) cycle intermediates (such as α-ketoglutaric acid and succinic acid), branched-chain amino acids, and metabolites of lysine and tryptophan were significantly elevated in the BOLA3 group. Data collected during the patients' lives showed increased lactic acid and glycine levels. In BN-PAGE/Western blot analysis and in-gel enzyme staining, bands for complexes I and II were barely detectable in all eight cases. These results indicate that BOLA3 variants decrease the activity of lipoic acid-dependent proteins (pyruvate dehydrogenase complex, α-ketoglutarate dehydrogenase, 2-oxoadipate dehydrogenase, branched-chain ketoacid dehydrogenase, and the glycine cleavage system), as well as mitochondrial respiratory chain complexes I and II, but do not affect aconitase. Thus, it is believed that BOLA3 is involved in transporting [4Fe-4S] clusters to respiratory chain complexes I and II and lipoic acid synthetase, but does not interfere with aconitase. These findings suggest that while lipoic acid supplementation or vitamin cocktails may provide benefits, the impaired [4Fe-4S] cluster pathway itself should be targeted for treatment to improve the extensive metabolic abnormalities caused by BOLA3 deficiency.
    Keywords:  BOLA3; Lipoic acid; Mitochondria; TCA cycle
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109113
  11. J Cell Biol. 2025 May 05. pii: e202503004. [Epub ahead of print]224(5):
    TMBIM-2 links neuronal mitochondrial stress to systemic adaptation via calcium signaling.
    Yu Sun, Terytty Yang Li.
      Mitochondrial function is critical for neuronal activity and systemic metabolic adaptation. In this issue, Li et al. (https://doi.org/10.1083/jcb.202408050) identify TMBIM-2 as a key regulator of calcium dynamics, coordinating the neuronal-to-intestinal mitochondrial unfolded protein response (UPRmt), pathogen-induced aversive learning, and aging.
    DOI:  https://doi.org/10.1083/jcb.202503004
  12. J Transl Med. 2025 Apr 24. 23(1): 471
    OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation.
    Kexuan Zhang, Wenqing Zhang, Lin Zhang, Xiaorong Hou, Runyi Tian, Zhengmao Hu, Lili Yin, Zhonghua Hu.
       BACKGROUND: Autosomal dominant optic atrophy (ADOA), a leading common inherited optic neuropathy, arises from progressive retinal ganglion cell degeneration, often linked to OPA1 mutations. OPA1, a mitochondrial GTPase, regulates mitochondrial fusion, crista structure, and apoptosis. While GTPase-related dysfunction is well-studied, the role of other OPA1 domains in ADOA pathology remains unclear.
    METHODS: To investigate ADOA-linked OPA1 mutations, we assessed mitochondrial morphology, membrane potential, cytochrome c release, and cell viability in primary cortical neurons and N2a cells expressing OPA1 wild-type or mutant constructs. RNA sequencing and structural predictions (SWISS-MODEL) provided insights into molecular pathways and structural impacts.
    RESULTS: Two ADOA-associated mutations were characterized: V465F (GTPase β-fold) and V560F (BSE α-helix). Both mutations impaired mitochondrial fusion and cell survival under apoptotic stimuli. Notably, the BSE-located V560F mutation caused greater deficits in membrane potential maintenance, earlier apoptosis, and distinct molecular pathway changes compared to V465F.
    CONCLUSIONS: This study highlights the domain-specific impacts of OPA1 mutations on mitochondrial function and ADOA pathology, revealing unique roles of the BSE domain in apoptosis regulation and mitochondrial integrity. These findings provide insights into ADOA mechanisms and potential therapeutic targets.
    Keywords:  Apoptosis; Autosomal dominant optic atrophy (ADOA); Bundle signaling element (BSE); GTPase activity; Mitochondrial dynamics; OPA1 mutations
    DOI:  https://doi.org/10.1186/s12967-025-06471-w
  13. Proc Natl Acad Sci U S A. 2025 Apr 29. 122(17): e2426338122
    PPARα regulates ER-lipid droplet protein Calsyntenin-3β to promote ketogenesis in hepatocytes.
    Lauren F Uchiyama, Alexander Nguyen, Kevin Qian, Liujuan Cui, Khoi T Pham, Xu Xiao, Yajing Gao, Yuta Shimanaka, Marcus J Tol, Laurent Vergnes, Karen Reue, Peter Tontonoz.
      Ketogenesis requires fatty acid flux from intracellular (lipid droplets) and extrahepatic (adipose tissue) lipid stores to hepatocyte mitochondria. However, whether interorganelle contact sites regulate this process is unknown. Recent studies have revealed a role for Calsyntenin-3β (CLSTN3β), an endoplasmic reticulum-lipid droplet contact site protein, in the control of lipid utilization in adipose tissue. Here, we show that Clstn3b expression is induced in the liver by the nuclear receptor PPARα in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte-specific loss of CLSTN3β in mice impairs ketogenesis independent of changes in PPARα activation. Conversely, hepatic overexpression of CLSTN3β promotes ketogenesis in mice. Mechanistically, CLSTN3β affects LD-mitochondria crosstalk, as evidenced by changes in fatty acid oxidation, lipid-dependent mitochondrial respiration, and the mitochondrial integrated stress response. These findings define a function for CLSTN3β-dependent membrane contacts in hepatic lipid utilization and ketogenesis.
    Keywords:  hepatocyte; ketogenesis; ketogenic diet; lipid metabolism
    DOI:  https://doi.org/10.1073/pnas.2426338122
  14. J Inherit Metab Dis. 2025 May;48(3): e70029
    YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.
    Anthi Demetriadou, Olga Grafakou, Theodoros Georgiou, Daniela Burska, Anna Malekkou, Jana Krizova, Efstathia Paramera, Gavriella Mavrikiou, Maria Dionysiou, Athina Theodosiou, Carolina Sismani, Violetta Anastasiadou, Ioannis Ioannou, Evangelos Papakonstantinou, Hana Hansikova, Anthi Drousiotou, Petros P Petrou.
