bims-mitmed 2025-05-11 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–05–11
eighteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

The role of mitochondrial mRNA translation in cellular communication.
SARM1 loss protects retinal ganglion cells in a mouse model of Autosomal Dominant Optic Atrophy.
Phase separation in mitochondrial fate and mitochondrial diseases.
Modifier variants in metabolic pathways are associated with an increased penetrance of Leber's Hereditary Optic Neuropathy.
Case Report: Unusual Neurological Features of Leigh Syndrome due to m.8993T>G Pathogenic Variant in the MT-ATP6 Gene.
Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.
Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.
The association of mitochondrial morphology and supercomplex redistribution with skeletal muscle oxidative capacity in older adults.
Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.
Targeting mitochondrial transfer as a promising therapeutic strategy.
Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.
Opportunities and Challenges of Fetal Gene Therapy.
Hypoxic pregnancy promotes fibrosis and increases stress metabolites in the ovine fetal liver.
Uncovering a Novel Pathogenic Mechanism of BCS1L in Mitochondrial Disorders: Insights from Functional Studies on the c.38A>G Variant.
A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress.
Nicotinamide riboside promoted cardiac energetics and alleviated doxorubicin-induced cardiotoxicity via SIRT1/ERRα signal in human pluripotent stem cells-derived cardiomyocytes.
NAMPT regulates mitochondria and oxidative stress level for mouse early embryo development.
Compound Heterozygous MRPS14 Variants Associated With Leigh Syndrome.

J Cell Sci. 2025 May 01. pii: jcs263753. [Epub ahead of print]138(9):

The role of mitochondrial mRNA translation in cellular communication.

Eleonora Zilio, Tim Schlegel, Marta Zaninello, Elena I Rugarli.

  Mitochondria are dynamic and heterogeneous organelles that rewire their network and metabolic functions in response to changing cellular needs. To this end, mitochondria integrate a plethora of incoming signals to influence cell fate and survival. A crucial and highly regulated node of cell-mitochondria communication is the translation of nuclear-encoded mitochondrial mRNAs. By controlling and monitoring the spatio-temporal translation of these mRNAs, cells can rapidly adjust mitochondrial function to meet metabolic demands, optimise ATP production and regulate organelle biogenesis and turnover. In this Review, we focus on how RNA-binding proteins that recognise nuclear-encoded mitochondrial mRNAs acutely modulate the rate of translation in response to nutrient availability. We further discuss the relevance of localised translation of these mRNAs for subsets of mitochondria in polarised cells. Finally, we highlight quality control mechanisms that monitor the translation process at the mitochondrial surface and their connections to mitophagy and stress responses. We propose that these processes collectively contribute to mitochondrial specialisation and signalling function.

Keywords:  Cell signalling; Mitochondria; RNA-binding proteins; Ribosome quality control; Translation; mRNA

DOI:  https://doi.org/10.1242/jcs.263753
J Clin Invest. 2025 May 09. pii: e191315. [Epub ahead of print]

SARM1 loss protects retinal ganglion cells in a mouse model of Autosomal Dominant Optic Atrophy.

Chen Ding, Papa S Ndiaye, Sydney R Campbell, Michelle Y Fry, Jincheng Gong, Sophia R Wienbar, Whitney Gibbs, Philippe Morquette, Luke H Chao, Michael Tri H Do, Thomas Schwarz.

  Autosomal Dominant Optic Atrophy (ADOA), the most prevalent hereditary optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the OPA1 gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. We generated a mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulated key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identified SARM1, a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 knockout nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation. Additionally, we showed that a portion of SARM1 localized within the mitochondrial intermembrane space (IMS). These findings indicated that SARM1 was activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.

Keywords:  Cell biology; Mitochondria; Neurodegeneration; Neuroscience; Therapeutics

DOI:  https://doi.org/10.1172/JCI191315
Proc Natl Acad Sci U S A. 2025 May 27. 122(21): e2422255122

Phase separation in mitochondrial fate and mitochondrial diseases.

Qingyi Chen, Sanqi An, Chuanlong Wang, Yanshuang Zhou, Xingguo Liu, Wenkai Ren.

