bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–03–09
47 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.
  2. Pulling back the mitochondria's iron curtain.
  3. Vitamin A treatment restores vision failures arising from Leber's hereditary optic neuropathy-linked mtDNA mutation.
  4. Improving acute care for Primary Mitochondrial Disease: Development of a publicly available clinical care pathway.
  5. Dodging mitochondrial mislocalization.
  6. Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5.
  7. Mitochondria in aging and age-associated diseases.
  8. Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.
  9. PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.
  10. Heart of the matter: mitochondrial dynamics and genome alterations in cardiac aging.
  11. Altered Fibroblast Glutamine Metabolism Is Linked to the Severity of Cardiac Dysfunction in DCMA, a Mitochondrial Cardiomyopathy.
  12. Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.
  13. Novel reporter of the PINK1-Parkin mitophagy pathway identifies its damage sensor in the import gate.
  14. NDUFB7 mutations cause brain neuronal defects, lactic acidosis, and mitochondrial dysfunction in humans and zebrafish.
  15. Platelets and mitochondria: the calcium connection.
  16. Mitochondrial fusion and cristae reorganization facilitate acquisition of cardiomyocyte identity during reprogramming of murine fibroblasts.
  17. Leber's hereditary optic neuropathy and multiple sclerosis: overlap between mitochondrial disease and neuroinflammation.
  18. Mitochondrial proteostasis and cellular health: insights from chaperones and autophagy.
  19. A multiomic network approach uncovers disease modifying mechanisms of inborn errors of metabolism.
  20. Impact of SDHA Mutations on Yeast Growth and Mitochondrial Function. Case Study Linking Genetic Findings to Clinical Phenotypes.
  21. Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.
  22. Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.
  23. Engineered mitochondria in diseases: mechanisms, strategies, and applications.
  24. Urolithin A provides cardioprotection and mitochondrial quality enhancement preclinically and improves human cardiovascular health biomarkers.
  25. Gene prioritisation for enhancing molecular diagnosis in rare skeletal muscle disease cohort.
  26. scMitoMut for calling mitochondrial lineage-related mutations in single cells.
  27. Sengers syndrome caused by biallelic TIMM29 variants and RNAi silencing in Drosophila orthologue recapitulates the human phenotype.
  28. Mitochondrial exonuclease EXOG supports DNA integrity by the removal of single-stranded DNA flaps.
  29. A non-redundant role of EAAT3 for ATP synthesis mediated by GDH in dopaminergic neuronal cells: a new avenue for glutamate metabolism and protection in Parkinson's disease.
  30. Mapping the regulatory effects of common and rare non-coding variants across cellular and developmental contexts in the brain and heart.
  31. Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration.
  32. Infantile TK2 Deficiency Causing Mitochondrial Encephalomyopathy With Migrating Focal Seizures.
  33. Functional Specialization of S-Adenosylmethionine Synthases Links Phosphatidylcholine to Mitochondrial Function and Stress Survival.
  34. Loss-of-function mitochondrial DNA polymerase gamma variants cause vascular smooth muscle cells to secrete a diffusible mitogenic factor.
  35. Development of a Microfluidic System for Mitochondrial Extraction, Purification, and Analysis.
  36. SNX10 functions as a modulator of piecemeal mitophagy and mitochondrial bioenergetics.
  37. Two tales of therapeutic innovations for Leigh syndrome spectrum.
  38. Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow.
  39. Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men.
  40. Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites.
  41. A novel, rapidly progressive ataxia due to a spontaneous Myo5a mutation in mice impairs transport proteins and alters mitochondria.
  42. Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
  43. Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy.
  44. Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.
  45. A long-lived pool of PINK1 imparts a molecular memory of depolarization-induced activity.
  46. Leber's Hereditary Optic Neuropathy with Retinal Hemorrhage.
  47. Restoring vision with optogenetics.
  1. J Cell Biol. 2025 Apr 07. pii: e202407110. [Epub ahead of print]224(4):
    Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.
    Ya-Ting Chang, Benjamin A Barad, Juliette Hamid, Hamidreza Rahmani, Brian M Zid, Danielle A Grotjahn.
      Most of the mitochondria proteome is nuclear-encoded, synthesized by cytoplasmic ribosomes, and targeted to the mitochondria posttranslationally. However, a subset of mitochondrial-targeted proteins is imported co-translationally, although the molecular mechanisms governing this process remain unclear. We employ cellular cryo-electron tomography to visualize interactions between cytoplasmic ribosomes and mitochondria in Saccharomyces cerevisiae. We use surface morphometrics tools to identify a subset of ribosomes optimally oriented on mitochondrial membranes for protein import. This allows us to establish the first subtomogram average structure of a cytoplasmic ribosome at the mitochondrial surface in the native cellular context, which showed three distinct connections with the outer mitochondrial membrane surrounding the peptide exit tunnel. Further, this analysis demonstrated that cytoplasmic ribosomes primed for mitochondrial protein import cluster on the outer mitochondrial membrane at sites of local constrictions of the outer and inner mitochondrial membranes. Overall, our study reveals the architecture and the spatial organization of cytoplasmic ribosomes at the mitochondrial surface, providing a native cellular context to define the mechanisms that mediate efficient mitochondrial co-translational protein import.
    DOI:  https://doi.org/10.1083/jcb.202407110
  2. NPJ Metab Health Dis. 2025 ;3(1): 6
    Pulling back the mitochondria's iron curtain.
    Shani Ben Zichri-David, Liraz Shkuri, Tslil Ast.
      Mitochondrial functionality and cellular iron homeostasis are closely intertwined. Mitochondria are biosynthetic hubs for essential iron cofactors such as iron-sulfur (Fe-S) clusters and heme. These cofactors, in turn, enable key mitochondrial pathways, such as energy and metabolite production. Mishandling of mitochondrial iron is associated with a spectrum of human pathologies ranging from rare genetic disorders to common conditions. Here, we review mitochondrial iron utilization and its intersection with disease.
    Keywords:  Biochemistry; Cell biology; Metabolic pathways
    DOI:  https://doi.org/10.1038/s44324-024-00045-y
  3. JCI Insight. 2025 Mar 04. pii: e188962. [Epub ahead of print]
    Vitamin A treatment restores vision failures arising from Leber's hereditary optic neuropathy-linked mtDNA mutation.
    Cheng Ai, Huiying Li, Chunyan Wang, Yanchun Ji, Douglas C Wallace, Junbin Qian, Yimin Zhu, Min-Xin Guan.
      Leber hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy due to mitochondrial DNA (mtDNA) mutations. However, the mechanism underlying retinal cell-specific effects of LHON-linked mtDNA mutations remains poorly understood and there has been no effective treatment or cure for this disorder. Using a mice model bearing a LHON-linked ND6P25L mutation, we demonstrated that the mutation caused retinal cell-specific deficiencies, especially in retinal ganglion cells (RGC), rods and Müller cells. Single-cell RNA sequencing revealed cell-specific dysregulation of oxidative phosphorylation and visual signaling pathways in the mutant retina. Strikingly, ND6 mutation-induced dysfunctions caused abnormal vitamin A (VA) metabolism essential for visual function. VA supplementation remarkably alleviated retinal deficiencies, including reduced fundus lesion and retinal thickness, and increasing numbers of RGCs, photoreceptors and Müller cell neurites. The restoration of visual functions with VA treatment were further evidenced by correcting dysregulations of phototransduction cascade and neurotransmitter transmission and restoring electrophysiological properties. Interestingly, VA supplementation markedly rescued the abnormal mitochondrial morphologies and functions in the mutant retina. These findings provide new insight into retina-specific pathophysiology of mitochondrial retinopathy arising from vitamin A deficiency and mitochondrial dysfunction induced by mtDNA mutation and step toward for therapeutic intervention for LHON and other mitochondrial retinopathy.
    Keywords:  Genetic diseases; Genetics; Metabolism; Mitochondria; Mouse models; Ophthalmology
    DOI:  https://doi.org/10.1172/jci.insight.188962
  4. Mol Genet Metab. 2025 Feb 21. pii: S1096-7192(25)00049-6. [Epub ahead of print]144(4): 109058
    Improving acute care for Primary Mitochondrial Disease: Development of a publicly available clinical care pathway.
    Matthew M Demczko, Rebecca D Ganetzky, Cassandra Tormey, Brandon C Ku, Bridget Blowey, Jane Lavelle, Amy Goldstein.
      Primary mitochondrial diseases (PMD) are an increasingly recognized cause of multi-system organ dysfunction. Children frequently require acute care in an inpatient setting, though many hospitals do not have access to metabolic specialists. We developed a publicly available, evidenced-based clinical pathway utilizing expert consensus guidelines to guide the care of PMD patients during an emergency department visit and/or hospitalization. Utilization of the pathway may help improve triage time, clarify therapeutic options, and help initiate disease-specific screening.
    Keywords:  Acute care; Care pathways; Mitochondrial disease; Rare disease
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109058
  5. Nat Rev Mol Cell Biol. 2025 Mar 06.
    Dodging mitochondrial mislocalization.
    Lisa Heinke.
      
    DOI:  https://doi.org/10.1038/s41580-025-00840-5
  6. Front Mol Neurosci. 2025 ;18 1548255
    Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5.
    Menekse Oeztuerk, Diran Herebian, Kale Dipali, Andreas Hentschel, Nina Rademacher, Florian Kraft, Rita Horvath, Felix Distelmaier, Sven G Meuth, Tobias Ruck, Ulrike Schara-Schmidt, Andreas Roos.
