bims-mitdis 2025-05-11 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2025–05–11
39 papers selected by
Catalina Vasilescu, Helmholz Munich

SARM1 loss protects retinal ganglion cells in a mouse model of Autosomal Dominant Optic Atrophy.
Phase separation in mitochondrial fate and mitochondrial diseases.
A lipid in transit - the journey of cholesterol into the heart of mitochondrial research.
Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.
Modifier variants in metabolic pathways are associated with an increased penetrance of Leber's Hereditary Optic Neuropathy.
Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.
Synthetic DNA and mitochondrial donation: no need for donor eggs?
The role of mitochondrial mRNA translation in cellular communication.
Parkin mediates the mitochondrial dysfunction through mRpL18.
Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling.
Uncovering a Novel Pathogenic Mechanism of BCS1L in Mitochondrial Disorders: Insights from Functional Studies on the c.38A>G Variant.
Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.
Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.
Cryo-EM of Mitochondrial Complex I and ATP Synthase.
Isolated and Syndromic Genetic Optic Neuropathies: A Review of Genetic and Phenotypic Heterogeneity.
A Novel Presentation and Variable Phenotypic Spectrum of Homozygous Start-Loss Variant in LYRM7-Associated Mitochondrial Complex III Deficiency.
Agent-based modeling of neuronal mitochondrial dynamics using intrinsic variables of individual mitochondria.
Case Report: Unusual Neurological Features of Leigh Syndrome due to m.8993T>G Pathogenic Variant in the MT-ATP6 Gene.
A nuclear-encoded endonuclease governs the paternal transmission of mitochondria in Cucumis plants.
Mitochondrial Dysfunction in Cardiac Diseases: Insights into Pathophysiology and Clinical Outcomes.
Ratiometric Covalent Fluorescent Probes for Dynamic Super-Resolution Imaging of Mitochondrial HClO.
Msp1 and Pex19-Pex3 cooperate to achieve correct localization of Pex15 to peroxisomes.
Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases.
Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.
A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress.
Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males.
SNX10 at the crossroad of endocytosis and piecemeal mitophagy.
The Role of N6-Methyladenosine in Mitochondrial Dysfunction and Pathology.
Neuronal FGF13 Inhibits Mitochondria-Derived Damage Signals to Prevent Neuroinflammation and Neurodegeneration in a Mouse Model of Parkinson's Disease.
Small-scale protocols to characterize mitochondrial Complex V activity and assembly in peripheral blood mononuclear cells.
Stem cell therapies for Parkinson's disease.
NAD replenishment restores mitochondrial function and thermogenesis in the brown adipose tissue of mice with obesity.
A murine model of Barth syndrome with cardiac and skeletal muscle selective inactivation of tafazzin.
Compound Heterozygous MRPS14 Variants Associated With Leigh Syndrome.
Evolution-guided protein design of IscB for persistent epigenome editing in vivo.
DNA methyltransferase 1 modulates mitochondrial function through bridging m5C RNA methylation.
Design of diverse, functional mitochondrial targeting sequences across eukaryotic organisms using variational autoencoder.
Toward clinical long-read genome sequencing for rare diseases.
Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variants.

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
J Cell Sci. 2025 May 01. pii: jcs263907. [Epub ahead of print]138(9):

A lipid in transit - the journey of cholesterol into the heart of mitochondrial research.

Thomas Simmen, Luca Pellegrini.

  Mitochondrial cholesterol biology in non-steroidogenic tissues remains understudied in cell science. Although detecting cholesterol in mitochondria is challenging due to isolation difficulties, studies using mitoplasts (mitochondria stripped of their outer membrane) and imaging approaches confirm its presence in the inner mitochondrial membrane. Through analysis of published evidence and first-principles reasoning, we advance a model of cholesterol trafficking into and out of mitochondria via phospholipids at mitochondria-associated membranes (MAMs), challenging the traditional view of protein-driven transport. In this model, cholesterol enters mitochondria alongside phosphatidylserine and exits with phosphatidylethanolamine - either unchanged or in a hydroxylated form after modification by the enzyme CYP27A1. Strong cholesterol-phospholipid binding energies, ∼17 kcal/mol (71.128 kJ/mol), support this lipid-mediated mechanism, suggesting it complements protein-based pathways. Future research should explore how these mechanisms collaborate to regulate mitochondrial cholesterol trafficking. By rethinking cholesterol dynamics, we raise the possibility that cholesterol plays a larger role in mitochondrial biology, influencing membrane-dependent functions like cristae structure, respiratory efficiency and inter-organelle communication. This Perspective also highlights the potential of mitochondria to regulate both dietary and endogenous cholesterol flux and homeostasis across the cell.

Keywords:  Lipid biology; Membrane trafficking; Organelles

DOI:  https://doi.org/10.1242/jcs.263907
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
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
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
J Med Ethics. 2025 May 07. pii: jme-2024-110122. [Epub ahead of print]

Synthetic DNA and mitochondrial donation: no need for donor eggs?

Adrian Villalba, Iain Brassington, Anna Smajdor, Daniela Cutas.