  Mitochondria are central metabolic organelles that control cell fate and the development of mitochondrial diseases. Traditionally, phase separation directly regulates cell functions by driving RNA, proteins, or other molecules to concentrate into lipid droplets. Recent studies show that phase separation regulates cell functions and diseases through the regulation of subcellular organelles, particularly mitochondria. In fact, phase separation is involved in various mitochondrial activities including nucleoid assembly, autophagy, and mitochondria-related inflammation. Here, we outline the key mechanisms through which phase separation influences mitochondrial activities and the development of mitochondrial diseases. Insights into how phase separation regulates mitochondrial activities and diseases will help us develop interventions for related diseases.

Keywords:  mitochondrial disease; mitochondrial dynamics; mitophagy; nucleoid assembly; phase separation

DOI:  https://doi.org/10.1073/pnas.2422255122
Eur J Hum Genet. 2025 May 09.

Modifier variants in metabolic pathways are associated with an increased penetrance of Leber's Hereditary Optic Neuropathy.

Eszter Sara Arany, Catarina Olimpio, Ida Paramonov, Rita Horvath.

Leber's hereditary optic neuropathy (LHON) is a debilitating mitochondrial disease characterised by bilateral painless vision loss. Despite being the most prevalent mitochondrial disorder, the precise pathophysiological mechanisms underlying the penetrance of LHON remain poorly understood. Nuclear modifier genes have been long suspected to affect phenotype-severity, however, specific cellular pathways implicated in the disease penetrance have been only suggested recently. In recent years, autosomal recessive variants in nuclear genes involved in complex I function and metabolic pathways were recognised to cause a typical LHON phenotype. This was proposed as a new autosomal recessive disease mechanism for LHON (arLHON). The association between nuclear variants and the LHON phenotype makes the nuclear pathways disrupted in arLHON the strongest candidates to act as modifiers of mitochondrial LHON (mLHON). In this study we systematically investigated a large cohort of 23 symptomatic and 28 asymptomatic individuals carrying one of the three primary mitochondrial LHON variants. We identified several heterozygous pathogenic nuclear variants amongst the affected individuals that were consistently linked to metabolic and complex I related pathways, mirroring those disrupted in arLHON. Our findings are consistent with the presence of a second hit in specific biological pathways impairing ATP production. We propose that in addition to the primary mitochondrial variants, disruption in these nuclear-encoded pathways drives the clinical manifestation of LHON. Genes involved in the same pathways also emerge as exciting candidates for future association with arLHON. The present study deepens our understanding of LHON's pathophysiology and provides a new framework for identifying novel disease-modifying targets.

DOI: https://doi.org/10.1038/s41431-025-01860-7
Am J Med Genet A. 2025 May 09. e64112

Case Report: Unusual Neurological Features of Leigh Syndrome due to m.8993T>G Pathogenic Variant in the MT-ATP6 Gene.

Ramya Treitel, Julie McLaughlin, Marta Frigeni.

  The MT-ATP6 gene m.8993T>G pathogenic variant has been associated with Leigh syndrome, especially in patients exhibiting a high degree of heteroplasmy. Although patients may present with a wide phenotypic spectrum, characteristic findings include bilateral, symmetric hyperintensities in the basal ganglia and brainstem on brain MRI, particularly on T2-weighted and fluid-attenuated inversion recovery sequences. Additionally, the biochemical phenotype associated with this pathogenic variant often mimics that of multiple carboxylase deficiency and proximal urea cycle disorders. This report describes a male infant with an atypical neurological presentation of Leigh syndrome. At 2 months of age, he presented with status epilepticus of left temporal origin that was refractory to treatment. Initial brain MRI revealed a large region of non-enhancing signal abnormality in the left temporal lobe, raising concern for an infectious etiology. However, biochemical testing revealed hypocitrullinemia, elevated 3-hydroxyisovalerylcarnitine, elevated propionylcarnitine, and urinary excretion of lactate and pyruvate, prompting further investigation for MT-ATP6 mitochondrial disease. Mitochondrial DNA analysis confirmed the presence of a homoplasmic m.8993T>G pathogenic variant in the MT-ATP6 gene. Despite treatment with citrulline and high-dose biotin, the patient died 5 weeks later due to cardiorespiratory failure following a severe respiratory infection. Retrospective review of his newborn screening revealed two screens positive for low citrulline that were ultimately cleared on a third screen, delaying the diagnosis. This case underscores the importance of considering MT-ATP6 mitochondrial disease in the differential diagnosis of patients presenting with atypical neurological symptoms and biochemical abnormalities. It also highlights the value of newborn screening in identifying potential mitochondrial disorders, where early diagnosis and timely intervention may improve outcomes, even in severe cases.

