bims-mitmed 2025-09-07 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–09–07
25 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
Metformin may alter the course of Leber's hereditary optic neuropathy: a case report.
Improved AAV9-based gene therapy design for SURF1-related Leigh syndrome with minimal toxicity.
MitoTraP: mitochondrial protection for cellular proteostasis.
Alterations in mitochondrial base editors enhance targeted editing efficiency for mouse model generation.
Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.
Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
Vesicle-guided mitochondria: A new perspective for brain mitochondrial transplantation.
Underestimation of mitochondrial respiratory capacity in gray matter voxels of the human brain map due to limited OXPHOS and TCA cycle in astrocytes.
Late-onset Leber's hereditary optic neuropathy and antiandrogens for prostate cancer: is there a causative link?
Combination treatment with antioxidants and creatine alleviates common and variant-specific mitochondrial impairments in Leber's hereditary optic neuropathy patient-derived fibroblasts.
Mitochondrial Complex V Deficiency Caused by a Homozygous Splice Variant in ATP5PO.
PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.
Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.
Retinal multimodal-imaging and functional tests in a mitochondrial disease with focal and segmental glomerulosclerosis.
Accumulation of pathogenic mitochondrial DNA mutations in the kidney.
Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
Mitochondrial Biogenesis in Skeletal Muscle.
Molecular mechanisms of mitochondrial quality control.
Mitochondria: Key Mediator for Environmental Toxicant-Induced Neurodegeneration.
The integrated stress response in the brain: cell type-specific functions in health and neurological disorders.
Genetic suppression features ABHD18 as a Barth syndrome therapeutic target.
C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.
Intracellular and Extracellular Vesicle miRNA Signatures in Human iPSC-Derived Neural Stem Cells and Floor Plate Progenitors.
FOXQ1 Regulates Brain Endothelial Mitochondrial Function by Orchestrating Calcium Signaling and Cristae Morphology.

EMBO Rep. 2025 Aug 29.

Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.

Tak Shun Fung, Amrapali Ghosh, Maite R Zavala, Zuzana Nichtova, Dhavalkumar Shukal, Marco Tigano, Gyorgy Csordas, Henry N Higgs, Rajarshi Chakrabarti.

  Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.

Keywords:  Actin; Arp2/3 Complex; ER; LC3; Parkin

DOI:  https://doi.org/10.1038/s44319-025-00561-y
Front Med (Lausanne). 2025 ;12 1609941

Metformin may alter the course of Leber's hereditary optic neuropathy: a case report.

Shenoda Abd Elmaseh, Danielle A Gauthier, Maryam Golmohammadi, Nutsa Pargalava, Valerio Carelli, Alfredo A Sadun.

  Leber's hereditary optic neuropathy (LHON) is a rare inherited mitochondrial disease caused by variants in mitochondrial DNA (mtDNA) transmitted exclusively through the maternal line. The disease predominantly affects young males and is characterized by progressive bilateral vision loss. Idebenone, a well-studied drug, modestly enhances the mitochondrial function and visual acuity in many patients with LHON. In this study, we report the case of a 48-year-old woman diagnosed with LHON (m.11778G>A/MT-ND4) and type 2 diabetes mellitus who experienced visual field improvement following metformin treatment after 26 months of progressive vision loss unresponsive to idebenone, nicotinamide adenine dinucleotide (NAD+), and hormone replacement therapy (HRT). Our findings offer an intriguing perspective on LHON management but require more investigations, particularly on the molecular effects of metformin on the mitochondrial function in LHON patients.

Keywords:  LHON; NAD+; idebenone; metformin; mitochondrial dysfunction; vision Loss

DOI:  https://doi.org/10.3389/fmed.2025.1609941
Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101554

Improved AAV9-based gene therapy design for SURF1-related Leigh syndrome with minimal toxicity.

Qinglan Ling, Matthew Rioux, Harrison Higgs, Yuhui Hu, Scarlett E Dwyer, Steven J Gray.

  Surfeit locus protein 1 (SURF1)-related Leigh syndrome is an early-onset neurodegenerative disorder characterized by a reduction in complex IV activity that disrupts mitochondrial function. Currently, there are no disease-modifying treatments available. Previously, we reported that a gene replacement therapy for SURF1-related Leigh syndrome was developed, which showed improved complex IV activity and restored exercise-induced lactate acidosis, as well as a high safety profile in wild-type (WT) mice. However, further investigations of this original SURF1 vector design uncovered cytotoxicity in multiple tissues of WT rats despite having minimal immune responses. We hypothesized that this cytotoxicity was elicited by SURF1 protein overexpression driven by a strong ubiquitous promoter, CBh. Here, we report the development of an improved gene therapy for SURF1 Leigh syndrome by utilizing a different promoter and polyadenylation sequence. Our data showed that, with lower SURF1 protein expression, the new design conferred a similar level of efficacy, but with minimal cytotoxicity in mice or rats. We propose this new vector design as a promising therapeutic candidate for SURF1-related Leigh syndrome, warranting further translational studies.