      Mitochondrial integrity is fundamental to cellular function, upheld by a network of proteases that regulate proteostasis and mitochondrial dynamics. Among these proteases, AFG3L2 is critical due to its roles in maintaining mitochondrial homeostasis, regulating mitochondrial protein quality, and facilitating mitochondrial biogenesis. Mutations in AFG3L2 are implicated in a spectrum of diseases, including spinocerebellar ataxia type 28 (SCA28) and spastic ataxia 5 (SPAX5), as well as other systemic conditions. This study employs a multi-omics approach to investigate the biochemical impact of AFG3L2 mutations in immortalized lymphoblastoid cell lines derived from a patient with biallelic variants leading to spastic ataxia (SPAX5). Our proteomic analysis revealed AFG3L2 impairment, with significant dysregulation of proteins critical for mitochondrial function, cytoskeletal integrity, and cellular metabolism. Specifically, disruptions were observed in mitochondrial dynamics and calcium homeostasis, alongside downregulation of key proteins like COX11, a copper chaperone for complex IV assembly, and NFU1, an iron-sulfur cluster protein linked to spastic paraparesis and infection-related worsening. Lipidomic analysis highlighted substantial alterations in lipid composition, with significant decreases in sphingomyelins, phosphatidylethanolamine, and phosphatidylcholine, reflecting disruptions in lipid metabolism and membrane integrity. Metabolomic profiling did not reveal any significant findings. Our comprehensive investigation into loss of functional AFG3L2 elucidates a pathophysiology extending beyond mitochondrial proteostasis, implicating a wide array of cellular processes. The findings reveal substantial cellular disturbances at multiple levels, contributing to neurodegeneration through disrupted mitochondrial respiratory chain, calcium homeostasis, cytoskeletal integrity, and altered lipid homeostasis. This study underscores the complexity of SPAX5 pathophysiology and the importance of multi-omics approaches in developing effective strategies to address the impact of loss of functional AFG3L2. Our data also highlight the value of immortalized lymphoblastoid cells as a tool for pre-clinical testing and research, offering a detailed biochemical fingerprint that enhances our understanding of SPAX5 and identifies potential areas for further investigation.
    Keywords:  AFG3 like matrix AAA peptidase subunit 2; MCU; SPAX5; liquid biopsy; multi-omics lymphoblasts
    DOI:  https://doi.org/10.3389/fnmol.2025.1548255
  7. Mitochondrion. 2025 Feb 27. pii: S1567-7249(25)00019-4. [Epub ahead of print]82 102022
    Mitochondria in aging and age-associated diseases.
    Sonu Pahal, Nirjal Mainali, Meenakshisundaram Balasubramaniam, Robert J Shmookler Reis, Srinivas Ayyadevara.
      Mitochondria, essential for cellular energy, are crucial in neurodegenerative disorders (NDDs) and their age-related progression. This review highlights mitochondrial dynamics, mitovesicles, homeostasis, and organelle communication. We examine mitochondrial impacts from aging and NDDs, focusing on protein aggregation and dysfunction. Prospective therapeutic approaches include enhancing mitophagy, improving respiratory chain function, maintaining calcium and lipid balance, using microRNAs, and mitochondrial transfer to protect function. These strategies underscore the crucial role of mitochondrial health in neuronal survival and cognitive functions, offering new therapeutic opportunities.
    DOI:  https://doi.org/10.1016/j.mito.2025.102022
  8. Am J Hum Genet. 2025 Feb 25. pii: S0002-9297(25)00053-9. [Epub ahead of print]
    Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.
    Huw B Thomas, Leigh A M Demain, Alfredo Cabrera-Orefice, Isabelle Schrauwen, Hanan E Shamseldin, Alessandro Rea, Thashi Bharadwaj, Thomas B Smith, Monika Oláhová, Kyle Thompson, Langping He, Namanpreet Kaur, Anju Shukla, Musaad Abukhalid, Muhammad Ansar, Sakina Rehman, Saima Riazuddin, Firdous Abdulwahab, Janine M Smith, Zornitza Stark, Hanifenur Mancilar, Sait Tumer, Fatma N Esen, Eyyup Uctepe, Vehap Topcu, Ahmet Yesilyurt, Erum Afzal, Mehri Salari, Christopher Carroll, Giovanni Zifarelli, Peter Bauer, Deniz Kor, Fatma D Bulut, Henry Houlden, Reza Maroofian, Samantha Carrera, Wyatt W Yue, Kevin J Munro, Fowzan S Alkuraya, Peter Jamieson, Zubair M Ahmed, Suzanne M Leal, Robert W Taylor, Ilka Wittig, Raymond T O'Keefe, William G Newman.
      Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.
    Keywords:  MRPL49; Perrault syndrome; combined oxidative phosphorylation deficiency; learning disability; leukodystrophy; mitochondria; mitoribosome; primary ovarian insufficiency; rare disease; sensorineural hearing loss
    DOI:  https://doi.org/10.1016/j.ajhg.2025.02.005
  9. Cell Death Dis. 2025 Mar 01. 16(1): 145
    PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.
    Xiayun Xu, Yingji Chen, Siqi Fei, Xinyue Jiang, Xiaoting Zhou, Yimeng Xue, Yao Li, Shi-Min Zhao, Yan Huang, Chenji Wang.
      Mitophagy is a selective process that targets the damaged, dysfunctional, or superfluous mitochondria for degradation through autophagy. The SCFFBXL4 E3 ubiquitin ligase complex suppresses basal mitophagy by targeting BNIP3 and BNIP3L, two key mitophagy cargo receptors, for ubiquitin-proteasomal degradation. FBXL4 loss-of-function mutations lead to excessive BNIP3/3L-dependent mitophagy, thereby causing a devastating multi-system disorder called mitochondrial DNA depletion syndrome, type 13 (MTDPS13). PPTC7, a mitochondrial matrix phosphatase, is essential for proper mitochondrial function and biogenesis. Here, we show that a proportion of PPTC7 is located on the outer mitochondrial membrane, where it interacts with FBXL4 and BNIP3/3L. PPTC7 decreases BNIP3/3L protein stability in a protein phosphatase activity-independent manner. Using in vitro cell culture and Pptc7 knockout mouse model, we demonstrate that PPTC7 deficiency activates high levels of basal mitophagy in a BNIP3/3L-dependent manner. Mechanistically, PPTC7 facilitates SCFFBXL4-mediated ubiquitin-proteasomal degradation of BNIP3/3L. Overall, these findings establish PPTC7 as an essential co-factor of the SCFFBXL4 complex and a suppressor of BNIP3/3L-dependent mitophagy.
    DOI:  https://doi.org/10.1038/s41419-025-07463-w
  10. Mech Ageing Dev. 2025 Feb 27. pii: S0047-6374(25)00020-X. [Epub ahead of print] 112044
    Heart of the matter: mitochondrial dynamics and genome alterations in cardiac aging.
    Claudie Gabillard-Lefort, Théophile Thibault, Guy Lenaers, Rudolf J Wiesner, Jeanne Mialet-Perez, Olivier R Baris.
      Cardiac pathological aging is a serious health issue, with cardiovascular diseases still being a leading cause of deaths worldwide. Therefore, there is an urgent need to identify culprit factors involved in this process. In the last decades, mitochondria, which are crucial for cardiac function, have emerged as major contributors. Mitochondria are organelles involved in a plethora of metabolic pathways and cell processes ranging from ATP production to calcium homeostasis or regulation of apoptotic pathways. This review provides a general overview of the pathomechanisms involving mitochondria during cardiac aging, with a focus on the role of mitochondrial dynamics and mitochondrial DNA (mtDNA). These mechanisms involve imbalanced mitochondrial fusion and fission, loss of mtDNA integrity leading to tissue mosaic of mitochondrial deficiency, as well as mtDNA release in the cytoplasm, promoting inflammation via the NLRP3, cGAS/STING and TLR9 pathways. Potential links between mtDNA, mitochondrial damage and the accumulation of senescent cells in the heart are also discussed. A better understanding of how these factors impact on heart function and accelerate its pathological aging should lead to the development of new therapies to promote healthy aging and restore age-induced cardiac dysfunction.
    Keywords:  Aging; Cardiovascular diseases; Inflammation; Mitochondria; Mitochondrial dynamics; Senescence; mtDNA
    DOI:  https://doi.org/10.1016/j.mad.2025.112044
  11. J Inherit Metab Dis. 2025 Mar;48(2): e70018
    Altered Fibroblast Glutamine Metabolism Is Linked to the Severity of Cardiac Dysfunction in DCMA, a Mitochondrial Cardiomyopathy.
    Melissa A King, Katherine C Heger, Marija Drikic, Ayush Mandwal, Aneal Khan, David S Sinasac, Keir Pittman, Edward L Huttlin, Steven C Greenway, Ian A Lewis.
      The dilated cardiomyopathy with ataxia (DCMA) syndrome is a rare mitochondrial disorder caused by mutations in the poorly understood DNAJC19 gene. Cardiac involvement in DCMA ranges from mild conduction abnormalities to early severe myocardial dysfunction. Although evidence suggests that DCMA is linked to abnormalities in mitochondrial function, the molecular underpinnings of this condition are unclear, and there is no way to predict which patients will develop life-threatening disease. To address this, we developed a metabolic flux assay for assessing the metabolic function of mitochondria in fibroblasts derived from DCMA patients. Using this approach, we discovered that DCMA fibroblasts have elevated glutamine uptake, increased glutamate and ammonium secretion, and elevated lactate production. Moreover, we observed that these cellular perturbations were closely correlated with cardiac dysfunction in a blinded cohort of patient cell lines. These findings suggest that glutamine catabolism is abnormal in DCMA and may serve as a predictor of clinical progression.
    Keywords:  3‐methylglutaconic aciduria; DCMA; dilated cardiomyopathy; glutamine; metabolism
    DOI:  https://doi.org/10.1002/jimd.70018
  12. Sci Adv. 2025 Mar 07. 11(10): eadr0690
    Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.