      3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenced by abnormal proteolytic processing of substrate proteins, such as OPA1 and PRELID1. Consistent with the aberrant processing of the mitochondrial fusion protein OPA1, we demonstrate enhanced mitochondrial fission and fragmentation of the mitochondrial network in patient-derived fibroblasts. Furthermore, our results indicate that YME1L1L667V is associated with attenuated activity of rate-limiting Krebs cycle enzymes and reduced mitochondrial respiration, which may explain the build-up of 3-methylglutaconic and 3-methylglutaric acid due to the diversion of acetyl-CoA, not efficiently processed in the Krebs cycle, towards the formation of 3-methylglutaconyl-CoA, the precursor of these metabolites. In summary, our findings classify YME1L1 deficiency as a new type of secondary 3-MGCA, thus expanding the genetic landscape and facilitating the diagnosis of inherited metabolic disorders featuring this biochemical phenotype.
    Keywords:  3‐methylglutaconic aciduria; YME1L1; inherited metabolic disorders; mitochondrial disorders; mitochondrial dysfunction; mitochondrial fragmentation
    DOI:  https://doi.org/10.1002/jimd.70029
  15. Neuromuscul Disord. 2025 Mar 22. pii: S0960-8966(25)00067-7. [Epub ahead of print]50 105340
    280th ENMC International Workshop: The ERN EURO-NMD mitochondrial diseases working group; diagnostic criteria and outcome measures in primary mitochondrial myopathies. Hoofddorp, the Netherlands, 22-24 November 2024.
    280th ENMC workshop study group
      The 280th ENMC International Workshop, held in Hoofddorp, The Netherlands, November 22-24, 2024, focused on primary mitochondrial myopathies (PMM). The workshop aimed to update diagnostic criteria, outcome measures, and explore new digital health technologies (DHTs) in the context of clinical trial design and conduct for PMM. Key points discussed included: (i) PMM definition and phenotypes; PMM are genetically determined mitochondrial disorders with prominent skeletal muscle involvement with two major phenotypes: mitochondrial myopathy (MiMy) either with or without chronic progressive external ophthalmoplegia (PEO); (ii) diagnostic criteria, with emphasis on the importance of genetic testing and muscle biopsy for accurate diagnosis; (iii) outcome measures: consensus on clinical scales, functional tests, performance measures, and patient-reported outcome measures (PROMs) for both adults and children; (iv) digital health technologies, with exploration of wearable and non-wearable technologies for gait analysis, physical activity monitoring, and other assessments; (v) potential and limitations of biomarkers for PMM diagnosis and monitoring. The workshop concluded with a strong consensus on the updated definition of PMM, its phenotypes, and the recommended outcome measures for clinical studies. Further research is needed to validate digital health technologies and biomarkers for PMM.
    Keywords:  Biomarkers; Clinical trials; Diagnostic criteria; Outcome measures; Primary mitochondrial myopathy
    DOI:  https://doi.org/10.1016/j.nmd.2025.105340
  16. Nat Chem Biol. 2025 Apr 22.
    TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6.
    Anat Raiff, Shidong Zhao, Aizat Bekturova, Colin Zenge, Shir Mazor, Xinyan Chen, Wenwen Ru, Yaara Makaros, Tslil Ast, Alban Ordureau, Chao Xu, Itay Koren.
      Mitochondrial homeostasis is maintained through complex regulatory mechanisms, including the balance of mitochondrial dynamics involving fusion and fission processes. A central player in this regulation is the ubiquitin-proteasome system (UPS), which controls the degradation of pivotal mitochondrial proteins. In this study, we identified cullin-RING E3 ligase 2 (CRL2) and its substrate receptor, FEM1B, as critical regulators of mitochondrial dynamics. Through proteomic analysis, we demonstrate here that FEM1B controls the turnover of PLD6, a key regulator of mitochondrial dynamics. Using structural and biochemical approaches, we show that FEM1B physically interacts with PLD6 and that this interaction is facilitated by the direct association of FEM1B with the mitochondrial import receptor TOM20. Ablation of FEM1B or disruption of the FEM1B-TOM20 interaction impairs PLD6 degradation and induces mitochondrial defects, phenocopying PLD6 overexpression. These findings underscore the importance of FEM1B in maintaining mitochondrial morphology and provide further mechanistic insights into how the UPS regulates mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41589-025-01894-4
  17. Circ Res. 2025 Apr 25. 136(9): 943-945
    Impact of Cholesterol on Cardiac Mitochondrial Function.
    Gary D Lopaschuk.
      
    Keywords:  Editorials; cholesterol; heart failure; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326464
  18. Cell Commun Signal. 2025 Apr 22. 23(1): 192
    Mitochondrial DNA signals driving immune responses: Why, How, Where?
    Luca Giordano, Sarah A Ware, Claudia J Lagranha, Brett A Kaufman.
      There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.
    Keywords:  Circulating cell-free DNA; DNA-sensing receptors; Inflammation; Innate immunity; Mitochondria; Mitochondrial DNA
    DOI:  https://doi.org/10.1186/s12964-025-02042-0
  19. Comput Biol Chem. 2025 Apr 17. pii: S1476-9271(25)00137-9. [Epub ahead of print]118 108477
    Convolutional Neural Network approach to classify mitochondrial morphologies.
    Soumaya Zaghbani, Lukas Faber, Ana J Garcia-Saez.