Keywords:  AAV; Leigh syndrome; SURF1; adeno-associated virus; gene replacement therapy; gene therapy; mitochondrial diseases; overexpression toxicity

DOI:  https://doi.org/10.1016/j.omtm.2025.101554
Trends Biochem Sci. 2025 Aug 27. pii: S0968-0004(25)00193-8. [Epub ahead of print]

MitoTraP: mitochondrial protection for cellular proteostasis.

Michaela Oborská-Oplová, Michael A Ruoss, Vikram G Panse.

  Cells depend on the efficient import of thousands of nuclear-encoded mitochondrial proteins to maintain mitochondrial function. A new study by Flohr et al. reveals a quality control strategy that traps a subset of mitochondrial precursors in the intermembrane space during energy stress, preventing their toxic accumulation in the cytosol or nucleus.

Keywords:  mitochondrial import; mitochondrial intermembrane space; mitochondrial quality control; mitochondrial ribosomal proteins (MRPs); mitochondrial stress; proteotoxic stress

DOI:  https://doi.org/10.1016/j.tibs.2025.08.004
Mol Ther Nucleic Acids. 2025 Sep 09. 36(3): 102678

Alterations in mitochondrial base editors enhance targeted editing efficiency for mouse model generation.

Seongho Hong, Sol Pin Kim, Sanghun Kim, Soo Kyung Kang, Sungmo Jung, Yeji Oh, Seung Hee Choi, Su Bin Lee, Hou Cha, Jieun Kim, Jiyoung Bae, Jiyoon Park, Kyoungmi Kim, Chang Geun Choi, Soo-Ji Park, Do Hyun Kim, Lark Kyun Kim, Je Kyung Seong, Hyunji Lee.

  Mitochondrial DNA (mtDNA) base editors are powerful tools for investigating mitochondrial diseases. However, their editing efficiency can vary significantly depending on the target site within the mtDNA. In this study, we developed two improved versions of the mitochondrial adenine base editor (Hifi-sTALED and αnHifi-sTALED) by modifying components other than the TadA8e-V28R deaminase variant. These enhancements significantly increased editing efficiency while preserving minimal off-target effects across the transcriptome. Using these optimized editors, we achieved improved mtDNA editing in mouse embryos and successfully generated mt-Rnr1 mutant mice with high heteroplasmic loads. Functional analyses revealed that the mt-Rnr1 mutation impaired mitochondrial function, as indicated by reduced ATP production and decreased oxygen consumption rate (OCR). These findings demonstrate the utility of the enhanced base editors in generating mitochondrial disease models and advancing research in mitochondrial genetics.

Keywords:  MT: RNA/DNA Editing; TALED; base editing; mitochondria; mitochondrial editing; mtDNA

DOI:  https://doi.org/10.1016/j.omtn.2025.102678
Cell Rep. 2025 Sep 03. pii: S2211-1247(25)01005-8. [Epub ahead of print]44(9): 116234

Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.

Shuang Ma, Jianhua Qin, Yao Zhang, Jing Luan, Na Sun, Guoyuan Hou, Jiyuan He, Yang Xiao, Wei Zhang, Minghui Gao.

  Ferroptosis is a regulated necrosis driven by iron-dependent lipid peroxidation. Mitochondria play vital roles in ferroptosis. Mitochondrial dynamics is critical for the health of mitochondria and cells. But how this process regulates ferroptosis is not fully understood. Here, we found that mitochondrial fission is induced during ferroptosis. Disruption of mitochondrial dynamics by impeding the expression of the central players of mitochondrial dynamics control, dynamin-related protein 1 (DRP1) and Mitofusion1/2, or modifying the expression of optic atrophy 1 (OPA1) inhibits ferroptosis. Mechanistically, a defect in mitochondrial dynamics homeostasis increases the ratio of [AMP+ADP]/[ATP], thus activating AMP-activated protein kinase (AMPK), which further phosphorylates nuclear factor erythroid 2-related factor 2 (NRF2) and promotes NRF2 nuclear translocation. Subsequently, NRF2 triggers ferroptosis suppressor 1 (FSP1) upregulation, which renders the cells resistant to ferroptosis. Importantly, mitochondrial fusion promoter M1 can mitigate the chemotoxicity induced by doxorubicin without compromising its anti-cancer efficacy. Collectively, the results of this study demonstrate the crucial role of mitochondrial dynamics in ferroptosis and indicate a potential therapeutic protective approach for chemotoxicity.

Keywords:  AMPK; CP: Immunology; CP: Metabolism; FSP1; NRF2; chemotoxicity; ferroptosis; mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.celrep.2025.116234
EMBO Rep. 2025 Aug 29.

Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.

Lin Luo, Ana Victoria Lechuga-Vieco, Clara Sattentau, Mariana Borsa, Anna Katharina Simon.

  Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.