    Yu Nie, Kornélia Szebényi, Lea M D Wenger, András Lakatos, Patrick F Chinnery.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in C9ORF72 are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the C9ORF72 hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from C9ORF72-mutant organoids, with some de novo mtSNVs likely due to the C9ORF72 repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in C9ORF72 ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.
    DOI:  https://doi.org/10.1126/sciadv.adr0690
  13. bioRxiv. 2025 Feb 20. pii: 2025.02.19.639160. [Epub ahead of print]
    Novel reporter of the PINK1-Parkin mitophagy pathway identifies its damage sensor in the import gate.
    Julia A Thayer, Jennifer D Petersen, Xiaoping Huang, James Hawrot, Daniel M Ramos, Shiori Sekine, Yan Li, Michael E Ward, Derek P Narendra.
      Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. How mitochondrial damage is sensed by the PINK1-Parkin pathway, however, remains uncertain. Here, using a Parkin substrate-based reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Consistently, the MMP but not the presequence translocase-associated motor (PAM) import motor provided the essential driving force for endogenous PINK1 import through the inner membrane translocase TIM23. In the absence of TIM23, PINK1 arrested in the translocase of the outer membrane (TOM) during import. The energy-state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Our results identify separation of PINK1 from TOM by the MMP, as the key damage-sensing switch in the PINK1-Parkin mitophagy pathway.
    Highlights: MFN2-Halo is a quantitative single-cell reporter of PINK1-Parkin activation.Diverse forms of mitochondrial damage, identified in whole-genome screens, activate the PINK1-Parkin pathway by disrupting the mitochondrial membrane potential (MMP).The primary driving force for endogenous PINK1 import through the TIM23 translocase is the MMP with the PAM import motor playing a supporting role.Loss of TIM23 is sufficient to stabilize PINK1 in the TOM complex and activate Parkin.
    DOI:  https://doi.org/10.1101/2025.02.19.639160
  14. Cell Death Discov. 2025 Mar 01. 11(1): 82
    NDUFB7 mutations cause brain neuronal defects, lactic acidosis, and mitochondrial dysfunction in humans and zebrafish.
    Yen-Lin Chen, Brian Hon-Yin Chung, Masakazu Mimaki, Shumpei Uchino, Yin-Hsiu Chien, Christopher Chun-Yun Mak, Steven Shinn-Forng Peng, Wei-Chen Wang, Yu-Li Lin, Wuh-Liang Hwu, Shyh-Jye Lee, Ni-Chung Lee.
      Complex I of the mitochondrial electron transfer chain is one of the largest membrane protein assemblies ever discovered. A patient carrying a homozygous NDUFB7 intronic mutation died within two months after birth due to cardiorespiratory defects, preventing further study. Here, we report another patient with compound heterozygous mutations in NDUFB7 who suffers from pons abnormality, lactic acidosis, prematurity, prenatal and postnatal growth deficiency, incomplete closure of the abdominal wall (ventral hernia), and a poorly functioning gastrointestinal tract (pseudo-obstruction). We demonstrated that the patient's skin fibroblasts are deficient in Complex I assembly and reduced supercomplex formation. This report further broadens the spectrum of mitochondrial disorders. The patient has had several surgeries. After receiving treatment with Coenzyme Q10 and vitamin B complex, she has remained stable up to this point. To further explore the functionality of NDUFB7 in vivo, we knocked down Ndufb7 in zebrafish embryos. This resulted in brain ventricle and neuronal defects, elevated lactic acid levels, and reduced oxygen consumption, indicating defective mitochondrial respiration. These phenotypes can be specifically rescued by ectopic expression of ndufb7. More importantly, Mitoquinone mesylate (MitoQ), a common remedy for mitochondrial disorders, can ameliorate these conditions. These results suggest a role for NDUFB7 in mitochondrial activity and the suitability of the zebrafish model for further drug screening and the development of therapeutic strategies for this rare disease.
    DOI:  https://doi.org/10.1038/s41420-025-02369-0
  15. Mol Biol Rep. 2025 Mar 03. 52(1): 276
    Platelets and mitochondria: the calcium connection.
    Durre Shehwar, Saima Barki, Alessandro Aliotta, Debora Bertaggia Calderara, Lucas Veuthey, Cindy Pereira Portela, Lorenzo Alberio, Muhammad Rizwan Alam.
      Calcium signaling has a fundamental importance in maintaining various platelet functions, such as those involved in hemostasis and thrombosis. Agonist-induced mobilization of calcium (Ca2+) from intracellular stores coupled with activation of store-operated calcium entry (SOCE) and non-SOCE or receptor-operated calcium entry (ROCE) regulates platelet degranulation, integrin activation, shape change, generation of thromboxane A2, and aggregation or procoagulant function. Platelet mitochondria also take up a small amount of cytosolic Ca2+ that contributes to bioenergetics, cytosolic Ca2+ buffering, cell signaling and death. Voltage-dependent anion channels (VDAC) in the outer mitochondrial membrane and mitochondrial Ca2+ uniporter complex (MCUC) in the inner mitochondrial membrane (IMM) are pivotal for transporting Ca2+ into the mitochondrial matrix. On the other hand, matrix Ca2+ efflux is dependent on the IMM localized sodium/calcium exchanger (NCLX). Despite the well-established role of cytosolic Ca2+, the participation of mitochondrial Ca2+ homeostasis in platelet physiology remains unknown. This mini-review summarizes the recent developments in the field of mitochondrial Ca2+ transport in platelet physiology.
    Keywords:  Apoptotic platelets; Mitochondrial calcium; Platelet activation; Procoagulant platelets
    DOI:  https://doi.org/10.1007/s11033-025-10389-3
  16. Cell Rep. 2025 Mar 05. pii: S2211-1247(25)00148-2. [Epub ahead of print]44(3): 115377
    Mitochondrial fusion and cristae reorganization facilitate acquisition of cardiomyocyte identity during reprogramming of murine fibroblasts.
    Brian M Spurlock, Yifang Xie, Yiran Song, Shea N Ricketts, James Rock Hua, Haley R Chi, Meenakshi Nishtala, Rustem Salmenov, Jiandong Liu, Li Qian.
      Cardiomyocytes (CMs) rely on mitochondrial energy produced in highly interconnected mitochondrial networks. Direct reprogramming of cardiac fibroblasts (CFs) into induced CMs (iCMs) shows promise for treating cardiac injury, but little work has investigated mitochondrial energetics and morphology during the conversion of CFs to iCMs. We characterized mitochondria during direct cardiac reprogramming of murine neonatal CFs (mnCFs). Reprogramming increased mitochondrial respiration and interconnectivity but not to the levels of native CMs. We therefore investigated whether perturbations to mitochondrial dynamics impacted reprogramming. Mitochondrial fusion (joining) was essential for iCM generation, while various fission (dividing) genes were reprogramming barriers. In particular, the loss of mitochondrial fission regulator 1 like (Mtfr1l) significantly increased the yield of functionally mature iCMs and induced mitochondrial fusion and respiration. These changes were countered by the concomitant loss of fusion effector optical atrophy protein 1 (Opa1). The present study advances our understanding of mitochondrial barriers to and mechanisms of direct cardiac reprogramming.
    Keywords:  CP: Metabolism; CP: Stem cell research; Mtfr1l; cell fate conversion; direct cardiac reprogramming; machine learning; mitochondria; mitochondrial dynamics; mitochondrial energetics; mitochondrial fission; mitochondrial fusion; regenerative medicine
    DOI:  https://doi.org/10.1016/j.celrep.2025.115377
  17. Front Neurol. 2025 ;16 1538358
    Leber's hereditary optic neuropathy and multiple sclerosis: overlap between mitochondrial disease and neuroinflammation.
    Golbarg Rahimi, Mackenzie Silverman, Maeve Lucas, Lilia Kazerooni, Mariam M Yousuf, Saba Jafarpour, Jonathan D Santoro.
      Although Multiple sclerosis (MS) and Leber hereditary optic neuropathy (LHON) have distinct pathophysiological mechanisms, they are both neurodegenerative conditions that involve mitochondrial dysfunction. MS is an autoimmune disease that is characterized by demyelination and neuroinflammation; and LHON is a mitochondrial disorder predominantly affecting the optic nerves, resulting in severe vision loss. Recent studies have highlighted the coexistence of these two conditions, particularly in females, suggesting that mitochondrial variants in LHON may predispose individuals to develop MS or affect its progression. Similar to MS, LHON-MS presents with visual impairment, neurological deficits, white matter lesions, and brain atrophy, which further supports a shared underlying pathophysiology. While MS is not inherently a mitochondrial disorder, its neuroinflammatory processes can lead to mitochondrial dysfunction. Reciprocally, mitochondrial impairment may be exacerbated in LHON-MS. Therefore, the role of mitochondrial dysfunction in these diseases is central, with impaired mitochondrial function contributing to cellular damage and neuroinflammation. This review explores the intersections of MS and LHON, emphasizing the need for further research to better understand mitochondrial dysfunction in these disorders.
    Keywords:  Harding’s syndrome; Leber’s hereditary optic neuropathy; mitochondrial dysfunction; multiple sclerosis; neuroimmunology; neuropathology
    DOI:  https://doi.org/10.3389/fneur.2025.1538358
  18. J Physiol. 2025 Mar 06.
    Mitochondrial proteostasis and cellular health: insights from chaperones and autophagy.
    Yuvraj Anandrao Jagtap, Akash Choudhary, Sumit Kinger, Prashant Kumar, Sudipta Bhattacharyya, Hem Chandra Jha, Rohan Dhiman, Vivek Sharma, Anil K Suresh, Krishna Mohan Poluri, Amit Mishra.