Keywords:   MT‐ATP6 ; Leigh syndrome; hypocitrullinemia; newborn screening; status epilepticus

DOI:  https://doi.org/10.1002/ajmg.a.64112
Aging Cell. 2025 May 02. e70085

Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.

Hiroaki Tamashiro, Kaori Ishikawa, Koichi Sadotomo, Emi Ogasawara, Kazuto Nakada.

  mtDNA mutator mice (Polgmut/mut mice) have reinforced the mitochondrial theory of aging. These mice accumulate multiple mutations in mtDNA with age due to a homozygous proofreading-deficient mutation in mtDNA polymerase gamma (Polg), resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, whether the accumulation of multiple mutations in Polgmut/mut mice induces mitochondrial respiratory dysfunction remains unclear. Here, we determined the accurate mtDNA genotype, including the frequency of total mutations and the number of non-synonymous substitutions and pathogenic mutations, using next-generation sequencing in the progeny of all three genotypes obtained from the mating of heterozygous mtDNA mutator mice (Polg+/mut mice) and examined their correlation with mitochondrial respiratory activity. Although Polg+/mut mice showed equivalent mtDNA genotype to Polg+/+ (wild-type) mice, the mitochondrial respiratory activity in the Polg+/mut mice was mildly reduced. To further investigate the causal relationship between mtDNA genotype and mitochondrial respiratory activity, we experimentally varied the mtDNA genotype in Polg mice. However, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice and severely reduced in Polgmut/mut mice, regardless of the mtDNA genotype. Moreover, by varying the mtDNA genotype, some Polg+/+ mice showed mtDNA genotype equivalent to those of Polgmut/mut mice, but mitochondrial respiratory activity in Polg+/+ mice was normal. These results indicate that the mitochondrial respiratory dysfunction observed in mice with proofreading-deficient mutation in Polg is correlated with the nuclear genotype of Polg rather than the mtDNA genotype. Thus, the mitochondrial theory of aging in Polgmut/mut mice needs further re-examination.

Keywords:  aging; mitochondria; mitochondrial DNA

DOI:  https://doi.org/10.1111/acel.70085
Ageing Res Rev. 2025 May 02. pii: S1568-1637(25)00108-4. [Epub ahead of print]109 102762

Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.

Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.

  Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.

Keywords:  Aging; Liver; Mitochondria; Mitohormesis; Muscle; Sestrin2

DOI:  https://doi.org/10.1016/j.arr.2025.102762
Physiol Rep. 2025 May;13(9): e70359

The association of mitochondrial morphology and supercomplex redistribution with skeletal muscle oxidative capacity in older adults.

Mauricio Castro Sepulveda, Sylviane Lagarrigue, Francesca Amati.

  Skeletal muscle maximal oxidative capacity (ATPmax) is a key component of age-related sarcopenia and muscle health. The contribution of mitochondrial morphology and electron transport chain supercomplex (SC) assemblies to ATPmax has yet to be determined in human muscle. ATPmax measured in vivo by 31phosphorus magnetic resonance spectroscopy in the quadriceps femoris of nine volunteers (65.5 ± 3.3 years old) was correlated with muscle biopsy outcomes before and after 4 months of supervised exercise. Mitochondrial morphology was assessed in electron micrographs, and SCs were measured by blue native gel electrophoresis. In the sedentary conditions, ATPmax was positively associated with complex (C) I and CIII in SC I+III2+IVn and negatively associated with CI and CIII in SC I+III2. Regarding mitochondrial morphology, ATPmax was positively associated with markers of mitochondrial elongation. Exercise training-induced increases in ATPmax were accompanied by mitochondrial elongation and by the redistribution of free complex III. Indicators of mitochondrial elongation were associated with the redistribution of specific complexes to SC I+III2+IVn. Higher skeletal muscle oxidative capacity in older adults is associated with mitochondrial elongation and the redistribution of electron transport chain complexes into higher rank SCs in the same muscle. Further, we provide evidence that mitochondrial elongation favors mitochondrial SC assembly.