Keywords:  Asymmetric Cell Division; Mitochondrial Metabolism; Mitochondrial Transfer; Mitophagy; T Cell Ageing

DOI:  https://doi.org/10.1038/s44319-025-00536-z
Ageing Res Rev. 2025 Aug 26. pii: S1568-1637(25)00227-2. [Epub ahead of print]112 102881

Vesicle-guided mitochondria: A new perspective for brain mitochondrial transplantation.

Antonella Girgenti, Laura Palumbo, Gokhan Burcin Kubat, Ibrahim Turkel, Pasquale Picone, Domenico Nuzzo.

  Mitochondrial activity is essential for the proper functioning of higher brain processes, and its impairment has been linked to a wide range of neurological disorders. Increasing evidence shows that under physiological and pathological conditions, mitochondria can be secreted into the extracellular environment to regulate various biological responses, including cellular bioenergetics. Today, the therapeutic modality known as "mitochondrial transplantation" has emerged as a cutting-edge and highly promising intervention for the promotion of cell and tissue regeneration. This innovative approach entails the replacement of dysfunctional mitochondria in the recipient organism with healthy, functional exogenous mitochondria, thereby aiming to restore cellular function and promote tissue repair and recovery. Several studies have demonstrated the beneficial effects of local or systemic administration of mitochondria on in vitro and in vivo models of brain diseases. We discuss the effect of mitochondrial transplantation in various brain diseases and highlight some critical issues. In this regard, we propose vesicles as a delivery system for both whole mitochondria and mitochondrial components to target cells in the central nervous system. Furthermore, the aim of this review is twofold: firstly, to emphasize the significance of brain mitochondrial transplantation, and secondly, to prompt the scientific community to consider the practical applications of brain mitochondrial transplantation. To this end, the text highlights the as yet unresolved issues and challenges that must be addressed and surmounted if this field is to progress. In conclusion, the authors express their support for the development of new potential therapies for mitochondrial diseases of the central nervous system.

Keywords:  Brain diseases; Mitochondrial dysfunction; Mitochondrial transplantation; Vesicles

DOI:  https://doi.org/10.1016/j.arr.2025.102881
Front Cell Neurosci. 2025 ;19 1661231

Underestimation of mitochondrial respiratory capacity in gray matter voxels of the human brain map due to limited OXPHOS and TCA cycle in astrocytes.

Christos Chinopoulos.

  Considering that the aerobic energetic landscape of the brain is shaped by its mitochondria, Mosharov et al. generated an atlas of mitochondrial content and enzymatic OXPHOS activities at a resolution comparable to MRI by physically voxelizing frozen human brain tissue. However, astrocytes in the adult human brain lack expression of several TCA cycle and OXPHOS enzymes. Therefore, their formula expressing mitochondrial respiratory capacity (MRC) -defined as tissue respiratory capacity normalized to mitochondrial density- underestimates actual values by a factor proportional to the square root of the fraction of respiration-capable cells (primarily neurons) in gray matter voxels.

Keywords:  MRI; OXPHOS; astrocytes; mitochondria; neurons; respiratory capacity

DOI:  https://doi.org/10.3389/fncel.2025.1661231
Front Neurol. 2025 ;16 1616992

Late-onset Leber's hereditary optic neuropathy and antiandrogens for prostate cancer: is there a causative link?

Giulia Amore, Michele Carbonelli, Diego D'Angeli, Luigi Bonan, Marco Faustini-Fustini, Alessandra Maresca, Valerio Carelli, Chiara La Morgia.

   Introduction: Leber's hereditary optic neuropathy (LHON) is a maternally inherited condition due to mitochondrial DNA (mtDNA) mutations usually affecting young men within their thirties, while women seem protected by estrogens with a female-to-male ratio of 1:3. Late-onset cases (over 40 years of age) are usually associated to toxic exposure to tobacco smoke or drugs causing mitochondrial dysfunction.
Results: We describe two cases of LHON remarkable for their late onset (> 60 years) in the absence of classic toxic factors. They were both affected by advanced prostate cancer and developed LHON after introduction of enzalutamide, an antagonist of androgens' receptor, in association with leuprolide, a gonadotropin-releasing hormone (GnRH) analogue, used in the context of Androgen deprivation therapy (ADT). Both patients presented very low serum levels of gonadotropin, estrogens and androgens compatible with hormonotherapy. MtDNA copy number in our probands resulted significantly reduced (like other LHON affected cases), compared to age-matched LHON unaffected mutation carriers and controls.
Discussion: The role of hormones in LHON pathogenesis remains still debated. Recent evidence suggests a protective effect of estrogens in increasing mitochondrial biogenesis (and mtDNA copy number), partially explaining the gender bias of the disease, while the role of androgens is yet to be fully understood. Considering the effect of the ADT on circulating hormonal levels and their reciprocal interactions, we hypothesize that in a context of already low estrogens levels due to GnRH analogue, the block of androgens receptors by Leuprolide further imbalance the estrogens to androgens ratio and eventually trigger the disease.