      Mitochondria are a cell's powerhouse and also have a vital part in cellular processes. The emerging role of mitochondria in several crucial processes highlights their cellular and physiological importance. Mitochondrial homeostasis mechanisms, including proteostasis pathways, are vital for mitochondrial health. Failure of these processes has an important role in establishment of numerous complex disease conditions, such as neurodegeneration and imperfect ageing. However, details of mitochondrial impairments and their contribution to the pathology of neurodegeneration are poorly understood. This review systematically discusses the involvement of mitochondrial homeostasis mechanisms and their role in rejuvenating cellular health and fitness. We also focus on various cellular protein quality control mechanisms essential for mitochondrial proteostasis and how their failure leads to mitochondrial functional disturbances observed in disease conditions. We discuss recent findings based on mitostasis-associated chaperones, mitoproteases, and autophagy responses, which can lead to emergence of new possible therapeutic interventions against complex diseases.
    Keywords:  chaperones; mitochondrial dynamics; mitochondrial homeostasis; mitophagy; mitoproteases; neurodegeneration; proteostasis
    DOI:  https://doi.org/10.1113/JP287635
  19. bioRxiv. 2025 Feb 20. pii: 2025.02.19.639093. [Epub ahead of print]
    A multiomic network approach uncovers disease modifying mechanisms of inborn errors of metabolism.
    Aaron Bender, Pablo Ranea-Robles, Evan Williams, Mina Mirzaian, J Alexander Heimel, Christiaan N Levelt, Ronald J A Wanders, Johannes M Aerts, Jun Zhu, Johan Auwerx, Sander M Houten, Carmen Argmann.
      For many inborn errors of metabolism (IEM) the understanding of disease mechanisms remains limited in part explaining their unmet medical needs. We hypothesize that the expressivity of IEM disease phenotypes is affected by the activity of specific modifier pathways, which is controlled by rare and common polygenic variation. To identify these modulating pathways, we used RNA sequencing to generate molecular signatures of IEM in disease relevant tissues. We then integrated these disease signatures with multiomic data and gene regulatory networks generated from animal and human populations without overt IEM. We identified and subsequently validated glucocorticoid signaling as a candidate modifier of mitochondrial fatty acid oxidation disorders, and we re-capitulated complement signaling as a modifier of inflammation in Gaucher disease. Our work describes a novel approach that can overcome the rare disease-rare data dilemma, and reveal new IEM pathophysiology and potential drug targets using multiomics data in seemingly healthy populations.
    DOI:  https://doi.org/10.1101/2025.02.19.639093
  20. Clin Genet. 2025 Mar 06.
    Impact of SDHA Mutations on Yeast Growth and Mitochondrial Function. Case Study Linking Genetic Findings to Clinical Phenotypes.
    Camilla Meossi, Alessandro De Falco, Marco Marchi, Anna Rubegni, Stefano Pagano, Rosanna Trovato, Claudia Nesti, Flavio Dal Canto, Emanuele Bartolini, Leonardo Salviati, Filippo Maria Santorelli.
      We present the case of a child who developed focal seizures, emotional and behavioral dysregulation, and sleep abnormalities at age 5. Trio whole genome sequencing identified biallelic mutations in the SDHA gene, which encodes a key component of mitochondrial complex II. Mitochondrial respiratory chain activities and muscle biopsy confirmed impaired oxidative metabolism. Yeast Saccharomyces cerevisiae complementation assays showed that all the mutations were presumably disease related. Mutations in SDHA are associated with developmental delay, hypotonia, ataxia, together with bilateral hyperintensities in the basal ganglia at brain MRI. This case corroborates the phenotypic variability of SDHA variants and highlights the relevance of functional assays in validating genetic findings.
    Keywords:  chromatinopathies; functional tests; mitochondrial respiratory chain; neurodegenerative disorders; yeast complementation
    DOI:  https://doi.org/10.1111/cge.14738
  21. Nat Commun. 2025 Mar 06. 16(1): 2250
    Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.
    Alistair P Green, Florian Klimm, Aidan S Marshall, Rein Leetmaa, Juvid Aryaman, Aurora Gómez-Durán, Patrick F Chinnery, Nick S Jones.
      Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of somatic mitochondrial DNA mutations which are unique to single cells (cryptic mutations). We find evidence of cryptic mitochondrial DNA mutations from diverse single-cell datasets, from three species, and discover: cryptic mutations constitute the vast majority of mitochondrial DNA mutations in aged post-mitotic tissues, that they can avoid selection, that their accumulation is consonant with theory we develop, hitting high levels coinciding with species specific mid-late life, and that their presence covaries with a majority of the hallmarks of ageing including protein misfolding and endoplasmic reticulum stress. We identify mechanistic links to endoplasmic reticulum stress experimentally and further give an indication that aged brain cells with high levels of cryptic mutations show markers of neurodegeneration and that calorie restriction slows the accumulation of cryptic mutations.
    DOI:  https://doi.org/10.1038/s41467-025-57286-8
  22. EMBO J. 2025 Feb 28.
    Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.
    Scott A Jones, Alice P Sowton, Denis Lacabanne, Martin S King, Shane M Palmer, Thomas Zögg, Els Pardon, Jan Steyaert, Jonathan J Ruprecht, Edmund R S Kunji.
      Uncoupling protein 1 (UCP1, SLC25A7) is responsible for the thermogenic properties of brown adipose tissue. Upon fatty acid activation, UCP1 facilitates proton leakage, dissipating the mitochondrial proton motive force to release energy as heat. Purine nucleotides are considered to be the only inhibitors of UCP1 activity, binding to its central cavity to lock UCP1 in a proton-impermeable conformation. Here we show that pyrimidine nucleotides can also bind and inhibit its proton-conducting activity. All nucleotides bound in a pH-dependent manner, with the highest binding affinity observed for ATP, followed by dTTP, UTP, GTP and CTP. We also determined the structural basis of UTP binding to UCP1, showing that binding of purine and pyrimidine nucleotides follows the same molecular principles. We find that the closely related mitochondrial dicarboxylate carrier (SLC25A10) and oxoglutarate carrier (SLC25A11) have many cavity residues in common, but do not bind nucleotides. Thus, while UCP1 has evolved from dicarboxylate carriers, no selection for nucleobase specificity has occurred, highlighting the importance of the pH-dependent nucleotide binding mechanism mediated via the phosphate moieties.
    Keywords:  Bioenergetics; Pyrimidine Nucleotides; SLC25; Thermogenesis; Uncoupling Protein
    DOI:  https://doi.org/10.1038/s44318-025-00395-3
  23. Signal Transduct Target Ther. 2025 Mar 03. 10(1): 71
    Engineered mitochondria in diseases: mechanisms, strategies, and applications.
    Mingyang Li, Limin Wu, Haibo Si, Yuangang Wu, Yuan Liu, Yi Zeng, Bin Shen.
      Mitochondrial diseases represent one of the most prevalent and debilitating categories of hereditary disorders, characterized by significant genetic, biological, and clinical heterogeneity, which has driven the development of the field of engineered mitochondria. With the growing recognition of the pathogenic role of damaged mitochondria in aging, oxidative disorders, inflammatory diseases, and cancer, the application of engineered mitochondria has expanded to those non-hereditary contexts (sometimes referred to as mitochondria-related diseases). Due to their unique non-eukaryotic origins and endosymbiotic relationship, mitochondria are considered highly suitable for gene editing and intercellular transplantation, and remarkable progress has been achieved in two promising therapeutic strategies-mitochondrial gene editing and artificial mitochondrial transfer (collectively referred to as engineered mitochondria in this review) over the past two decades. Here, we provide a comprehensive review of the mechanisms and recent advancements in the development of engineered mitochondria for therapeutic applications, alongside a concise summary of potential clinical implications and supporting evidence from preclinical and clinical studies. Additionally, an emerging and potentially feasible approach involves ex vivo mitochondrial editing, followed by selection and transplantation, which holds the potential to overcome limitations such as reduced in vivo operability and the introduction of allogeneic mitochondrial heterogeneity, thereby broadening the applicability of engineered mitochondria.
    DOI:  https://doi.org/10.1038/s41392-024-02081-y
  24. iScience. 2025 Feb 21. 28(2): 111814
    Urolithin A provides cardioprotection and mitochondrial quality enhancement preclinically and improves human cardiovascular health biomarkers.
    Sophia Liu, Julie Faitg, Charlotte Tissot, Dimitris Konstantopoulos, Ross Laws, Guillaume Bourdier, Pénélope A Andreux, Tracey Davey, Hector Gallart-Ayala, Julijana Ivanisevic, Anurag Singh, Chris Rinsch, David J Marcinek, Davide D'Amico.
      Cardiovascular diseases (CVDs) remain the primary cause of global mortality. Nutritional interventions hold promise to reduce CVD risks in an increasingly aging population. However, few nutritional interventions are proven to support heart health and act mostly on blood lipid homeostasis rather than at cardiac cell level. Here, we show that mitochondrial quality dysfunctions are common hallmarks in human cardiomyocytes upon heart aging and in chronic conditions. Preclinically, the post-biotic and mitophagy activator, urolithin A (UA), reduced both systolic and diastolic cardiac dysfunction in models of natural aging and heart failure. At a cellular level, this was associated with a recovery of mitochondrial ultrastructural defects and mitophagy. In humans, UA supplementation for 4 months in healthy older adults significantly reduced plasma ceramides clinically validated to predict CVD risks. These findings extend and translate UA's benefits to heart health, making UA a promising nutritional intervention to support cardiovascular function as we age.