      The morphology of the mitochondrial network is a major indicator of cellular health and function, with changes often linked to various physiological and pathological conditions. As a result, efficient methods to quickly assess mitochondrial shape in cellular populations from microscopy images in a quantitative manner are of high interest for the health and life sciences. Here, we present MitoClass, a deep learning-based software designed for automated mitochondrial classification. MitoClass employs a classification algorithm that categorizes mitochondrial network shapes into three classes: fragmented, intermediate, and elongated. By leveraging super-resolution images, we curated a comprehensive dataset for training, including both high- and low-resolution representations of mitochondrial networks. Using a Convolutional Neural Network (CNN) architecture, our model effectively distinguishes between different mitochondrial morphologies. Through rigorous training and validation, MitoClass provides a fast, accurate, and user-friendly solution for researchers and clinicians to assess the organization of the mitochondrial network as a proxy for studying organelle health and dynamics.
    Keywords:  Cellular imagin; Convolutional neural network; Deep learning; Image classification; Mitochondria classification; Mitochondria dynamics
    DOI:  https://doi.org/10.1016/j.compbiolchem.2025.108477
  20. Nature. 2025 Apr 24.
    Parkinson's gut-microbiota links raise treatment possibilities.
    Sarah DeWeerdt.
      
    Keywords:  Microbiome; Neurodegeneration; Parkinson's disease
    DOI:  https://doi.org/10.1038/d41586-025-01253-2
  21. Int J Nanomedicine. 2025 ;20 4903-4917
    Exosome-Mediated Mitochondrial Regulation: A Promising Therapeutic Tool for Alzheimer's Disease and Parkinson's Disease.
    Young Hyun Jung, Hyo Youn Jo, Dae Hyun Kim, Yeon Ju Oh, Minsoo Kim, Seunghyun Na, Ho-Yeon Song, Hyun Jik Lee.
      Alzheimer's disease (AD) and Parkinson's disease (PD) are representative neurodegenerative diseases with abnormal energy metabolism and altered distribution and deformation of mitochondria within neurons, particularly in brain regions such as the hippocampus and substantia nigra. Neurons have high energy demands; thus, maintaining a healthy mitochondrial population is important for their biological function. Recently, exosomes have been reported to have mitochondrial regulatory potential and antineurodegenerative properties. This review presents the mitochondrial abnormalities in brain cells associated with AD and PD and the potential of exosomes to treat these diseases. Specifically, it recapitulates research on the molecular mechanisms whereby exosomes regulate mitochondrial biogenesis, fusion/fission dynamics, mitochondrial transport, and mitophagy. Furthermore, this review discusses exosome-triggered signaling pathways that regulate nuclear factor (erythroid-derived 2)-like 2-dependent mitochondrial antioxidation and hypoxia inducible factor 1α-dependent metabolic reprogramming. In summary, this review aims to provide a profound understanding of the regulatory effect of exosomes on mitochondrial function in neurons and to propose exosome-mediated mitochondrial regulation as a promising strategy for AD and PD.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; exosome; mitochondria; neurodegenerative disease
    DOI:  https://doi.org/10.2147/IJN.S513816
  22. Am J Med Genet A. 2025 Apr 24. e64101
    Clinical and Radiological Characterization of TEFM-Associated Neurological Disorder.
    Naik Adarsha, Haseena Sait, Deepak Ravichandran.
      Transcription Elongation Factor Mitochondrial (TEFM) is a crucial component of the mitochondrial transcription machinery, playing a key role in regulating mitochondrial RNA (mtRNA) polymerase activity and ensuring efficient mitochondrial DNA transcription. Recent studies have identified pathogenic variations in the TEFM gene as the cause of a childhood-onset neurological disorder with varying severity. To date, only seven cases have been reported in the literature, all from a single study. We report the case of an adolescent male presenting with intellectual disability, behavioral abnormalities, intermittent ataxia, muscle fatigability, lateral rectus ophthalmoplegia, and generalized seizures, along with cerebellar and upper motor neuron signs, as well as unique neuroimaging findings. The intermittent nature of certain symptoms, along with muscle fatigability, resembled a neuromuscular junction (NMJ)-like disorder; however, the repetitive nerve stimulation test (RNST) was normal. Exome sequencing revealed a missense variant (c.469C>G, p.Pro157Ala), which was also observed previously in two Indian siblings. This case expands the phenotypic spectrum of TEFM-related mitochondrial disorders by presenting novel radiological findings not previously described. The identified missense variant may represent a population-specific variant and exhibits a recognizable phenotypic spectrum warranting consideration in individuals presenting with an NMJ-like disorder.
    Keywords:  intellectual disability; muscle fatiguability; neuromuscular junction‐like disorder; ophthalmoplegia; transcription elongation factor mitochondrial
    DOI:  https://doi.org/10.1002/ajmg.a.64101
  23. ACS Bio Med Chem Au. 2025 Apr 16. 5(2): 262-267
    Hidden β-γ Dehydrogenation Products in Long-Chain Fatty Acid Oxidation Unveiled by NMR: Implications on Lipid Metabolism.
    Simone Fabbian, Beatrice Masciovecchio, Elisabetta Schievano, Gabriele Giachin.
      We present a comprehensive analysis of the initial α,β-dehydrogenation step in long-chain fatty acid β-oxidation (FAO). We focused on palmitoyl-CoA oxidized by two mitochondrial acyl-CoA dehydrogenases, very-long-chain acyl-CoA dehydrogenase (VLCAD) and acyl-CoA dehydrogenase family member 9 (ACAD9), both implicated in mitochondrial diseases. By combining MS and NMR, we identified the (2E)-hexadecenoyl-CoA as the expected α-β-dehydrogenation product and also the E and Z stereoisomers of 3-hexadecenoyl-CoA: a "γ-oxidation" product. This finding reveals an alternative catalytic pathway in mitochondrial FAO, suggesting a potential regulatory role for ACAD9 and VLCAD during fatty acid metabolism.