Keywords:  Leber’s hereditary optic neuropathy; androgen deprivation therapy; estrogens; hormones; mitochondrial disease

DOI:  https://doi.org/10.3389/fneur.2025.1616992
Hum Mol Genet. 2025 Aug 29. pii: ddaf125. [Epub ahead of print]

Combination treatment with antioxidants and creatine alleviates common and variant-specific mitochondrial impairments in Leber's hereditary optic neuropathy patient-derived fibroblasts.

Donald Xhuti, Alessandra Chiarot, Mahek Minhas, Samantha Tobia, Nicoletta de Maat, Katherine Manta, Sean Y Ng, Mark A Tarnopolsky, Joshua P Nederveen.

  Leber's hereditary optic neuropathy (LHON) is characterized by painless and rapidly progressive central vision loss, caused by various mutations in mitochondrial DNA, leading to a high genetic and phenotypic heterogeneity. Currently, the only approved therapy is idebenone, a CoQ10 synthetic analogue, that improved visual acuity in some LHON patients; however, results are highly variable due its dependency on functional NAD(P)H oxidoreductase I (NQO1) protein levels, thus limiting broader applicability. Targeting the biochemical respiratory chain defect and mitigating reactive oxygen species emission using alternative treatments which act independent of NQO1 protein content, represent a promising therapeutic strategy for all LHON patients. Here, we first characterized mitochondrial biology of three distinct LHON mutations in patient-derived fibroblasts and evaluated the effects of a nutraceutical combination treatment in addressing these shared pathophysiological mechanisms. We identified a range of mitochondrial characteristics common among various LHON mutations, including higher ROS levels, altered autophagy programming, and reduced mitochondrial bioenergetics. Repeated antioxidant and creatine-based treatment (ACT) conferred a favorable stress-resistant phenotype in LHON cells, which was similar to, and in some cases superior to, the effects observed with idebenone treatment, irrespective of NQO1 protein expression. This phenotype was associated with enhanced mitochondrial biology, as evidenced by reduced reactive oxygen species levels, increased cellular respiration, and correction of autophagic flux. Overall, our findings reveal both common and divergent mitochondrial phenotypes among LHON-related mutations and highlight the potential of accessible multi-ingredient nutraceutical interventions that could benefit all LHON patients.

Keywords:  Antioxidant; Autophagy; Creatine; Leber hereditary optic neuropathy; Mitochondria

DOI:  https://doi.org/10.1093/hmg/ddaf125
Am J Med Genet A. 2025 Sep 06. e64239

Mitochondrial Complex V Deficiency Caused by a Homozygous Splice Variant in ATP5PO.

Zainab Al Masseri, Laura Guilder, Michal Inbar-Feigenberg, Jessie Cameron, Siddika Venkatachalam, David Chitayat.

  Most complex V subunits are nuclear encoded and so far, were not found in association with recognized Mendelian disorders. ATP5PO is a candidate gene for complex V mitochondrial disease. It encodes the oligomycin sensitivity-conferring protein (OSCP), an essential component of the "stalk" region that links the F1 and F0 domains of the ATP synthase complex. We report a 4-month-old girl, born at 35 weeks' gestation to a consanguineous couple via cesarean section due to fetal growth restriction and antenatal echocardiographic findings of moderate biventricular hypertrophy. At birth, she required intubation, ventilation, and surfactant therapy. The patient experienced intermittent hyperlactatemia, apneic spells, encephalopathy, axial hypotonia, and abnormal neonatal reflexes. She passed away at 4 months of age, and whole-exome sequencing revealed a homozygous splice variant (c.87 + 3A > G; p?) in ATP5PO. This gene was reported as a candidate gene, where additional evidence is needed to establish whether there is a relationship between this gene variant and human disease. So far and to our best knowledge, only four cases with a pathogenic variant in this gene have been reported. Mitochondrial respiratory chain analysis performed on fibroblasts revealed reduced ATPase enzyme activity with approximately 35% of the mean enzyme activity observed in the control reference range, with a decreased enzyme activity ratio relative to citrate synthase. These results suggest that isolated complex V enzyme deficiency is associated with the homozygous VUS identified in the ATP5PO gene in this patient and provide further functional support that ATP5PO is involved in complex V assembly and function.

Keywords:  ATP synthase; ATP5PO; MC5DN7; OSCP; complex V; encephalopathy; mitochondrial

DOI:  https://doi.org/10.1002/ajmg.a.64239
Autophagy. 2025 Aug 27.

PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.

Soumya Ranjan Mishra, Priyadarshni Mishra, Kewal Kumar Mahapatra, Bishnu Prasad Behera, Gajanan Kendre, Moureq Rashed Alotaibi, Vijay Pandey, Birija Sankar Patro, Daniel J Klionsky, Sujit Kumar Bhutia.