Keywords:  ATPmax; electron transport chain; mitochondrial elongation; respirasome

DOI:  https://doi.org/10.14814/phy2.70359
Cell Rep. 2025 May 07. pii: S2211-1247(25)00453-X. [Epub ahead of print]44(5): 115682

Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.

Juan Xu, Qiqi Zhang, Xinyu Yang, Qiqi Tang, Yitong Han, Jiahui Meng, Jiaqi Zhang, Xin Lu, Danni Wang, Jing Liu, Bo Shan, Xue Bai, Kai Zhang, Longhao Sun, Lingdi Wang, Lu Zhu.

  The relationship between mitochondrial architecture and energy homeostasis in adipose tissues is not well understood. In this study, we utilized GCN5L1-knockout mice in white (AKO) and brown (BKO) adipose tissues to examine mitochondrial homeostasis in adipose tissues. GCN5L1, a regulator of mitochondrial metabolism and dynamics, influences resistance to high-fat-diet-induced obesity in AKO but not BKO mice. This resistance is mediated by an increase in mitochondrial cristae that stabilizes oxidative phosphorylation (OXPHOS) complexes and enhances energy expenditure. Our protein-interactome analysis reveals that GCN5L1 is associated with the mitochondrial crista complex MICOS (MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction results in decreased OXPHOS levels and subsequent adipocyte expansion. Accumulation of GCN5L1 in the mitochondrial intermembrane space is triggered by a high-fat diet. Our findings highlight a regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.

Keywords:  CP: Cell biology; CP: Metabolism; MICOS; OXPHOS; YME1L; beige; mitochondria; mitochondrial crista remodeling; white adipose tissue

DOI:  https://doi.org/10.1016/j.celrep.2025.115682
Trends Mol Med. 2025 May 06. pii: S1471-4914(25)00089-9. [Epub ahead of print]

Targeting mitochondrial transfer as a promising therapeutic strategy.

Bo Li, Bingzhi Li, Xianghe Qiao, Wanrong Meng, Yuhang Xie, Jiajing Gong, Yi Fan, Zhihe Zhao, Longjiang Li.

  Despite the primary impression of mitochondria as energy factories, these organelles are increasingly recognized for their multifaceted roles beyond energy production. Intriguingly, mitochondria can transfer between cells, influencing physiological and pathological processes through intercellular trafficking termed 'mitochondrial transfer.' This phenomenon is important in maintaining metabolic homeostasis, enhancing tissue regeneration, exacerbating cancer progression, and facilitating immune modulation, depending on the cell type and microenvironment. Recently, mitochondrial transfer has emerged as a promising therapeutic target for tissue repair and antitumor therapy. Here, we summarize and critically review recent advances in this field. We aim to provide an updated overview of the mechanisms and potential therapeutic avenues associated with mitochondrial transfer in various diseases from the perspective of different donor cells.

Keywords:  cancer; immunity; mesenchymal stem/stromal cells MSCs; mitochondrial transfer; regeneration

DOI:  https://doi.org/10.1016/j.molmed.2025.04.002
Nat Struct Mol Biol. 2025 May 05.

Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.

Nafizul Haque Kazi, Nikolas Klink, Kai Gallant, Gian-Marvin Kipka, Malte Gersch.

The mitochondrial deubiquitinase ubiquitin-specific protease (USP) 30 negatively regulates PINK1-parkin-driven mitophagy. Whether enhanced mitochondrial quality control through inhibition of USP30 can protect dopaminergic neurons is currently being explored in a clinical trial for Parkinson's disease. However, the molecular basis for specific inhibition of USP30 by small molecules has remained elusive. Here we report the crystal structure of human USP30 in complex with a specific inhibitor, enabled by chimeric protein engineering. Our study uncovers how the inhibitor extends into a cryptic pocket facilitated by a compound-induced conformation of the USP30 switching loop. Our work underscores the potential of exploring induced pockets and conformational dynamics to obtain deubiquitinase inhibitors and identifies residues facilitating specific inhibition of USP30. More broadly, we delineate a conceptual framework for specific USP deubiquitinase inhibition based on a common ligandability hotspot in the Leu73 ubiquitin binding site and on diverse compound extensions. Collectively, our work establishes a generalizable chimeric protein-engineering strategy to aid deubiquitinase crystallization and enables structure-based drug design with relevance to neurodegeneration.