    DOI:  https://doi.org/10.1021/acsbiomedchemau.4c00140
  24. Cell Death Differ. 2025 Apr 20.
    Age-associated reduction in ER-Mitochondrial contacts impairs mitochondrial lipid metabolism and autophagosome formation in the heart.
    Weilong Hong, Xue Zeng, Ruiyan Ma, Yu Tian, Huimin Miu, Xiaoping Ran, Rui Song, Zhenchun Luo, Dapeng Ju, Daqing Ma, Milad Ashrafizadeh, Sujit Kumar Bhutia, João Conde, Gautam Sethi, He Huang, Chenyang Duan.
      The accumulation of dysfunctional giant mitochondria is a hallmark of aged cardiomyocytes. This study investigated the core mechanism underlying this phenomenon, focusing on the disruption of mitochondrial lipid metabolism and its effects on mitochondrial dynamics and autophagy, using both naturally aging mouse models and etoposide-induced cellular senescence models. In aged cardiomyocytes, a reduction in endoplasmic reticulum-mitochondrial (ER-Mito) contacts impairs lipid transport and leads to insufficient synthesis of mitochondrial phosphatidylethanolamine (PE). A deficiency in phosphatidylserine decarboxylase (PISD) further hinders the conversion of phosphatidylserine to PE within mitochondria, exacerbating the deficit of PE production. This PE shortage disrupts autophagosomal membrane formation, leading to impaired autophagic flux and the accumulation of damaged mitochondria. Modulating LACTB expression to enhance PISD activity and PE production helps maintain mitochondrial homeostasis and the integrity of aging cardiomyocytes. These findings highlight the disruption of mitochondrial lipid metabolism as a central mechanism driving the accumulation of dysfunctional giant mitochondria in aged cardiomyocytes and suggest that inhibiting LACTB expression could serve as a potential therapeutic strategy for mitigating cardiac aging and preserving mitochondrial function.
    DOI:  https://doi.org/10.1038/s41418-025-01511-w
  25. Autophagy. 2025 Apr 25. 1-3
    SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.
    Mingzhu Tang, Guang Lu, Han-Ming Shen.
      Mitophagy, selective degradation of dysfunctional mitochondria by the autophagy-lysosome pathway, is critical for maintaining cellular homeostasis. In recent years, significant progress has been made in understanding how PINK1 (PTEN-induced kinase 1)-mediated phosphorylation and the E3 ubiquitin (Ub) ligase (PRKN/parkin)-mediated ubiquitination form a positive feedforward loop in control of mitophagy. Nevertheless, a fundamental question remains: How is PINK1 transcriptionally modulated under mitochondrial stress to finely support mitophagy? Recently, we unveiled a novel mechanism in control of PINK1 transcription by SMAD3 (SMAD family member 3), an essential component of the TGFB/TGFβ (transforming growth factor beta)-SMAD signaling pathway. Upon mitochondrial depolarization, SMAD3 is activated through PINK1-mediated phosphorylation of SMAD3 at serine 423/425 independent of canonical TGFB signaling. More importantly, the SMAD3-PINK1 regulatory axis appears to functionally provide a pro-survival mechanism against mitochondrial stress. Therefore, PINK1 and SMAD3 constitute a newly discovered positive feedforward loop to regulate mitophagy, highlighting the need for further exploring the crosstalk between TGFB-SMAD signaling and mitophagy.
    Keywords:  Mitophagy; PINK1; SMAD3; phosphorylation; transcription
    DOI:  https://doi.org/10.1080/15548627.2025.2496364
  26. Cells. 2025 Apr 12. pii: 582. [Epub ahead of print]14(8):
    Neuroprotection by Mitochondrial NAD Against Glutamate-Induced Excitotoxicity.
    Bruna S Paiva, Diogo Neves, Diogo Tomé, Filipa J Costa, Inês C Bruno, Diogo Trigo, Raquel M Silva, Ramiro D Almeida.
      Excitotoxicity is a pathological process that occurs in many neurological diseases, such as stroke or epilepsy, and is characterized by the extracellular accumulation of high concentrations of glutamate or other excitatory amino acids (EAAs). Nicotinamide adenine dinucleotide (NAD) depletion is an early event following excitotoxicity in many in vitro and in vivo excitotoxic-related models and contributes to the deregulation of energy homeostasis. However, the interplay between glutamate excitotoxicity and the NAD biosynthetic pathway is not fully understood. To address this question, we used a primary culture of rat cortical neurons and found that an excitotoxic glutamate insult alters the expression of the NAD biosynthetic enzymes. Additionally, using a fluorescent NAD mitochondrial sensor, we observed that glutamate induces a significant decrease in the mitochondrial NAD pool, which was reversed when exogenous NAD was added. We also show that exogenous NAD protects against the glutamate-induced decrease in mitochondrial membrane potential (MMP). Glutamate excitotoxicity changed mitochondrial retrograde transport in neurites, which seems to be reversed by NAD addition. Finally, we show that NAD and NAD precursors protect against glutamate-induced cell death. Together, our results demonstrate that glutamate-induced excitotoxicity acts by compromising the NAD biosynthetic pathway, particularly in the mitochondria. These results also uncover a potential role for mitochondrial NAD as a tool for central nervous system (CNS) regenerative therapies.
    Keywords:  NAD metabolism; excitotoxicity; glutamate; mitochondria
    DOI:  https://doi.org/10.3390/cells14080582
  27. Sci Adv. 2025 Apr 25. 11(17): eadq6077
    Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.
    Laurent Guillaud, Anna Garanzini, Sarah Zakhia, Sandra De la Fuente, Dimitar Dimitrov, Susan Boerner, Marco Terenzio.
      Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.
    DOI:  https://doi.org/10.1126/sciadv.adq6077
  28. Sci Rep. 2025 Apr 19. 15(1): 13585
    SIRT1-based therapy targets a gene program involved in mitochondrial turnover in a model of retinal neurodegeneration.