  The inorganic pyrophosphatase PPA2, a matrix-localized protein, maintains mitochondrial function. Here, we identified the role of PPA2 in activating mitochondrial fission signaling. We found that PPA2 overexpression promotes mitochondrial fission by upregulating the mitochondrial translocation of phosphorylated DNM1L S616. Moreover, PPA2 interacts with MTFP1, a mitochondrial inner membrane protein, to induce fission signaling; cells knocked down for MTFP1 and overexpressing PPA2 failed to induce DNM1L activation and subsequent mitochondrial fission. Furthermore, in physiological conditions, PPA2 directed mitochondrial fission at the midzone through MFF-DNM1L, leading to mitochondrial proliferation. Interestingly, during mitochondrial stress following CCCP treatment, PPA2 triggers peripheral fission through FIS1 and DNM1L to segregate parts of damaged mitochondria, which is essential for mitophagy. In addition, PPA2 utilized the C-terminal LC3-interacting region (LIR) of MTFP1 for mitophagy-mediated clearance of damaged mitochondria. In conclusion, PPA2 activates mitochondrial fission signaling through MTFP1-DNM1L and is essential in defining the site of mitochondrial fission, leading to mitochondrial proliferation or mitophagy for maintaining mitochondrial homeostasis.

Keywords:  MTFP1; Mitochondria; PPA2; mitochondrial fission; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2552900
Adv Exp Med Biol. 2025 ;1478 343-363

Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.

Jonathan Wanagat, Robert Musci, Allen Herbst, Judd M Aiken.

  This chapter describes a molecular basis for age-induced muscle fiber loss involving the mammalian mitochondrial genome (mtDNA). Early studies of human mitochondrial myopathies, which display many phenotypes associated with muscle aging, led to the search for and subsequent discovery of similar genetic and histopathological changes in aging skeletal muscle. A diverse spectrum of mtDNA deletion mutations increase in abundance with age and clonally accumulate to high abundance within individual cells. Deletion accumulation results in a focal loss of electron transport and oxidative phosphorylation. These metabolic derangements activate apoptosis, leading to necrosis, fiber splitting, and eventual fiber loss. We have identified a number of interventions that are capable of modulating mtDNA deletion mutation frequency and the abundance of electron transport chain deficient fibers. Interestingly, in each case, the genetic and histological measures of mtDNA quality predict the lifespan effects of these interventions. We highlight the value of incorporating a geroscience view into the study of sarcopenia. The sequence of events from the deletion mutation of a single mtDNA molecule to muscle fiber death is not limited to skeletal muscle and has been observed in most other aging tissues, where these events likely contribute to cell loss.

Keywords:  Mitochondria; Mitochondrial DNA; Mutations; Sarcopenia

DOI:  https://doi.org/10.1007/978-3-031-88361-3_14
Int J Ophthalmol. 2025 ;18(9): 1770-1776

Retinal multimodal-imaging and functional tests in a mitochondrial disease with focal and segmental glomerulosclerosis.

Xiao-Hong Liu, Xi Shen, Yi-Sheng Zhong.

  The phenotypes of the adenine-to-guanine transition at position 3243 of mitochondrial DNA (m.3243A>G) are highly variable, with different symptoms observed in different patients. These include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); maternally inherited diabetes and deafness syndrome (MIDD); other syndromic conditions; or non-syndromic mitochondrial disorders. Renal involvement associated with this mutation generally manifests as subnephrotic proteinuria, progressive deterioration of kidney function, and increased morbidity. The retinopathies linked to the m.3243A>G mutation have heterogeneous presentations, characterized by variable degrees of retinal pigment epithelium (RPE) atrophy and hyperpigmentation at the posterior pole. As a severe phenotype of the m.3243A>G mutation, MELAS combined with focal and segmental glomerulosclerosis (FSGS) is rare. We herein firstly reported in detail the ophthalmic manifestations of a patient with this condition. Additionally, we reviewed the literature on fundus, ophthalmic electrophysiology, and optical coherence tomography (OCT) findings related to the m.3243A>G mutation.

Keywords:  MELAS; m.3243A>G; mitochondrial retinopathy; multimodal imaging; ophthalmic electrophysiology; optical coherence tomography

DOI:  https://doi.org/10.18240/ijo.2025.09.19
Nat Rev Nephrol. 2025 Aug 29.

Accumulation of pathogenic mitochondrial DNA mutations in the kidney.

Ellen F Carney.

DOI: https://doi.org/10.1038/s41581-025-01002-8
Cell. 2025 Aug 25. pii: S0092-8674(25)00916-X. [Epub ahead of print]

Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.

Jingchuan Luo, Stuti Khandwala, Jingjie Hu, Song-Yi Lee, Kelsey L Hickey, Zebulon G Levine, J Wade Harper, Alice Y Ting, Jonathan S Weissman.

  Localized translation broadly enables spatiotemporal control of gene expression. Here, we present LOV-domain-controlled ligase for translation localization (LOCL-TL), an optogenetic approach for monitoring translation with codon resolution at any defined subcellular location under physiological conditions. Application of LOCL-TL to mitochondrially localized translation revealed that ∼20% of human nuclear-encoded mitochondrial genes are translated on the outer mitochondrial membrane (OMM). Mitochondrially translated messages form two classes distinguished by encoded protein length, recruitment mechanism, and cellular function. An evolutionarily ancient mechanism allows nascent chains to drive cotranslational recruitment of long proteins via an unanticipated bipartite targeting signal. Conversely, mRNAs of short proteins, especially eukaryotic-origin electron transport chain (ETC) components, are specifically recruited by the OMM protein A-kinase anchoring protein 1 (AKAP1) in a translation-independent manner that depends on mRNA splicing. AKAP1 loss lowers ETC levels. LOCL-TL thus reveals a hierarchical strategy that enables preferential translation of a subset of proteins on the OMM.