DOI: https://doi.org/10.1038/s41594-025-01534-4
Prenat Diagn. 2025 May 05.

Opportunities and Challenges of Fetal Gene Therapy.

Médéric Jeanne, Wendy K Chung.

OBJECTIVE: Fetal gene therapy represents a promising approach to treat severe congenital disorders by intervening during a critical developmental period. This review aims to explore the unique advantages, specific applications, and challenges of this early intervention strategy.
METHOD: We reviewed preclinical and emerging clinical studies evaluating the biological rationale, feasibility, and therapeutic potential of gene therapy administered in utero.
RESULTS: The fetal window offers unique advantages, including enhanced tissue accessibility and biodistribution, immune tolerance to new therapeutic molecules, and has the potential to prevent irreversible organ damage before birth. However, this approach requires ethical considerations including risks to both the fetus and mother, complexities of informed consent, and broad societal implications.
CONCLUSION: Although substantial challenges remain, fetal gene therapy has the potential to improve outcomes in early-onset severe disorders that currently lack effective postnatal treatments.

DOI: https://doi.org/10.1002/pd.6809
J Physiol. 2025 May 05.

Hypoxic pregnancy promotes fibrosis and increases stress metabolites in the ovine fetal liver.

Molly M McGuckin, Dong Wang, Jasmine Ortiz, Evgenia Dobrinskikh, Wen Tong, Kimberley J Botting-Lawford, Youguo Niu, Dino A Giussani, Stephanie R Wesolowski.

  Fetal chronic hypoxia is a common pregnancy complication associated with fetal growth restriction. Growth-restricted offspring have a higher risk for liver metabolic disease. Our objective was to better understand how chronic hypoxia impacts the developing fetal liver. We hypothesized that hypoxia promotes hepatocellular injury, shifts nutrient metabolism, and activates energetic and oxidative stress in the fetal liver. We used an ovine model of chronic hypoxia where pregnant ewes were housed under normoxic (CON) or hypoxic (HOX) conditions for 30 days in late gestation. Fetal liver was obtained, histologically analysed and profiled using bulk-RNA sequencing and metabolomics. Nutrient and oxidative stress signalling pathways were also measured. HOX fetuses had greater hepatic periportal collagen deposition. Metabolomics and transcriptomics predicted disruptions in central carbon metabolism, mitochondrial dysfunction and decreased oxidative phosphorylation. In support, we found potentiation of the gluconeogenic pathway and increased lactate production, pyruvate oxidation and AMPK activation. By contrast to the predicted effects, hypoxic livers maintained mitochondrial oxidation and antioxidant capacity. Interestingly, acylcarnitines were increased, yet hepatic triglyceride content was similar. Although there was little activation of oxidative stress markers, such as lipid peroxidation or oxidized glutathione, we uncovered a unique profile of liver stress-related metabolites in association with periportal collagen. Thus, hypoxic pregnancy increased fetal hepatic collagen deposition, indicating liver injury, in association with a unique profile of liver stress metabolites and adaptations in central carbon metabolism. These results provide new insight into how chronic fetal hypoxia may initiate fibrotic and metabolic liver disease risk in offspring of adverse pregnancy. KEY POINTS: Chronic exposure to hypoxic pregnancy increased fetal hepatic collagen deposition, indicating hepatocellular injury. Hypoxic fetal livers had a unique profile of stress metabolites and adaptations in central carbon metabolism. This provides new insight into how hypoxia, a common pregnancy complication associated with fetal growth restriction, may initiate fibrotic and metabolic liver disease risk.

Keywords:  fetal; hypoxemia; metabolism

DOI:  https://doi.org/10.1113/JP288724
Int J Mol Sci. 2025 Apr 12. pii: 3670. [Epub ahead of print]26(8):

Uncovering a Novel Pathogenic Mechanism of BCS1L in Mitochondrial Disorders: Insights from Functional Studies on the c.38A>G Variant.