    Brahim Chaqour, Jacob B Rossman, Miranda Meng, Kimberly E Dine, Ahmara G Ross, Kenneth S Shindler.
      Neurodegenerative diseases of the eye such as optic neuritis (ON) are hallmarked by retinal ganglion cell (RGC) loss and optic nerve degeneration leading to irreversible blindness. Therapeutic interventions enhancing expression or activity of SIRT1, an NAD+-dependent deacetylase, support, at least in part, survival of RGCs in the face of injury. Herein, we used mice with experimental autoimmune encephalomyelitis (EAE) which recapitulates axonal and neuronal damages characteristic of ON to identify gene regulatory networks affected by constitutive ubiquitous Sirt1 expression in SIRT1 knock-in mice and wild-type mice upon targeted adeno-associated virus (AAV)-mediated SIRT1 expression in RGCs. RNA seq data analysis showed that the most upregulated genes in EAE mouse retinas include those involved in inflammation, immune response, apoptosis, and mitochondrial turnover. The latter includes genes regulating mitophagy (e.g., Atg4), mitochondrial transport (e.g., Ipo- 6, Xpo- 6), and mitochondrial localization (e.g., Chrna4, Scn9a). The constitutive or RGC-targeted SIRT1 overexpression in EAE mice upregulated the expression of non-mitochondrial genes such as Ecel1 and downregulated the expression of mitophagy genes (e.g., Atg2b, Arifip1) which were upregulated by EAE alone. Thus, SIRT1 induces neuroprotection by, at least in part, balancing mitochondrial biogenesis and mitophagy and/or enhancing mitochondrial self-repair to preserve the bioenergetic capacity of RGCs.
    Keywords:  Experimental autoimmune encephalomyelitis; Optic neuritis; SIRT1
    DOI:  https://doi.org/10.1038/s41598-025-97456-8
  29. Pediatr Res. 2025 Apr 23.
    Cardiac dysfunction due to mitochondrial impairment assessed by human iPS cells caused by DNM1L mutations.
    Madori T Osawa, Yasunori Fujita, Kazuki Kagami, Masataka Ito, Yoshiteru Tamura, Shoichiro Tateishi, Junya Take, Fumi Hirose, Hidetoshi Hagiwara, Kohsuke Imai, Daisuke Yoshinaga, Shiro Baba, Mitsujiro Osawa, Hiroko Harashima, Kei Murayama, Yuko Akioka, Akira Ohtake, Ikuro Suzuki, Takeshi Adachi, Takeru Yamazaki, Satoshi Arai, Shiro Matsumoto, Tetsuya Kitaguchi, Megumu K Saito, Ikuroh Ohsawa, Shigeaki Nonoyama.
       BACKGROUND: DNM1L encodes dynamin-related protein 1, which plays an important role in mitochondrial and peroxisomal division. The DNM1L mutation leads to cardiac dysfunction in patients and animal models. However, the mechanism of cardiac dysfunction caused by DNM1L mutation has not been elucidated clearly at least in the studies of human cardiomyocytes.
    METHODS: We established human induced pluripotent stem cells (hiPSCs) from two pediatric patients with DNM1L mutation. The hiPSCs were differentiated into hiPSC-derived cardiomyocytes (hiPS-CMs). Mitochondrial morphology and function, cardiomyocyte Ca2+ dynamics, and contractile and diastolic function of hiPS-CMs were analyzed.
    RESULTS: The morphology of the mitochondria was abnormally elongated in patient-derived hiPS-CMs. The mitochondrial membrane potential and oxygen consumption rate were significantly decreased, resulting in reduced ATP production. In the analysis of Ca2+ dynamics, the 50% time to decay was significantly longer in patient-derived hiPS-CMs than in healthy control. High-precision live-imaging system analysis revealed that contractile and diastolic function was significantly impaired under isoproterenol stimulation.
    CONCLUSION: DNM1L mutations cause mitochondrial impairment with less production of ATP in cardiomyocytes. This leads to abnormal intracellular Ca2+ dynamics, resulting in contractile and diastolic dysfunction.
    IMPACT: DNM1L mutations was identified in two pediatric patients who developed cardiac dysfunction and human induced pluripotent stem cells (hiPSCs) were established from these two patients and differentiated into hiPSC-derived cardiomyocytes (hiPS-CMs). DNM1L mutations induced abnormal mitochondrial morphology, mitochondrial dysfunction, and insufficient ATP production in hiPS-CMs. In addition, hiPS-CMs with DNM1L mutation showed abnormal Ca2+ kinetics and impaired contractile and diastolic function. This is the first study that elucidate the mechanism of cardiac dysfunction caused by DNM1L mutations by using hiPSCs.
    DOI:  https://doi.org/10.1038/s41390-025-04045-6
  30. Sci Adv. 2025 Apr 25. 11(17): eadv4410
    Conformational plasticity of mitochondrial VDAC2 controls the kinetics of its interaction with cytosolic proteins.
    William M Rosencrans, Harisankar Khuntia, Motahareh Ghahari Larimi, Radhakrishnan Mahalakshmi, Tsyr-Yan Yu, Sergey M Bezrukov, Tatiana K Rostovtseva.
      The voltage-dependent anion channel (VDAC) is a key conduit of the mitochondrial outer membrane for water-soluble metabolites and ions. Among the three mammalian isoforms, VDAC2 is unique because of its embryonic lethality upon knockout. Using single-molecule electrophysiology, we investigate the biophysical properties that distinguish VDAC2 from VDAC1 and VDAC3. Unlike the latter, VDAC2 exhibits dynamic switching between multiple high-conductance, anion-selective substates. Using α-synuclein (αSyn)-a known VDAC1 cytosolic regulator-we found that higher-conductance substates correlate with increased on-rates of αSyn-VDAC2 interaction but shorter blockage times, maintaining a consistent equilibrium constant across all substates. This suggests that αSyn detects VDAC2's dynamic structural variations before final binding. We explored the dependence of VDAC2's unique amino-terminal extension and cysteines on substate behavior, finding that both structural elements modulate substate occurrence. The discovered conformational flexibility enables VDAC2 recognition by diverse binding partners, explaining its critical physiological role via dynamical adaptation to mitochondrial metabolic conditions.