Keywords:  AKAP1; OXPHOS; cis-element analysis; cotranslational targeting; localized translation; mitochondrial bipartite targeting signal; outer mitochondrial membrane; oxidative phosphorylation; translation-independent mRNA targeting

DOI:  https://doi.org/10.1016/j.cell.2025.08.002
Adv Exp Med Biol. 2025 ;1478 19-50

Mitochondrial Biogenesis in Skeletal Muscle.

David A Hood, Jonathan M Memme, Ashley N Oliveira, Neushaw Moradi, Sabrina Champsi.

  Mitochondrial biogenesis refers to the synthesis of nuclear- and mitochondrially encoded proteins, along with phospholipids, that aid in the expansion of the mitochondrial network. In skeletal muscle, mitochondria are organized as a reticulum, as this ideal morphology complements the elongated shape of a myofibre. This allows for efficient substrate diffusion and supports the vigorously dynamic metabolic capabilities of this tissue type. Mitochondria are central responders to deviations in metabolic homeostasis and are thus required to support acute or chronic bouts of endurance exercise, cold exposure, starvation, or other externally imposed stimuli. This chapter marks the introduction to skeletal muscle mitochondrial adaptability as we discuss the subcellular events that contribute to mitochondrial biogenesis. Topics range from mitochondrial content and subpopulations in different muscle fibre types to signaling cascades and regulatory elements that support this mechanism. The characterization of mitochondrial biogenesis was made possible through clever models of both exercise and muscle disuse, at times with genetic modifications to important regulators, and is incorporated in this discussion. The chapter concludes with reviews on changes to signaling towards biogenesis with age. Altogether, our review attempts to highlight the vast revelations on the targeting, contribution, and significance of mitochondrial biogenesis in skeletal muscle.

Keywords:  Aging; Calcium; Exercise signaling; Exercise training; Gene expression; Mitochondria; Mitochondrial dynamics; Muscle disuse; Protein import; ROS

DOI:  https://doi.org/10.1007/978-3-031-88361-3_2
Transl Neurodegener. 2025 Sep 01. 14(1): 45

Molecular mechanisms of mitochondrial quality control.

Wensheng Li, Yuran Gui, Cuiping Guo, Yuting Huang, Yi Liu, Xuan Yu, Huiliang Zhang, Jianzhi Wang, Rong Liu, Yacoubou Abdoul Razak Mahaman, Qiuhong Duan, Xiaochuan Wang.

  Mitochondria produce adenosine triphosphate (ATP), the main source of cellular energy. To maintain normal function, cells rely on a complex mitochondrial quality control (MQC) system that regulates mitochondrial homeostasis, including mitochondrial dynamics, mitochondrial dynamic localization, mitochondrial biogenesis, clearance of damaged mitochondria, oxygen radical scavenging, and mitochondrial protein quality control. The MQC system also involves coordination of other organelles, such as the endoplasmic reticulum, lysosomes, and peroxisomes. In this review, we discuss various ways by which the MQC system maintains mitochondrial homeostasis, highlight the relationships between these pathways, and characterize the life cycle of individual mitochondria under the MQC system.

Keywords:  Evidence-based therapies; Mitochondria; Mitochondrial diseases; Mitochondrial homeostasis; Mitochondrial quality control

DOI:  https://doi.org/10.1186/s40035-025-00505-5
Int J Toxicol. 2025 Aug 28. 10915818251369414

Mitochondria: Key Mediator for Environmental Toxicant-Induced Neurodegeneration.

Nishi Shah, Bhagawati Saxena, Richa Gupta.

  Compiling evidence strongly suggests the involvement of environmental toxicants, including heavy metals (aluminum, arsenic, lead, copper, cadmium, mercury, and manganese), pesticides, and solvents, as the prime culprits of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The pathogenesis of environmental toxicant-induced neurodegenerative disease remains elusive. Studies carried out in the last decade suggest that dysfunctional mitochondria are increasingly recognized as a key factor in the progression of neurodegenerative diseases. Mitochondria, the essential organelles that regulate cellular energy production, are particularly vital in neurons, which have high energy demands and depend on proper mitochondrial function for survival. Environmental toxicants have been shown to impair mitochondrial membranes, disrupt the electron transport chain, increase oxidative stress, and damage mitochondrial DNA, leading to progressive neurodegeneration, with mitochondrial fragmentation and oxidative stress that worsens neurodegeneration. There are currently no disease-modifying treatments available for most neurodegenerative disorders, largely due to the lack of suitable molecular targets. Targeting mitochondria presents a rational strategy for neuroprotective therapy, with the potential to slow or halt disease progression. In view of this, this review highlights the central role of mitochondria in environmental toxicant-induced neurodegeneration, emphasizing how environmental exposures drive mitochondrial dysfunction and accelerate disease progression. Understanding these mechanisms is crucial for identifying environmental risk factors and developing targeted interventions. This will provide a foundation for future research targeting mitochondria and developing suitable therapeutic interventions for neurodegenerative diseases.