    Keywords:  Biological sciences; Cardiovascular medicine; Health sciences; Internal medicine; Medical specialty; Medicine; Natural sciences; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2025.111814
  25. J Med Genet. 2025 Mar 05. pii: jmg-2024-110212. [Epub ahead of print]
    Gene prioritisation for enhancing molecular diagnosis in rare skeletal muscle disease cohort.
    Victoria Lillback, Gaber Bergant, Maria Francesca Di Feo, Ivana Babić Bozović, Annalaura Torella, Mridul Johari, Aleš Maver, Katarina Pelin, Filippo M M Santorelli, Vincenzo Nigro, Peter Hackman, Borut Peterlin, Bjarne Udd, Marco Savarese.
       BACKGROUND: Inherited rare skeletal muscle diseases cause muscle weakness and wasting of variable severity. Without a molecular diagnosis, patients often endure prolonged diagnostic journeys, leading to delays in appropriate management of the disease. This occurs in approximately 60% of patients with rare diseases.
    METHODS: To facilitate reanalysis of 278 unsolved patients, we used a gene prioritisation tool Exomiser, which standardises analysis by ranking causative variants based on phenotype relevance and variant pathogenicity. Before analysis, we benchmarked Exomiser for variant prioritisation with solved cases and for novel disease gene discovery with mock cases with variants in candidate disease genes. Additionally, we studied the significance of the specificity of the phenotype descriptions.
    RESULTS: In our study, Exomiser ranked genes in the top 10 correctly in 97.4% of controls with previously detected causative variants. Moreover, 57.1% of candidate genes in mock cases were similarly prioritised in the top 10. We also showed that three parental muscle disease human phenotype ontologies describing the patient phenotype performed as well as patient-specific ones, with a p value of 0.68 for difference in performance. The provided automation and standardisation of variant interpretation resulted in two novel diagnoses and in findings, either in known muscle disease genes or in novel candidate genes, which need further investigation.
    CONCLUSIONS: Exomiser is recommended for initial and periodic reanalyses of exomes in unsolved patients with myopathy, as it benefits from literature updates and minimises effort. This approach could also extend to whole genome sequencing data, aiding the interpretation of variants beyond coding regions.
    Keywords:  Genetics, Medical; Neuromuscular Diseases; Phenotype; Whole Exome Sequencing
    DOI:  https://doi.org/10.1136/jmg-2024-110212
  26. Brief Bioinform. 2024 Nov 22. pii: bbaf072. [Epub ahead of print]26(1):
    scMitoMut for calling mitochondrial lineage-related mutations in single cells.
    Wenjie Sun, Daphne van Ginneken, Leïla Perié.
      Tracing cell lineages has become a valuable tool for studying biological processes. Among the available tools for human data, mitochondrial DNA (mtDNA) has a high potential due to its ability to be used in conjunction with single-cell chromatin accessibility data, giving access to the cell phenotype. Nonetheless, the existing mutation calling tools are ill-equipped to deal with the polyploid nature of the mtDNA and lack a robust statistical framework. Here we introduce scMitoMut, an innovative R package that leverages statistical methodologies to accurately identify mitochondrial lineage-related mutations at the single-cell level. scMitoMut assigns a mutation quality q-value based on beta-binomial distribution to each mutation at each locus within individual cells, ensuring higher sensitivity and precision of lineage-related mutation calling in comparison to current methodologies. We tested scMitoMut using single-cell DNA sequencing, single-cell transposase-accessible chromatin (scATAC) sequencing, and 10× Genomics single-cell multiome datasets. Using a single-cell DNA sequencing dataset from a mixed population of cell lines, scMitoMut demonstrated superior sensitivity in identifying a small proportion of cancer cell line compared to existing methods. In a human colorectal cancer scATAC dataset, scMitoMut identified more mutations than state-of-the-art methods. Applied to 10× Genomics multiome datasets, scMitoMut effectively measured the lineage distance in cells from blood or brain tissues. Thus, the scMitoMut is a freely available, and well-engineered toolkit (https://www.bioconductor.org/packages/devel/bioc/html/scMitoMut.html) for mtDNA mutation calling with high memory and computational efficiency. Consequently, it will significantly advance the application of single-cell sequencing, facilitating the precise delineation of mitochondrial mutations for lineage-tracing purposes in development, tumour, and stem cell biology.
    Keywords:  lineage tracing; mitochondrial mutation; single-cell sequencing
    DOI:  https://doi.org/10.1093/bib/bbaf072
  27. Hum Genomics. 2025 Feb 28. 19(1): 21
    Sengers syndrome caused by biallelic TIMM29 variants and RNAi silencing in Drosophila orthologue recapitulates the human phenotype.
    Adel Shalata, Ann Saada, Mohammed Mahroum, Yarin Hadid, Chaya Furman, Zaher Eldin Shalata, Robert J Desnick, Avraham Lorber, Asaad Khoury, Adnan Higazi, Avraham Shaag, Varda Barash, Ronen Spiegel, Euvgeni Vlodavsky, Pierre Rustin, Shmuel Pietrokovski, Irena Manov, Dan Gieger, Galit Tal, Adi Salzberg, Hanna Mandel.
       PURPOSE: Sengers-syndrome (S.S) is a genetic disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. All reported cases were genetically caused by biallelic mutations in the AGK gene. We herein report a pathogenic variant in TIMM29 gene, encoding Tim29 protein, as a novel cause of S.S. Notably, AGK and Tim29 proteins are components of the TIM22 complex, which is responsible for importing carrier proteins into the inner mitochondrial membrane.
    METHOD: Clinical data of 17 consanguineous patients featuring S.S was obtained. Linkage analysis, and sequencing were used to map and identify the disease-causing gene. Tissues derived from the study participants and a Drosophila melanogaster model were used to evaluate the effects of TIMM29 variant on S.S.
    RESULTS: The patients presented with a severe phenotype of S.S, markedly elevated serum creatine-phosphokinase, combined mitochondrial-respiratory-chain-complexes deficiency, reduced pyruvate-dehydrogenase complex activity, and reduced adenine nucleotide translocator 1 protein. Histopathological studies showed accumulation of abnormal mitochondria. Homozygosity mapping and gene sequencing revealed a biallelic variant in TIMM29 NM_138358.4:c.514T > C NP_612367.1:p.(Trp172Arg). The knockdown of the Drosophila TIMM29 orthologous gene (CG14270) recapitulated the phenotype and pathology observed in the studied cohort. We expand the clinical phenotype of S.S and provide substantial evidence supporting TIMM29 as the second causal gene of a severe type of S.S, designated as S.S- TIMM29.
    CONCLUSION: The present study uncovers several biochemical differences between the two S.S types, including the hyperCPKemia being almost unique for S.S-TIMM29 cohort, the different frequency of MMRCC and PDHc deficiencies among the two S.S types. We propose to designate the S.S associated with TIMM29 homozygous variant as S.S-TIMM29.
    Keywords:   TIMM29 ; AGK; CK; RCC; Sengers syndrome
    DOI:  https://doi.org/10.1186/s40246-025-00723-y
  28. Nucleic Acids Res. 2025 Feb 27. pii: gkaf099. [Epub ahead of print]53(5):
    Mitochondrial exonuclease EXOG supports DNA integrity by the removal of single-stranded DNA flaps.
    Anna Karlowicz, Andrzej B Dubiel, Marta Wyszkowska, Kazi Amirul Hossain, Jacek Czub, Michal R Szymanski.
      Single-stranded DNA (ssDNA) is an important intermediate generated during various cellular DNA transactions, primarily during long-patch base excision repair. When displaced by DNA polymerase during strand displacement DNA synthesis, ssDNA forms 5' overhangs (flaps) that are either cleaved by DNA nucleases or protected from degradation upon binding of single-stranded DNA-binding proteins (SSB). Several nucleases are involved in the removal of ssDNA flaps in human mitochondria, namely the endonucleases FEN1 and DNA2, as well as the exonuclease MGME1. In this study, we show that another mitochondrial nuclease, EXOG, cleaves DNA flaps in both free and SSB-protected forms. We established that the presence of the Wing domain in EXOG structure provides additional binding site for ssDNA and 5' flaps irrespective of monovalent salt concentration. Importantly, DNA flap cleavage by EXOG is compatible with the activity of other mitochondrial enzymes involved in DNA replication/repair, e.g. mtSSB, Pol γ, and Lig III, as we were able to reconstitute a multistep reaction of DNA synthesis, flap removal, and nick ligation. Our findings highlight the versatile role of EXOG in maintaining mitochondrial DNA integrity, expanding its DNA processing repertoire to include ssDNA flap removal.
    DOI:  https://doi.org/10.1093/nar/gkaf099
  29. FEBS J. 2025 Mar 05.
    A non-redundant role of EAAT3 for ATP synthesis mediated by GDH in dopaminergic neuronal cells: a new avenue for glutamate metabolism and protection in Parkinson's disease.
    Alessandra Preziuso, Tiziano Serfilippi, Marwa Toujani, Valentina Terenzi, Salvatore Amoroso, Simona Magi, Vincenzo Lariccia, Silvia Piccirillo.