    DOI:  https://doi.org/10.1126/sciadv.adv4410
  31. Biochem Biophys Res Commun. 2025 Apr 16. pii: S0006-291X(25)00543-1. [Epub ahead of print]765 151829
    Mitochondrial calpain-1 truncates ATP synthase beta subunit.
    Yusaku Chukai, Nanami Furukawa, On Kosegawa, Lanlan Bai, Eriko Sugano, Tomokazu Fukuda, Hiroshi Tomita, Taku Ozaki.
      Calpains cleave proteins in a calcium concentration-dependent manner, modulating their intracellular functions. Calpain-1, a member of the calpain family, is localized in the cytosol and mitochondria. Mitochondrial calpain-1 induces mitochondrial dysfunction and apoptosis by cleaving its substrate. Thus, identifying the substrate of calpain-1 is essential to understand its function. However, little is known about the substrates of mitochondrial calpain-1. To address this issue, we screened mitochondrial proteins using bioinformatics approaches and two-dimensional gel electrophoresis. We identified ATP5B as a potential substrate of mitochondrial calpain-1. Calpeptin, a pan-calpain inhibitor, and Tat-μCL, a mitochondrial calpain-1 specific inhibitor, prevented the truncation of ATP5B during in vitro Ca2+ incubation. Using recombinant human calpain-1 and ATP5B proteins, we demonstrated that calpain-1 directly cleaved ATP5B, generating a fragment of ATP5B. Based on the predicted cleavage sites in ATP5B, this cleavage may disrupt its interaction with ATP5A1, leading to mitochondrial dysfunction in ATP production. This study identified ATP5B as a novel substrate of mitochondrial calpain-1. The results provide new insights into mitochondrial dysfunction.
    Keywords:  ATP5B; Calpain-1; Mitochondria
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151829
  32. Cell Rep. 2025 Apr 21. pii: S2211-1247(25)00381-X. [Epub ahead of print]44(5): 115610
    Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells.
    Benjamin A S Willett, Scott B Thompson, Vincent Chen, Anza Dareshouri, Conner L Jackson, Tonya Brunetti, Angelo D'Alessandro, Jared Klarquist, Travis Nemkov, Ross M Kedl.
      Short-lived effector cells are characterized metabolically by a highly glycolytic state, driving energy and biomass acquisition, whereas memory-fated T cells have historically been described as meeting these requirements through mitochondrial metabolism. Here, we show that the mitochondrial protein optic atrophy 1 (OPA1) is critical for rapidly dividing CD8 T cells in vivo, the requirement for which is most pronounced in effector CD8 T cells. More specifically, OPA1 supports proper cell cycle initiation and progression and the viability and survival of CD8 T cells during clonal expansion. Use of mice deficient in the mitochondrial membrane fusion proteins Mitofusin 1 and 2 (MFN1/2) in both in vivo proliferation/differentiation assays and ex vivo metabolic analysis indicates that the requirement for OPA1 during cell division supersedes its role in mitochondrial fusion. We conclude that OPA1 is critical for the generation and accumulation of short-lived effector cells that arise during the response to infection.
    Keywords:  CD8; CP: Immunology; Mitofusins; Opa1; T cell; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2025.115610
  33. Cell Metab. 2025 Apr 18. pii: S1550-4131(25)00211-6. [Epub ahead of print]
    Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction.
    Yuki Tatekoshi, Amir Mahmoodzadeh, Jason S Shapiro, Mingyang Liu, George M Bianco, Ayumi Tatekoshi, Spencer Duncan Camp, Adam De Jesus, Navid Koleini, Santiago De La Torre, J Andrew Wasserstrom, Wolfgang H Dillmann, Benjamin R Thomson, Kenneth C Bedi, Kenneth B Margulies, Samuel E Weinberg, Hossein Ardehali.
      Heart failure with preserved ejection fraction (HFpEF) is a common cause of morbidity and mortality worldwide, but its pathophysiology remains unclear. Here, we report a mouse model of HFpEF and show that hexokinase (HK)-1 mitochondrial binding in endothelial cells (ECs) is critical for protein O-GlcNAcylation and the development of HFpEF. We demonstrate increased mitochondrial dislocation of HK1 within ECs in HFpEF mice. Mice with deletion of the mitochondrial-binding domain of HK1 spontaneously develop HFpEF and display impaired angiogenesis. Spatial proximity of dislocated HK1 and O-linked N-acetylglucosamine transferase (OGT) causes increased OGT activity, shifting the balance of the hexosamine biosynthetic pathway intermediates into the O-GlcNAcylation machinery. EC-specific overexpression of O-GlcNAcase and an OGT inhibitor reverse angiogenic defects and the HFpEF phenotype, highlighting the importance of protein O-GlcNAcylation in the development of HFpEF. Our study demonstrates a new mechanism for HFpEF through HK1 cellular localization and resultant protein O-GlcNAcylation, and provides a potential therapy for HFpEF.
    Keywords:  HFpEF; O-GlcNAcylation; endothelial cell; hexokinase 1; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.001
  34. Front Pediatr. 2025 ;13 1571426
    Compound heterozygous variants of the NARS2 gene in siblings with refractory seizures: two case report and literature review.
    Heyan Wu, Min Zhou, Xiaoting Ye, Huabao Chen, Hongxin Lin, Li Wang, Xing Nie, Lidan Zhang.