Valeria Capaci, Luisa Zupin, Martina Magistrati, Maria Teresa Bonati, Fulvio Celsi, Irene Marrone, Francesco Baldo, Blendi Ura, Beatrice Spedicati, Anna Morgan, Irene Bruno, Massimo Zeviani, Cristina Dallabona, Giorgia Girotto, Andrea Magnolato.

  The BCS1L gene encodes a mitochondrial chaperone which inserts the Fe2S2 iron-sulfur Rieske protein into the nascent electron transfer complex III. Variants in the BCS1L gene are associated with a spectrum of mitochondrial disorders, ranging from mild to severe phenotypes. Björnstad syndrome, a milder condition, is characterized by sensorineural hearing loss (SNHL) and pili torti. More severe disorders include Complex III Deficiency, which leads to neuromuscular and metabolic dysfunctions with multi-systemic issues and Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, and Lactic Acidosis syndrome (GRACILE). The severity of these conditions varies depending on the specific BCS1L mutation and its impact on mitochondrial function. This study describes a 27-month-old child with SNHL, proximal renal tubular acidosis, woolly hypopigmented hair, developmental delay, and metabolic alterations. Genetic analysis revealed a homozygous BCS1L variant (c.38A>G, p.Asn13Ser), previously reported in a patient with a more severe phenotype that, however, was not functionally characterized. In this work, functional studies in a yeast model and patient-derived fibroblasts demonstrated that the variant impairs mitochondrial respiration, complex III activity (CIII), and also alters mitochondrial morphology in affected fibroblasts. Interestingly, we unveil a new possible mechanism of pathogenicity for BCS1L mutant protein. Since the interaction between BCS1L and CIII is increased, this suggests the formation of a BCS1L-containing nonfunctional preCIII unable to load RISP protein and complete CIII assembly. These findings support the pathogenicity of the BCS1L c.38A>G variant, suggesting altered interaction between the mutant BCS1L and CIII.

Keywords:  BCS1L; assembly chaperone; complex III; electron transfer chain; mitochondrial disorder

DOI:  https://doi.org/10.3390/ijms26083670
Nat Commun. 2025 May 06. 16(1): 4187

A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress.

Suman Pokhrel, Gwangbeom Heo, Irimpan Mathews, Shun Yokoi, Tsutomu Matsui, Ayori Mitsutake, Soichi Wakatsuki, Daria Mochly-Rosen.

Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find that conformational change involving α1 helix in Fis1 exposes its only cysteine, Cys41. In the presence of oxidative stress, the exposed Cys41 in activated Fis1 forms a disulfide bridge and the Fis1 covalent homodimers cause increased mitochondrial fission through increased Drp1 recruitment to mitochondria. Our discovery of a small molecule, SP11, that binds only to activated Fis1 by engaging Cys41, and data from genetically engineered cell lines lacking Cys41 strongly suggest a role of Fis1 homodimerization in Drp1 recruitment to mitochondria and excessive mitochondrial fission. The structure of activated Fis1-SP11 complex further confirms these insights related to Cys41 being the sensor for oxidative stress. Importantly, SP11 preserves mitochondrial integrity and function in cells during oxidative stress and thus may serve as a candidate molecule for the development of treatment for diseases with underlying Fis1-mediated mitochondrial fragmentation and dysfunction.

DOI: https://doi.org/10.1038/s41467-025-59434-6
Life Sci. 2025 May 03. pii: S0024-3205(25)00320-0. [Epub ahead of print]373 123685

Nicotinamide riboside promoted cardiac energetics and alleviated doxorubicin-induced cardiotoxicity via SIRT1/ERRα signal in human pluripotent stem cells-derived cardiomyocytes.

Rui Wang, Hua Zhang, Qin Yi, Yun Peng Wang, Hao Xu, Bin Tan, Jing Zhu.