      Parkinson's disease (PD) is a devastating neurodegenerative disorder with a distinct loss of the nigrostriatal dopaminergic pathway. Despite the multiplicity in etiology, alterations that disrupt neuronal integrity can be traced back to defects in fundamental processes that typically run under mitochondrial inputs. Evidence indicates that mitochondrial activities are hierarchically integrated with the energetic performance of these organelles, so that an interesting perspective holds that interventions aimed at improving mitochondrial bioenergetics can potentially mitigate the severity of PD phenotype expression. In this mechanistic framework, approaches that facilitate the mitochondrial anaplerotic use of glutamate (Glut) might counteract the detrimental shift from Glut metabolism, which is typically altered in PD, to excessive Glut transmission that feeds excitotoxicity and the neurodegenerative spiral. In this study, we investigated whether the enhancement of glutamate dehydrogenase (GDH) activity, by using the GDH activator 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), has neuroprotective potential against PD injury. In both retinoic acid-differentiated SH-SY5Y cells and primary rat mesencephalic neurons challenged with α-synuclein plus rotenone to mimic PD, BCH-dependent GDH activation significantly ameliorated cell viability, improved mitochondrial ATP synthesis and lessened to control levels the cellular redox burden. Strikingly, we collected evidence for the existence of a functional axis connecting GDH activity to a specific intracellular pool of the Excitatory Amino Acid Transporters (EAATs), namely the EAAT3. Overall, our results reveal a novel and non-redundant role of EAAT3 for GDH-dependent protection against PD injury, which may inspire new pharmacological approaches against PD pathology.
    Keywords:  Parkinson's disease; energy deficit; mitochondria; neuroprotection; oxidative stress
    DOI:  https://doi.org/10.1111/febs.70053
  30. bioRxiv. 2025 Feb 20. pii: 2025.02.18.638922. [Epub ahead of print]
    Mapping the regulatory effects of common and rare non-coding variants across cellular and developmental contexts in the brain and heart.
    Andrew R Marderstein, Soumya Kundu, Evin M Padhi, Salil Deshpande, Austin Wang, Esther Robb, Ying Sun, Chang M Yun, Diego Pomales-Matos, Yilin Xie, Daniel Nachun, Selin Jessa, Anshul Kundaje, Stephen B Montgomery.
      Whole genome sequencing has identified over a billion non-coding variants in humans, while GWAS has revealed the non-coding genome as a significant contributor to disease. However, prioritizing causal common and rare non-coding variants in human disease, and understanding how selective pressures have shaped the non-coding genome, remains a significant challenge. Here, we predicted the effects of 15 million variants with deep learning models trained on single-cell ATAC-seq across 132 cellular contexts in adult and fetal brain and heart, producing nearly two billion context-specific predictions. Using these predictions, we distinguish candidate causal variants underlying human traits and diseases and their context-specific effects. While common variant effects are more cell-type-specific, rare variants exert more cell-type-shared regulatory effects, with selective pressures particularly targeting variants affecting fetal brain neurons. To prioritize de novo mutations with extreme regulatory effects, we developed FLARE, a context-specific functional genomic model of constraint. FLARE outperformed other methods in prioritizing case mutations from autism-affected families near syndromic autism-associated genes; for example, identifying mutation outliers near CNTNAP2 that would be missed by alternative approaches. Overall, our findings demonstrate the potential of integrating single-cell maps with population genetics and deep learning-based variant effect prediction to elucidate mechanisms of development and disease-ultimately, supporting the notion that genetic contributions to neurodevelopmental disorders are predominantly rare.
    DOI:  https://doi.org/10.1101/2025.02.18.638922
  31. Neurobiol Dis. 2025 Mar 04. pii: S0969-9961(25)00078-6. [Epub ahead of print] 106862
    Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration.
    Yifei Zheng, Jiahui Yang, Xuanyao Li, Linjie Qi, Zhuo Zheng, Jiming Kong, Guohui Zhang, Ying Guo.
      Mitochondria play a central role in essential cellular processes, including energy metabolism, biosynthesis of metabolic substances, calcium ion storage, and regulation of cell death. Maintaining mitochondrial quality control is critical for preserving mitochondrial health and ensuring cellular function. Given their high energy demands, neurons depend on effective mitochondrial quality control to sustain their health and functionality. Neuronal senescence, characterized by a progressive decline in structural integrity and function, is a hallmark of neurodegenerative diseases. In senescent neurons, abnormal mitochondrial morphology, functional impairments, increased reactive oxygen species production and disrupted quality control mechanisms are frequently observed. Understanding the pathological changes in neuronal structure, exploring the intricate relationship between mitochondrial quality control and neuronal health, and leveraging mitochondrial quality control interventions provide a promising foundation for addressing age-related neurodegenerative diseases. This review highlights key mitochondrial quality control, including biogenesis, dynamics, the ubiquitin-proteasome system, autophagy pathways, mitochondria-derived vesicles, and inter-organelle communication, while discussing their roles in neuronal senescence and potential therapeutic strategies. These insights may pave the way for innovative treatments to mitigate neurodegenerative disorders.
    Keywords:  Mitochondrial quality control; Neurodegenerative diseases; Neuron; Senescence; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.nbd.2025.106862
  32. Neurology. 2025 Apr 08. 104(7): e213373
    Infantile TK2 Deficiency Causing Mitochondrial Encephalomyopathy With Migrating Focal Seizures.
    Luca Bergonzini, Sara Carli, Silvia Pelle, Ilaria Pettenuzzo, Silvia Bonetti, Erika Santi, Caterina Visconti, Monica Maffei, Marta Sheremet, Eleonora Lamantea, Andrea Marsala, Olena Klub, Valentina Gentile, Duccio Maria Cordelli, Caterina Garone.
       OBJECTIVE: Recessive variants in the TK2 gene cause thymidine kinase 2 deficiency (TK2d) presenting with infantile, childhood, or adult-onset myopathy. CNS involvement is reported in only 25% of the infantile form. Compassionate use of deoxynucleoside substrate enhancement therapy (dC/dT) has been demonstrated safe and effective in TK2d myopathy, but no data are available on the potential efficacy on the human brain disease.
    METHODS: Here, we report for the first time a patient with infantile TK2d epileptic encephalomyopathy enrolled in an early access program with dC/dT treatment (MT1621).
    RESULTS: At age 3 months, he presented progressive hypotonia, motor regression, failure to thrive, and respiratory failure. At age 8 months, he developed drug-resistant epilepsy with migrating focal seizures. Brain MRI showed progressive atrophy and bilateral subcortical lesions with lactate peak. Exome sequencing revealed 2 novel biallelic heterozygous variants in the TK2 gene (c.182G>A, p.Ser61Asn, c.704 T>C, p.Ile235Thr) whose pathogenicity was confirmed with in vitro studies. Early access compassionate use of dC/dT at 400 mg/kg prolonged the survival and stabilized the muscle disease but was not effective on the brain.
    DISCUSSION: Our report highlights the importance of deep-phenotyping infantile TK2d before dC/dT supplementation to stratify disease severity further and suggests a limited tissue-specific brain efficacy.
    DOI:  https://doi.org/10.1212/WNL.0000000000213373
  33. bioRxiv. 2025 Feb 22. pii: 2025.02.20.639242. [Epub ahead of print]
    Functional Specialization of S-Adenosylmethionine Synthases Links Phosphatidylcholine to Mitochondrial Function and Stress Survival.
    Athena L Munden, Dominique S Lui, Daniel P Higgins, Matthew J Fanelli, Thien-Kim Ngyuen, Katherine M Edwards, Maria Ericsson, Adwait A Godbole, John A Haley, Caroline Lewis, Jessica B Spinelli, Benjamin Harrison, Daniel Raftery, Danijel Djukovic, Daniel E L Promislow, Dana L Miller, Amy K Walker.
      S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Studies have often equated the effects of knocking down one synthase with broader SAM-dependent outcomes such as histone methylation or phosphatidylcholine (PC) production. Humans and many other organisms express multiple SAM synthases. Evidence in Caenorhabditis elegans , which possesses four SAM synthase genes, suggest that the enzymatic source of SAM impacts its function. For instance, loss of sams-1 leads to enhanced heat shock survival and increased lifespan, whereas reducing sams-4 adversely affects heat stress survival. Here, we show that SAMS-1 contributes to a variety of intermediary metabolic pathways, whereas SAMS-4 is more important to generate SAM for methylation reactions. We demonstrate that loss of sams-1 exerts age-dependent effects on nuclear-encoded mitochondrial gene expression, mitochondrial metabolites, and may induce mitophagy. We propose a mechanistic model where reduced SAM from SAMS-1 acts through PC to impact mitochondria, thereby enhancing survival during heat stress.
    DOI:  https://doi.org/10.1101/2025.02.20.639242
  34. Front Physiol. 2024 ;15 1488248
    Loss-of-function mitochondrial DNA polymerase gamma variants cause vascular smooth muscle cells to secrete a diffusible mitogenic factor.
    Samantha Rothwell, Irvin Ng, Sophia Shalchy-Tabrizi, Pola Kalinowski, Omnia M Taha, Italia Paris, Angelica Baniqued, Lisa Lin, Michelle M Mezei, Anna Lehman, Lisa M Julian, Damon Poburko.
       Introduction: Mitochondrial dysfunction promotes vascular aging and disease through diverse mechanisms beyond metabolic supply, including calcium and radical signaling and inflammation. Mitochondrial DNA (mtDNA) replication by the POLG-encoded mitochondrial DNA polymerase (POLG) is critical for mitochondrial health. Loss-of-function POLG variants are associated with a predisposition to hypertension. We hypothesized that impaired POLG, through reduced mtDNA copy number or other mechanisms, would promote smooth muscle hypertrophy or hyperplasia that drives vascular remodeling associated with hypertension.
    Methods: We characterized the effect of over-expressing POLG variants that were previously observed in a cohort of hypertensive patients (p.Tyr955Cys, p.Arg964Cys, p.Asn1098Ile, and p.Arg1138Cys) in A7r5 cells.