       Background: Biallelic variants in NARS2 that encodes the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes. Herein, we report on two siblings carrying the same compound heterozygous missense variants in NARS2, to improve the understanding of the phenotypic heterogeneity of NARS2 variants.
    Case presentation: The two probands, a 3-year-old female (Patient 1) and a 16-month-old male (Patient 2), were clinically suspected of Combined oxidative phosphorylation deficiency 24 (COXPD24). Both presented with neurological manifestations, including refractory epilepsy, developmental delay and motor developmental regression, within the first year of life, accompanied by symmetrical brain lesions identified on magnetic resonance imaging (MRI). To elucidate the underlying genetic etiology, whole-exome sequencing (WES) was performed, followed by Sanger sequencing validation in the patients and their non-consanguineous parents. Genetic analysis revealed that both probands harbored identical compound heterozygous variants in the NARS2 gene: c.1253G>A (p.Arg418His) and c.1163C>T (p.Thr388Met). Notably, the c.1163C>T (p.Thr388Met) variant in NARS2 represents a novel finding, further expanding the genetic spectrum associated with this disorder.
    Conclusions: Our findings expand the mutational spectrum of NARS2 and highlight the associated phenotypic heterogeneity, underscoring the critical role of NARS2 in epilepsy and neurodevelopmental processes. For pediatric patients with refractory epilepsy, early genetic testing is essential to improve diagnostic accuracy, refine prognostic stratification, and guide personalized treatment strategies. Additionally, mitochondrial drug cocktail therapy may be beneficial for epilepsy caused by NARS2 mutations.
    Keywords:  NARS2; biallelic variants; combined oxidative phosphorylation deficiency 24 (COXPD24); mitochondrial drug cocktail therapy; pediatric; refractory epilepsy
    DOI:  https://doi.org/10.3389/fped.2025.1571426
  35. Neurol Sci. 2025 Apr 21.
    Palatal tremor as the clue sign of POLG-related syndrome.
    Sara Satolli, Andrea Mignarri, Filippo Maria Santorelli.
      We present the case of a man who complained of clinical features of a mitochondrial ataxia. He ultimately harbored a homozygous variant in the POLG gene. The patient also showed evidence of palatal tremor, a possible clue for POLG-related condition.
    Keywords:  Ataxia; POLG; Palatal; Tremor
    DOI:  https://doi.org/10.1007/s10072-025-08178-8
  36. Cell Mol Neurobiol. 2025 Apr 21. 45(1): 38
    Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration.
    Donghui Na, Zechen Zhang, Meng Meng, Meiyu Li, Junyan Gao, Jiming Kong, Guohui Zhang, Ying Guo.
      Aging is characterized by a gradual decline in physiological functions, with brain aging being a major risk factor for numerous neurodegenerative diseases. Given the brain's high energy demands, maintaining an adequate ATP supply is crucial for its proper function. However, with advancing age, mitochondria dysfunction and a deteriorating energy metabolism lead to reduced overall energy production and impaired mitochondrial quality control (MQC). As a result, promoting healthy aging has become a key focus in contemporary research. This review examines the relationship between energy metabolism and brain aging, highlighting the connection between MQC and energy metabolism, and proposes strategies to delay brain aging by targeting energy metabolism.
    Keywords:  Brain aging; Energy metabolism; Mitochondrial quality control; Neurons
    DOI:  https://doi.org/10.1007/s10571-025-01555-z
  37. Mov Disord. 2025 Apr 25.
    Expanding the Allelic and Clinical Heterogeneity of Movement Disorders Linked to Defects of Mitochondrial Adenosine Triphosphate Synthase.
    Philip Harrer, Magdalena Krygier, Martin Krenn, Volker Kittke, Martin Danis, Georgi Krastev, Alice Saparov, Virginie Pichon, Marlène Malbos, Clarisse Scherer, Ivana Dzinovic, Matej Skorvanek, Robert Kopajtich, Holger Prokisch, Sara Silvaieh, Anna Grisold, Maria Mazurkiewicz-Bełdzińska, Jean-Madeleine de Sainte Agathe, Juliane Winkelmann, Jan Necpal, Robert Jech, Michael Zech.
       BACKGROUND: Defects of mitochondrial ATP synthase (ATPase) represent an emerging, yet incompletely understood group of neurodevelopmental diseases with abnormal movements.
    OBJECTIVE: The aim of this study was to redefine the phenotypic and mutational spectrum of movement disorders linked to the ATPase subunit-encoding genes ATP5F1A and ATP5F1B.
    METHODS: We recruited regionally distant patients who had been genome or exome sequenced. Fibroblast cultures from two patients were established to perform RNA sequencing, immunoblotting, mass spectrometry-based high-throughput quantitative proteomics, and ATPase activity assays. In silico three-dimensional missense variant modeling was performed.
    RESULTS: We identified a patient with developmental delay, myoclonic dystonia, and spasticity who carried a heterozygous frameshift c.1404del (p.Glu469Serfs*3) variant in ATP5F1A. The patient's cells exhibited significant reductions in ATP5F1A mRNA, underexpression of the α-subunit of ATPase in association with other aberrantly expressed ATPase components, and compromised ATPase activity. In addition, a novel deleterious heterozygous ATP5F1A missense c.1252G>A (p.Gly418Arg) variant was discovered, shared by three patients from two families with hereditary spastic paraplegia (HSP). This variant mapped to a functionally important intersubunit communication site. A third heterozygous variant, c.1074+1G>T, affected a canonical donor splice site of ATP5F1B and resulted in exon skipping with significantly diminished ATP5F1B mRNA levels, as well as impaired ATPase activity. The associated phenotype consisted of cerebral palsy (CP) with prominent generalized dystonia.