Keywords:  environmental toxicants; heavy metals; mitochondrial dysfunction; neurodegenerative disorders; pesticides

DOI:  https://doi.org/10.1177/10915818251369414
Trends Neurosci. 2025 Sep 02. pii: S0166-2236(25)00169-9. [Epub ahead of print]

The integrated stress response in the brain: cell type-specific functions in health and neurological disorders.

David Ho-Tieng, Vijendra Sharma, Nahum Sonenberg, Christos G Gkogkas, Arkady Khoutorsky.

  The integrated stress response (ISR) is an evolutionarily conserved signaling network that regulates protein synthesis in response to diverse cellular stressors to promote stress adaptation. The ISR also responds to physiological stimuli to modify the cellular proteome in an activity-dependent manner. Many common brain pathologies, including neurodegenerative and neurodevelopmental disorders, induce chronic cellular stress and subsequent ISR activation, which substantially contributes to disease progression. Importantly, various brain cell types exhibit disparate levels of sensitivity to cellular stress and differ in how the activation of the ISR influences their physiology. In this review, we highlight cell type-specific roles of the ISR in brain health and disease. We also discuss how therapeutically targeting the ISR in pathological states should account for the cell types being affected.

Keywords:  astrocytes; brain; memory; microglia; neurons; protein synthesis; synaptic plasticity

DOI:  https://doi.org/10.1016/j.tins.2025.08.002
Nature. 2025 Sep 03.

Genetic suppression features ABHD18 as a Barth syndrome therapeutic target.

Sanna N Masud, Anchal Srivastava, Patricia Mero, Victoria Saba Echezarreta, Eve Anderson, Lennard van Buren, Jiarun Wei, David Thomson Taylor, Adrian Granda Farias, Nicholas Mikolajewicz, Angela Shaw, Brandon M Murareanu, Michelle Lohbihler, Olivia Sniezek Carney, Simon van Heeringen, Linda Clijsters, Olga Sizova, Jeroen van Ameijde, Freya Nye, Andrea Habsid, Lucy Nedyalkova, Laura McDonald, Craig Simpson, Leanne Wybenga-Groot, Kevin R Brown, Nhi Nho, Radu M Suciu, Katherine Chan, Amy H Y Tong, Frédéric M Vaz, Bastiaan Evers, Robert Lesurf, Tanya Papaz, Lauryl M J Nutter, Stephanie Protze, Maximilian Billmann, Michael Costanzo, Brenda J Andrews, Chad L Myers, Seema Mital, Hilary Vernon, Thijn R Brummelkamp, Charles Boone, Ian C Scott, Micah J Niphakis, Douglas Strathdee, Sebastian M B Nijman, Vincent A Blomen, Jason Moffat.

Cardiolipin (CL) is the signature phospholipid of the inner mitochondrial membrane, where it stabilizes electron transport chain protein complexes1. The final step in CL biosynthesis relates to its remodelling: the exchange of nascent acyl chains with longer, unsaturated chains1. However, the enzyme responsible for cleaving nascent CL (nCL) has remained elusive. Here, we describe ABHD18 as a candidate deacylase in the CL biosynthesis pathway. Accordingly, ABHD18 converts CL into monolysocardiolipin (MLCL) in vitro, and its inactivation in cells and mice results in a shift to nCL in serum and tissues. Notably, ABHD18 deactivation rescues the mitochondrial defects in cells and the morbidity and mortality in mice associated with Barth syndrome. This rare genetic disease is characterized by the build-up of MLCL resulting from inactivating mutations in TAFAZZIN (TAZ), which encodes the final enzyme in the CL-remodelling cascade1. We also identified a selective, covalent, small-molecule inhibitor of ABHD18 that rescues TAZ mutant phenotypes in fibroblasts from human patients and in fish embryos. This study highlights a striking example of genetic suppression of a monogenic disease revealing a canonical enzyme in the CL biosynthesis pathway.

DOI: https://doi.org/10.1038/s41586-025-09373-5
Glia. 2025 Sep 01.

C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.

Marika Mearelli, Insa Hirschberg, Christin Weissleder, Carmela Giachino, María José Pérez, Malvina Dubroux, Francesca Provenzano, Mafalda Rizzuti, Linda Ottoboni, Udit Sheth, Tania F Gendron, Stefania Corti, Michela Deleidi.