    Results: AlphaFold modeling of the POLG holoenzyme complexed with DNA predicted changes in the catalytic site in the p.Tyr955Cys and p.Asn1098Ile variants, while p.Arg964Cys and p.Arg1138Cys showed minimal effects. The POLG variants reduced mtDNA copy number, assessed by immunofluorescence and droplet digital PCR, by up to 27% in the order p.Tyr955Cys > p.Arg964Cys > p.Asn1098Ile > p.Arg1138Cys relative to wild-type-transfected cultures. Loss of mtDNA was reduced in cultures grown in low serum and glucose media, but the cell density was increased in the same rank order in both 10% serum and 1% serum. POLG constructs contained a Myc epitope, the counterstaining for which showed that the mtDNA copy number was reduced in both transfected cells and untransfected neighbors. Live-cell imaging of mitochondrial membrane potential with TMRM and radical oxygen species production with MitoSOX showed little effect of the POLG variants. POLG variants had little effect on oxygen consumption, assessed by Seahorse assay. Live-cell imaging growth analyses again showed increased growth in A7r5 cells transfected with p.Tyr955Cys but a decreased growth with p.Arg1138Cys, while p.Tyr955Cys increased growth of HeLa cells. Conditioned media from HeLa cells transfected with POLG variants reduced doubling times in naïve cultures. Pharmacologically, wedelolactone and MitoTEMPOL, but not indomethacin or PD98059, suppressed the mitogenic effects of p.Tyr955Cys and p.Arg964Cys in A7r5 cells.
    Discussion: We conclude that POLG dysfunction induces secretion of a mitogenic signal from A7r5 and HeLa cells even when changes in mtDNA copy number are below the limit of detection. Such mitogenic stimulation could stimulate hypertrophic remodeling that could contribute to drug-resistant hypertension in patient populations with loss-of-function POLG variants.
    Keywords:  A7r5; IncuCyte; POLG; StarDist; hypertension; mitochondrial DNA; rare disease; vascular smooth muscle
    DOI:  https://doi.org/10.3389/fphys.2024.1488248
  35. ACS Appl Mater Interfaces. 2025 Mar 04.
    Development of a Microfluidic System for Mitochondrial Extraction, Purification, and Analysis.
    Rukhsar Ajmal, Weisen Zhang, Hui Liu, Hua Bai, Lei Cao, Bo Peng, Lin Li.
      Mitochondria, as essential cellular organelles, play a key role in numerous diseases, from neurodegenerative disorders to cancer and rare conditions. The extraction of mitochondria from cells has many applications in disease diagnosis, pathological research, and emerging mitochondrial transplantation therapy (MTT). Recent advancements in microfluidic-on-chip systems offer promising improvements in mitochondrial extraction by enabling high-throughput processing, precise control, and flexibility while facilitating integration with other devices and platforms. Despite growing interest in microfluidic mitochondrial extraction (MME), there is a lack of comprehensive reviews on the latest developments in this field. This review aims to summarize recent advancements as well as the advantages and limitations of MME, providing deeper insights into microfluidic-based approaches for mitochondrial extraction, purification, and analysis.
    Keywords:  Microfluidic Mitochondrial Extraction; Microfluidic-based Separation; Microfluidics; Mitochondria; Mitochondrial Transplantation Therapy
    DOI:  https://doi.org/10.1021/acsami.4c18415
  36. J Cell Biol. 2025 May 05. pii: e202404009. [Epub ahead of print]224(5):
    SNX10 functions as a modulator of piecemeal mitophagy and mitochondrial bioenergetics.
    Laura Trachsel-Moncho, Chiara Veroni, Benan John Mathai, Ana Lapao, Sakshi Singh, Nagham Theres Asp, Sebastian W Schultz, Serhiy Pankiv, Anne Simonsen.
      We here identify the endosomal protein SNX10 as a negative regulator of piecemeal mitophagy of OXPHOS machinery components. In control conditions, SNX10 localizes to early endocytic compartments in a PtdIns3P-dependent manner and modulates endosomal trafficking but also shows dynamic connections with mitochondria. Upon hypoxia-mimicking conditions, SNX10 localizes to late endosomal structures containing selected mitochondrial proteins, including COX-IV and SAMM50, and the autophagy proteins SQSTM1/p62 and LC3B. The turnover of COX-IV was enhanced in SNX10-depleted cells, with a corresponding reduced mitochondrial respiration and citrate synthase activity. Importantly, zebrafish larvae lacking Snx10 show reduced levels of Cox-IV, as well as elevated ROS levels and ROS-mediated cell death in the brain, demonstrating the in vivo relevance of SNX10-mediated modulation of mitochondrial bioenergetics.
    DOI:  https://doi.org/10.1083/jcb.202404009
  37. J Neurogenet. 2025 Mar 06. 1-3
    Two tales of therapeutic innovations for Leigh syndrome spectrum.
    Wei-Sheng Lin.
      Leigh syndrome spectrum is the most common form of childhood-onset mitochondrial encephalopathy and is characterized by progressive neurodegeneration. Treatment options for this condition remain limited to date. Nonetheless, two lines of research endeavor in the past decade have shown encouraging results worthy of further investigations. First, therapeutic hypoxia appears to improve neurological outcomes, which is somewhat counterintuitive but supported by preclinical evidence. Furthermore, nicotinic acid or nicotinamide riboside could be an adjunctive therapy that enhances the neuroprotective effect of hypoxia. Second, preclinical studies and preliminary clinical experience suggest that sildenafil is potentially disease-modifying for Leigh syndrome. Sildenafil has already been used to treat pulmonary hypertension, and its repurposing for Leigh syndrome has been endorsed by European Medicines Agency. This perspective aims to raise awareness about these progresses, as well as to call for more clinical studies to ensure safe and effective implementation of these treatment approaches in clinical practice.
    Keywords:  Leigh syndrome; hypoxia; mitochondrial encephalopathy; sildenafil
    DOI:  https://doi.org/10.1080/01677063.2025.2473087
  38. Nat Aging. 2025 Mar 06.
    Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow.
    Haruhito Totani, Takayoshi Matsumura, Rui Yokomori, Terumasa Umemoto, Yuji Takihara, Chong Yang, Lee Hui Chua, Atsushi Watanabe, Takaomi Sanda, Toshio Suda.
      The aging of hematopoietic stem cells (HSCs) substantially alters their characteristics. Mitochondria, essential for cellular metabolism, play a crucial role, and their dysfunction is a hallmark of aging-induced changes. The impact of mitochondrial mass on aged HSCs remains incompletely understood. Here we demonstrate that HSCs with high mitochondrial mass during aging are not merely cells that have accumulated damaged mitochondria and become exhausted. In addition, these HSCs retain a high regenerative capacity and remain in the aging bone marrow. Furthermore, we identified GPR183 as a distinct marker characterizing aged HSCs through single-cell analysis. HSCs marked by GPR183 were also enriched in aged HSCs with high mitochondrial mass, possessing a high capacity of self-renewal. These insights deepen understanding of HSC aging and provide additional perspectives on the assessment of aged HSCs, underscoring the importance of mitochondrial dynamics in aging.
    DOI:  https://doi.org/10.1038/s43587-025-00828-y
  39. Nat Metab. 2025 Mar 06.
    Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men.
    Trine S Nicolaisen, Aslak E Lyster, Kim A Sjøberg, Daniel T Haas, Christian T Voldstedlund, Anne-Marie Lundsgaard, Jakob K Jensen, Ea M Madsen, Casper K Nielsen, Mads Bloch-Ibenfeldt, Nicolai J Wewer Albrechtsen, Adam J Rose, Natalie Krahmer, Christoffer Clemmensen, Erik A Richter, Andreas M Fritzen, Bente Kiens.
      Dietary protein restriction increases energy expenditure and enhances insulin sensitivity in mice. However, the effects of a eucaloric protein-restricted diet in healthy humans remain unexplored. Here, we show in lean, healthy men that a protein-restricted diet meeting the minimum protein requirements for 5 weeks necessitates an increase in energy intake to uphold body weight, regardless of whether proteins are replaced with fats or carbohydrates. Upon reverting to the customary higher protein intake in the following 5 weeks, energy requirements return to baseline levels, thus preventing weight gain. We also show that fasting plasma FGF21 levels increase during protein restriction. Proteomic analysis of human white adipose tissue and in FGF21-knockout mice reveal alterations in key components of the electron transport chain within white adipose tissue mitochondria. Notably, in male mice, these changes appear to be dependent on FGF21. In conclusion, we demonstrate that maintaining body weight during dietary protein restriction in healthy, lean men requires a higher energy intake, partially driven by FGF21-mediated mitochondrial adaptations in adipose tissue.
    DOI:  https://doi.org/10.1038/s42255-025-01236-7
  40. Nat Commun. 2025 Mar 03. 16(1): 2135
    Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites.
    Ayenachew Bezawork-Geleta, Camille J Devereux, Stacey N Keenan, Jieqiong Lou, Ellie Cho, Shuai Nie, David P De Souza, Vinod K Narayana, Nicole A Siddall, Carlos H M Rodrigues, Stephanie Portelli, Tenghao Zheng, Hieu T Nim, Mirana Ramialison, Gary R Hime, Garron T Dodd, Elizabeth Hinde, David B Ascher, David A Stroud, Matthew J Watt.
      Membrane contact sites between organelles are critical for the transfer of biomolecules. Lipid droplets store fatty acids and form contacts with mitochondria, which regulate fatty acid oxidation and adenosine triphosphate production. Protein compartmentalization at lipid droplet-mitochondria contact sites and their effects on biological processes are poorly described. Using proximity-dependent biotinylation methods, we identify 71 proteins at lipid droplet-mitochondria contact sites, including a multimeric complex containing extended synaptotagmin (ESYT) 1, ESYT2, and VAMP Associated Protein B and C (VAPB). High resolution imaging confirms localization of this complex at the interface of lipid droplet-mitochondria-endoplasmic reticulum where it likely transfers fatty acids to enable β-oxidation. Deletion of ESYT1, ESYT2 or VAPB limits lipid droplet-derived fatty acid oxidation, resulting in depletion of tricarboxylic acid cycle metabolites, remodeling of the cellular lipidome, and induction of lipotoxic stress. These findings were recapitulated in Esyt1 and Esyt2 deficient mice. Our study uncovers a fundamental mechanism that is required for lipid droplet-derived fatty acid oxidation and cellular lipid homeostasis, with implications for metabolic diseases and survival.