    CONCLUSIONS: Our data confirm and expand the role of dominant ATP5F1A and ATP5F1B variants in neurodevelopmental movement disorders. ATP5F1A/ATP5F1B-related ATPase diseases should be considered as a cause of dystonia, HSP, and CP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  ATP synthase; ATP5F1A; ATP5F1B; cerebral palsy; dominant variant; dystonia; mitochondrial disease; spasticity
    DOI:  https://doi.org/10.1002/mds.30209
  38. Nature. 2025 Apr 23.
    Human de novo mutation rates from a four-generation pedigree reference.
    David Porubsky, Harriet Dashnow, Thomas A Sasani, Glennis A Logsdon, Pille Hallast, Michelle D Noyes, Zev N Kronenberg, Tom Mokveld, Nidhi Koundinya, Cillian Nolan, Cody J Steely, Andrea Guarracino, Egor Dolzhenko, William T Harvey, William J Rowell, Kirill Grigorev, Thomas J Nicholas, Michael E Goldberg, Keisuke K Oshima, Jiadong Lin, Peter Ebert, W Scott Watkins, Tiffany Y Leung, Vincent C T Hanlon, Sean McGee, Brent S Pedersen, Hannah C Happ, Hyeonsoo Jeong, Katherine M Munson, Kendra Hoekzema, Daniel D Chan, Yanni Wang, Jordan Knuth, Gage H Garcia, Cairbre Fanslow, Christine Lambert, Charles Lee, Joshua D Smith, Shawn Levy, Christopher E Mason, Erik Garrison, Peter M Lansdorp, Deborah W Neklason, Lynn B Jorde, Aaron R Quinlan, Michael A Eberle, Evan E Eichler.
      Understanding the human de novo mutation (DNM) rate requires complete sequence information1. Here using five complementary short-read and long-read sequencing technologies, we phased and assembled more than 95% of each diploid human genome in a four-generation, twenty-eight-member family (CEPH 1463). We estimate 98-206 DNMs per transmission, including 74.5 de novo single-nucleotide variants, 7.4 non-tandem repeat indels, 65.3 de novo indels or structural variants originating from tandem repeats, and 4.4 centromeric DNMs. Among male individuals, we find 12.4 de novo Y chromosome events per generation. Short tandem repeats and variable-number tandem repeats are the most mutable, with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 16% of de novo single-nucleotide variants are postzygotic in origin with no paternal bias, including early germline mosaic mutations. We place all this variation in the context of a high-resolution recombination map (~3.4 kb breakpoint resolution) and find no correlation between meiotic crossover and de novo structural variants. These near-telomere-to-telomere familial genomes provide a truth set to understand the most fundamental processes underlying human genetic variation.
    DOI:  https://doi.org/10.1038/s41586-025-08922-2
  39. Pain Med Case Rep. 2025 Feb;9(1): 67-69
    Pain Relief in Mitochondrial Disorders: Use of Spinal Cord Stimulation in a Patient With NARP Syndrome.
    Augusta L Kiepper, Timothy Morgan, Christopher J Mallard.
       BACKGROUND: Neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome is a mitochondrial disorder of the ATPase 6 gene. There is a wide variation of symptoms, but damage to the neuronal structures can result in chronic pain.
    CASE REPORT: A 31-year-old woman's chronic back and lower extremity pain related to NARP syndrome was successfully treated with dorsal column spinal cord stimulation (SCS).
    CONCLUSIONS: SCS can be used as a means of pain management in patients with genetic etiologies. This case provides an example of treating symptoms related to genetic defects with simulation improving quality of life.
    Keywords:   Case report ; NARP syndrome ; causalgia ; chronic pain ; mitochondrial disease ; neuromodulation ; spinal cord stimulation
  40. Prenat Diagn. 2025 Apr 19.
    Prenatal FBXL4-Associated Mitochondrial DNA Depletion Syndrome-13: A New Case and Review of the Literature.
    Andrea Ros, Ivan Hurtado, Élida Vázquez-Méndez, Laura Monlleó-Neila, Montserrat Pauta, M Mar Rovira-Remisa, Belen García, Barbara Masotto, Carmina Comas, Ignacio Blanco, Aneta Zientalska.
       OBJECTIVE: Mitochondrial DNA depletion syndrome-13 associated with FBXL4 (MTDPS13) is an autosomal recessive disorder characterized by encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. This report aims to provide a comprehensive analysis of a new prenatal-onset case of MTDPS13 and to review previously documented cases.
    METHOD: We report a prenatal-onset case of MTDPS13 and review the three previously published cases.
    RESULTS: The fetus initially presented with abnormal ultrasound findings at 20 weeks of gestation, including a mega cisterna magna, hypoplasia of the cerebellar vermis, and large bilateral choroid plexus cysts. At 23 weeks of gestation, fetal magnetic resonance imaging (MRI) confirmed the ultrasound findings and revealed small periventricular cystic areas suggestive of cavitations in the ganglionic eminences. At 31 weeks, MRI identified vermian hypoplasia with an increased retrocerebellar space, elevated tentorial insertion, and unilateral ventriculomegaly. Later in pregnancy, exome sequencing identified the homozygous pathogenic variant NM_012160.4:c.141del in the FBXL4 gene, thereby confirming the diagnosis of MTDPS13.
    CONCLUSION: This case illustrates the prenatal onset of MTDPS13, with central nervous system abnormalities apparent from the second trimester. Only three similar cases have been reported, all in males, presenting at least one truncating variant in FBXL4 gene. The literature and our case highlight that the prenatal clinical manifestations can include ventriculomegaly, periventricular cysts, mega cisterna magna, cerebellar vermis hypoplasia, and cardiac anomalies.
    DOI:  https://doi.org/10.1002/pd.6794
  41. Nature. 2025 Apr 23.
    A protein tunnel that shuttles lipids around the cell.
      
    Keywords:  Cell biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-025-01167-z
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