  The C9orf72 hexanucleotide repeat expansion mutation is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but its cell type-specific effects on energy metabolism and immune pathways remain poorly understood. Using induced pluripotent stem cell (iPSC)-derived motor neurons, astrocytes, and microglia from C9orf72 patients and their isogenic controls, we investigated metabolic changes at the single-cell level under basal and inflammatory conditions. Our results showed that microglia are particularly susceptible to metabolic disturbances. While C9orf72 motor neurons exhibited impaired mitochondrial respiration and reduced ATP production, C9orf72 microglia presented pronounced increases in glycolytic activity and oxidative stress, accompanied by the upregulation of the expression of key metabolic enzymes. These metabolic changes in microglia were exacerbated by inflammatory stimuli. To investigate how these changes affect the broader cellular environment, we developed a human iPSC-derived triculture system comprising motor neurons, astrocytes, and microglia. This model revealed increased metabolic activity in all cell types and highlighted that microglia-driven metabolic reprogramming in astrocytes contributes to the vulnerability of motor neurons under inflammatory conditions. Our findings highlight the central role of microglia in driving metabolic dysregulation and intercellular crosstalk in ALS pathogenesis and suggest that targeting metabolic pathways in immune cells may provide new therapeutic avenues.

Keywords:   C9orf72 ; amyotrophic lateral sclerosis/frontotemporal dementia; glial‐neuronal communication; immune system; induced pluripotent stem cells; microglia

DOI:  https://doi.org/10.1002/glia.70080
FASEB J. 2025 Aug 31. 39(16): e70958

Intracellular and Extracellular Vesicle miRNA Signatures in Human iPSC-Derived Neural Stem Cells and Floor Plate Progenitors.

Lilian Cruz, Frederico Moraes Ferreira, Camila Miranda Lopes-Ramos, Zhiyun Wei, William T Hendriks, H A Jinnah, Helder I Nakaya, D Cristopher Bragg, Anna M Krichevsky, Xandra Owens Breakefield, Marilene Hohmuth Lopes.

  Refined control of intrinsic and extrinsic signals is critical for specific neuronal differentiation. Here, we differentiated human induced pluripotent stem cells (hiPSCs) from three different healthy donors into neural stem cells (NSCs) and floor plate progenitors (FPPs; progenitors of dopaminergic neurons) and further performed intracellular and extracellular vesicles' (EVs) miRNA profiling. While NSC and FPP cells differed significantly in levels of only 8 intracellular miRNAs, their differences were more evident in the EV miRNAs with 27 differentially expressed miRNAs. Target validation of intracellular miRNAs revealed that FPPs expressed more EXOC5 mRNA than NSCs, which is implicated in the function of primary cilia, an essential signaling organelle in FPPs. Moreover, we found a group of 5 miRNAs consistently enriched in EVs from these three cell types. This study presents a foundation for the field of miRNA regulation in neural development and provides new insights for disease modeling and regenerative medicine.

Keywords:  EXOC5; dopaminergic neurons; exosomes; floor plate progenitors; human induced pluripotent stem cells; microRNA; neural differentiation; neuronal development

DOI:  https://doi.org/10.1096/fj.202501157R
Adv Sci (Weinh). 2025 Aug 30. e03082

FOXQ1 Regulates Brain Endothelial Mitochondrial Function by Orchestrating Calcium Signaling and Cristae Morphology.

Wenzheng Zou, Yuqing Lv, Lin Li, Shukui Zhang, Jiaqi Liang, Chengchao Wu, Enyu Huang, Jianwei Jiao, Jingjing Zhang.

  The blood-brain barrier (BBB) maintains brain homeostasis through specialized functions including tight junction formation and selective transport of brain endothelial cells (ECs). While ECs are generally thought to rely primarily on glycolysis for energy production, the transcriptional mechanisms underlying their metabolic specialization in the brain endothelium remain poorly understood, especially considering the brain's extraordinary energy demands. Through comparative transcriptomic analysis, it is demonstrated that brain endothelial cells are enriched for mitochondrial function genes, with forkhead box protein 1 (FOXQ1) being selectively expressed in cerebral vasculature. Conditional knockout of Foxq1 in endothelial cells results in severe mitochondrial dysfunction, including disrupted cristae morphology, reduced oxygen consumption, and impaired adenosine triphosphate (ATP) production. Mechanistically, FOXQ1 directly regulates two key pathways: calcium signaling through huntingtin-associated protein (HAP1)-mediated endoplasmic reticulum (ER)-mitochondrial calcium transfer, and mitochondrial structural integrity via AarF domain-containing protein kinase 1 (ADCK1)-dependent cristae organization. These findings reveal that brain endothelial cells rely on oxidative phosphorylation rather than glycolysis alone, challenging the prevailing metabolic paradigm for endothelial cells. This work establishes FOXQ1 as an important regulator of brain endothelial metabolism and provides new insights into the molecular basis of cerebrovascular specialization, with implications for understanding vascular dysfunction in neurological diseases.

Keywords:  FOXQ1; brain endothelial cells; calcium signaling; cristae organization; mitochondrial metabolism

DOI:  https://doi.org/10.1002/advs.202503082