Doxorubicin is an antineoplastic chemotherapeutic drug that causes cardiotoxicity with energetics impairment and oxidative stress. Nicotinamide ribose (NR) is the precursor of NAD+ and has demonstrated beneficial effects in several animal models of cardiovascular disease. This study aimed to test the role and mechanism of nicotinamide ribose on human induced pluripotent stem cell-differentiated cardiomyocytes (HiPSCs-CMs) under normal and doxorubicin-treated states. We found that NR increased mitochondrial fusion and integrity in HiPSCs-CMs, promoted mitochondrial oxidative phosphorylation levels and ATP output, and increased ERRα expression. Inhibition of SIRT1 reversed the beneficial effects of NR. Protein-protein docking and immunoprecipitation showed that SIRT1 may bind directly to ERRα and regulates ERRα expression. Agonism of SIRT1 shows a facilitating effect on mitochondrial energetics, an effect that is counteracted by inhibitors of ERRα. Furthermore, NR promotes mitochondrial energetics via SIRT1/ERRα in doxorubicin-induced cardiac cytotoxicity, reduces cardiomyocyte oxidative stress injury, and attenuates apoptosis. Our findings reveal beneficial effects of nicotinamide ribose on HiPSCs-CMs under normal or disease conditions. In conclusion, our study provides the basis for advancing the clinical translation of nicotinamide ribose into the clinic.

DOI: https://doi.org/10.1016/j.lfs.2025.123685
Biol Res. 2025 May 04. 58(1): 25

NAMPT regulates mitochondria and oxidative stress level for mouse early embryo development.

Mei-Hua Liao, Xin Liu, Xiao-Ting Yu, Shun Zhang, You-Zhu Li, Lin-Lin Hu, Shao-Chen Sun, Jun-Li Wang.

   BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) is an enzyme that involves into NMN-NAD + synthesis which involves into cellular metabolism related with aging, immune function, and neurodegeneration. However, its roles in early embryo development are still unclear.
METHODS: In present study we disturbed the NAMPT activity and employed immunofluorescence staining and live cell imaging to explore its roles during early embryo development.
RESULTS: We showed that NAMPT mRNA level was stable during mouse early embryo development, and NAMPT accumulated in the nucleus of blastomeres in mouse embryos. The loss of NAMPT activity disturbed the early cleavage from zygote to 2-cell, 4-cell to morula formation in the dose-dependent manner. We found that NAMPT inhibition disrupted mitochondria function in 2-cell embryos, showing decreased mitochondria number and aberrant accumulation in the blastomeres, which further disturb mitochondrial membrane potential level and elevated ROS level in embryos, indicating the occurrence of oxidative stress. Moreover, NAMPT inhibition also increased the apoptotic index, showing with increased Annexin-V signals and apoptotic gene expression.
CONCLUSIONS: Taken together, our study provided the evidence that NAMPT was essential for the mitochondria function to control oxidative stress and apoptosis during mouse early embryo development.

Keywords:  Actin; Mitochondria; Oocyte; Oxidative stress; Parkinson’s disease

DOI:  https://doi.org/10.1186/s40659-025-00608-3
Ann Clin Transl Neurol. 2025 May 02.

Compound Heterozygous MRPS14 Variants Associated With Leigh Syndrome.

Maria Gabriela Otero, Christina Freeman, Ruchi Shah, Renkui Bai, Hong Cui, Marian Castro, Zachary Myers, Eric Choy, Derek Chan, Molly Easter, Sophia Y Zhao, Madeline Babros, Ruchi Garg, Matthew Deardorff, Franklin Moser, Tyler Mark Pierson.

  MRPS14 (uS14m) is a nuclear-encoded ribosomal protein important for mitochondria-specific translation. To date, only a single individual with a recessive MRPS14-related disorder (also known as COXPD38) has been reported. We report an additional subject possessing novel compound heterozygous MRPS14 variants (p.Asp37Asn, p.Asn60Asp). The subject presented at 2 years with motor and language delays associated with elevated serum lactate/alanine levels. Brain MRI showed a constellation of signal abnormalities consistent with Leigh Syndrome, while MR spectroscopy had an increased lactate peak. Western blots of fibroblasts showed decreased MRPS14 and COX2 protein levels. These results support the pathogenicity of the MRPS14 variants identified here.

Keywords:   MRPS14 ; Leigh Syndrome; mitochondrial ribosome; oxidative phosphorylation

DOI:  https://doi.org/10.1002/acn3.70065