    DOI:  https://doi.org/10.1038/s41467-025-57405-5
  41. FASEB J. 2025 Mar 15. 39(5): e70423
    A novel, rapidly progressive ataxia due to a spontaneous Myo5a mutation in mice impairs transport proteins and alters mitochondria.
    Alexander M Telenson, Ryan R Hsieh, Gabrielle J Cowen, Eoin P Sode, Jason M Kwon, Andy H Vo, Michele Hadhazy, Patrick G Page, Nalini R Rao, Lorenzo Pesce, Alexis R Demonbreun, Megan J Puckelwartz, Jeffrey N Savas, Elizabeth M McNally.
      Spontaneous mouse mutants have helped define genetic contributions to many phenotypes. Here we report a spontaneous Novel Ataxic Phenotype in mice. Ataxia findings were evident at post-natal day 11 in NAP mice and rapidly worsened, resulting in preweaning lethality. Using genome sequencing and genome-wide mapping, we identified a 3' donor splice variant in exon 14 of Myo5a, encoding an actin-based motor protein. The variant in Myo5a (c.1752g>a) excises exon 14 and ablates MYO5A protein expression, which is implicated in intracellular transport and Griscelli syndrome type I in humans. NAP mice displayed expansion of PAX6-positive cells in the external granule layer of the cerebellum, and mass spectrometry analysis of cerebellar extracts uncovered differentially abundant proteins involved in short-range organelle transport, and specifically proteins implicated with early endosomes. Using cerebellar lysates and primary neurons, we provide evidence for an interaction between MYO5A and ANKFY1, a known effector for the endosomal protein, RAB5A. We also found neurons from NAP mice had elongated mitochondria, linking MYO5A to mitochondrial homeostasis. This allele provides new insight into Myo5a function in developmental neuropathology.
    Keywords:  Myo5a; ataxia; cerebellum; mitochondria; motor proteins; spontaneous phenotype; transport; whole genome sequencing
    DOI:  https://doi.org/10.1096/fj.202402274R
  42. Nature. 2025 Mar 05.
    Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
    Zheng He, Jianxiu Zhang, Yan Xu, Eve J Fine, Carl-Mikael Suomivuori, Ron O Dror, Liang Feng.
      The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial matrix1-5. It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases4-6. However, despite MPC's critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC's function and pave the way for the development of more-effective therapeutic reagents that target MPC.
    DOI:  https://doi.org/10.1038/s41586-025-08667-y
  43. Commun Biol. 2025 Feb 28. 8(1): 338
    Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy.
    Dongqin Huang, Yang Li, Yuqian Guo, Mengcao Weng, Hui Ye, Yan Zhang, Fei Lin, Kai Zhang, Xiangming Fang.
      Sepsis-induced skeletal muscle atrophy is common in septic patients with the increases risk of mortality and is associated with myocellular mitochondrial dysfunction. Nevertheless, the specific mechanism of sepsis muscle atrophy remains unclear. Here we conducted a clinical retrospective analysis and observed the elevation of skeletal muscle index (ΔSMI) was an independent risk factor for 60-day mortality in septic patients. Moreover, in mouse model of sepsis, the skeletal muscle atrophy was also observed, which was associated with the upregulation of S100a8/a9-mediated mitochondrial dysfunction. Inhibition of S100a8/a9 significantly improved mitochondrial function and alleviated muscle atrophy. Conversely, administration of recombinant S100a8/a9 protein exacerbated mitochondrial energy exhaustion and myocyte atrophy. Mechanistically, S100a8/a9 binding to RAGE induced Drp1 phosphorylation and mitochondrial fragmentation, resulting in muscle atrophy. Additionally, RAGE ablation or administration of Drp1 inhibitor significantly reduced Drp1-mediated mitochondrial fission, improved mitochondrial morphology and function. Our findings indicated the pivotal role of S100a8/a9 in driving the mitochondrial fragmentation in septic muscle atrophy. Targeting S100a8/a9-RAGE-initiated mitochondrial fission might offer a promising therapeutic intervention against septic muscle atrophy.
    DOI:  https://doi.org/10.1038/s42003-025-07654-3
  44. bioRxiv. 2025 Feb 19. pii: 2025.02.18.638948. [Epub ahead of print]
    Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.
    Madeleine L Hart, Kristian Davidsen, Serwah Danquah, Eric Zheng, David Sokolov, Lucas B Sullivan.
      Impaired availability of the amino acid aspartate can be a metabolic constraint of cell proliferation in diverse biological contexts. However, the kinetics of aspartate depletion, and its ramifications on downstream metabolism and cell proliferation, remain poorly understood. Here, we deploy the aspartate biosensor jAspSnFR3 with live cell imaging to resolve temporal relationships between aspartate and cell proliferation from genetic, pharmacological, and nutritional manipulations. In cells with impaired aspartate acquisition from mitochondrial complex I inhibition or constrained uptake in aspartate auxotrophs, we find that the proliferation defects lag changes in aspartate levels and only manifest once aspartate levels fall below a critical threshold, supporting the functional link between aspartate levels and cell proliferation in these contexts. In another context of aspartate synthesis inhibition, impairing succinate dehydrogenase (SDH), we find a more complex metabolic interaction, with initial aspartate depletion followed by a rebound of aspartate levels over time. We find that this aspartate rebound effect results from SDH inhibition disproportionately impairing pyrimidine synthesis by inhibiting aspartate transcarbamoylase (ATCase) through the dual effect of diminishing aspartate substrate availability while accumulating succinate, which functions as a competitive inhibitor of aspartate utilization. Finally, we uncover that the nucleotide imbalance from SDH inhibition causes replication stress and introduces a vulnerability to ATR kinase inhibition. Altogether, these findings identify a mechanistic role for succinate in modulating nucleotide synthesis and demonstrate how cascading metabolic interactions can unfold to impact cell function.
    Keywords:  SDH; aspartate; biosensor; cancer; metabolism; metabolomics; proliferation; pyrimidines
    DOI:  https://doi.org/10.1101/2025.02.18.638948
  45. Sci Adv. 2025 Feb 28. 11(9): eadr1938
    A long-lived pool of PINK1 imparts a molecular memory of depolarization-induced activity.
    Liam Pollock, Ioanna Ch Georgiou, Emma V Rusilowicz-Jones, Michael J Clague, Sylvie Urbé.
      The Parkinson's disease-linked kinase, PINK1, is a short-lived protein that undergoes cleavage upon mitochondrial import leading to its proteasomal degradation. Under depolarizing conditions, it accumulates on mitochondria where it becomes activated, phosphorylating both ubiquitin and the ubiquitin E3 ligase Parkin, at Ser65. Our experiments reveal that in retinal pigment epithelial cells, only a fraction of PINK1 becomes stabilized after depolarization by electron transport chain inhibitors. Furthermore, the observed accrual of PINK1 cannot be completely accounted for without an accompanying increase in biosynthesis. We have used a ubiquitylation inhibitor TAK-243 to accumulate cleaved PINK1. Under these conditions, generation of unconjugated "free" phospho-ubiquitin serves as a proxy readout for PINK1 activity. This has enabled us to find a preconditioning phenomenon, whereby an initial depolarizing treatment leaves a residual pool of active PINK1 that remains competent to seed the activation of nascent cleaved PINK1 following a 16-hour recovery period.
    DOI:  https://doi.org/10.1126/sciadv.adr1938
  46. Neuroophthalmology. 2025 ;49(2): 127-131
    Leber's Hereditary Optic Neuropathy with Retinal Hemorrhage.
    Yasuyuki Takai, Akiko Yamagami, Mayumi Iwasa, Kenji Inoue, Ryoma Yasumoto, Hitoshi Ishikawa, Masato Wakakura.
      Leber's hereditary optic neuropathy (LHON) causes subacute visual loss, and, in the acute phase, the optic disc shows hyperemia, peripapillary telangiectasia, and swelling of the retinal nerve fiber layer (RNFL). Rarely, retinal hemorrhage may be present. In this study, we investigated LHON cases with retinal hemorrhage in the acute phase. Among 82 cases (164 eyes) of LHON who visited the Inoue Eye Hospital, retinal hemorrhage was observed in 5 cases (5 eyes). The age at onset was 36 (27-46) years, with 4 male cases. Mitochondrial DNA analysis revealed the presence of the m.11778G > A variant in four patients and the m.14484T > C variant in one patient. There was no medical history and no excessive smoking or alcohol consumption in any of the cases. In all cases, retinal hemorrhages were observed in the RNFL, accompanying the characteristic optic disc findings of LHON. Fluorescein angiography performed in three cases showed no leakage from the optic disc or blood vessels. While rare, the presence of retinal hemorrhage along the RNFL during the acute phase of LHON should be recognized, as it may warrant consideration of alternative diagnoses.
    Keywords:  Word; leber’s hereditary optic neuropathy; peripapillary telangiectasia; retinal hemorrhage; retinal nerve fiber layer
    DOI:  https://doi.org/10.1080/01658107.2024.2389957
  47. Nature. 2025 Mar;639(8053): S7-S9
    Restoring vision with optogenetics.
    Liam Drew.
      
    Keywords:  Sensory systems; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-025-00656-5
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