  Mitochondrial replacement therapy has been developed in order to prevent the transmission of mitochondrial mutations, yet it raises ethical concerns, particularly regarding the involvement of third-party DNA and the risks associated with donor procedures. This paper explores an alternative approach using synthetic DNA (synDNA) to construct mitochondrial organelles, thereby bypassing the need for donor oocytes and bypassing risks to donors. We argue that those who support mitochondrial replacement techniques as an ethically acceptable means of preventing the transmission of mitochondrial disease should consider the use of synthetic mitochondria as a preferable ethical alternative, should it prove technically viable. That this will be viable is more than we can demonstrate here. However, progress in synDNA technology suggests that it is not unreasonable to think that synthetic mitochondria creation is feasible, and perhaps even probable.

Keywords:  Reproductive Medicine

DOI:  https://doi.org/10.1136/jme-2024-110122
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 Biol Chem. 2025 May 07. pii: S0021-9258(25)02057-5. [Epub ahead of print] 110208

Parkin mediates the mitochondrial dysfunction through mRpL18.

Xiuxiu Ti, Hui Zuo, Guochun Zhao, Yuwei Li, Minghui Du, Liwen Xu, Shengnan Li, Zhaoliang Shan, Yuxue Gao, Guangming Gan, Yan Wang, Qing Zhang.

  Loss of function of parkin leads to the mitochondrial dysfunction, which is closely related to Parkinson's disease. However, the in vivo mechanism is far from clear. One of the dogmas is that impaired Parkin causes dysfunction of mitophagy mediated by Pink1-Parkin axis. The other is that impaired Parkin causes Mfn accumulation which leads to mitochondrial dysfunction. Surprisingly, in Drosophila muscles, as reported, the first dogma is not applicable; for the second dogma, our study suggests that Parkin mediates the mitochondrial dysfunction through modulating mitochondrial morphology, which is determined by synergy of both Marf and mitochondrial protein mRpL18 got from our genome-wide screen, whose RNAi rescues parkin RNAi phenotype. Mechanistically, we found that impaired Parkin upregulated both the transcription and protein levels of mRpL18 dependent on its E3 ligase activity, causing the mRpL18 accumulation outside mitochondria. Consequently, cytosolic accumulated mRpL18 competitively bound Drp1, leading to the reduction of the binding of Drp1 to its receptor Fis1, which finally inhibited the mitochondrial fission and tipped the balance to mitochondrial hyperfusion, thereby affected the mitochondrial function. Taken together, our study suggests that impaired Parkin causes mitochondrial hyperfusion due to two reasons: (1) Parkin defect impairs Pink1-Parkin axis-mediated Marf degradation, which promotes mitochondrial fusion; (2) Parkin defect causes mRpL18 accumulation, which inhibits Drp1/Fis1-mediated mitochondrial fission. These two ways function together to drive Parkin-mediated mitochondrial hyperfusion. Therefore, knockdown of either marf or mRpL18 can prevent mitochondrial hyperfusion, leading to the rescue of Parkin defect-triggered fly wing phenotypes. Overall, our study unveils a new facet of how Parkin regulates mitochondrial morphology to affect mitochondrial function, which provides new insights for the understanding and treatment of Parkinson's disease.

Keywords:  Drp1; Parkin; Parkinson's disease; mRpL18

DOI:  https://doi.org/10.1016/j.jbc.2025.110208
Sci Adv. 2025 May 09. 11(19): eadn2528

Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling.

Pawan K Singh, Shalini Agarwal, Ilaria Volpi, Léa P Wilhelm, Giada Becchi, Andrew Keenlyside, Thomas Macartney, Rachel Toth, Adrien Rousseau, Glenn R Masson, Ian G Ganley, Miratul M K Muqit.

Loss-of-function mutations in the PINK1 kinase lead to early-onset Parkinson's disease (PD). PINK1 is activated by mitochondrial damage to phosphorylate ubiquitin and Parkin, triggering mitophagy. PINK1 also indirectly phosphorylates Rab GTPases, such as Rab8A. Using an siRNA library targeting human Ser/Thr kinases in HeLa cells, we identified EIF2AK1 [heme-regulated inhibitor (HRI) kinase], a branch of the integrated stress response (ISR), as a negative regulator of PINK1. EIF2AK1 knockdown enhances mitochondrial depolarization-induced PINK1 stabilization and phosphorylation of ubiquitin and Rab8A. These results were confirmed in SK-OV-3, U2OS, and ARPE-19 cells. Knockdown of DELE1, an activator of EIF2AK1, produced similar effects. Notably, the ISR inhibitor ISRIB also enhanced PINK1 activation. In human cells with mito-QC mitophagy reporters, EIF2AK1 knockdown or ISRIB treatment increased PINK1-dependent mitophagy without affecting deferiprone-induced mitophagy. These findings suggest that the DELE1-EIF2AK1 ISR pathway is a negative regulator of PINK1-dependent mitophagy. Further evaluation in PD-relevant models is needed to assess the therapeutic potential of targeting this pathway.

DOI: https://doi.org/10.1126/sciadv.adn2528
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
J Biosci. 2025 ;pii: 33. [Epub ahead of print]50

Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.

Hye Jin Hwang, Francis R G Amrit, Brandon J Berry, Claudette St Croix, Andrew P Wojtovich, Sruti Shiva, Arjumand Ghazi.

Reproductive status influences metabolism and health across the lifespan in diverse ways, and mitochondrial function plays a critical role in mediating this relationship. Using the Caenorhabditis elegans germline ablation model, we investigated the impact of germline stem cell (GSC) loss on mitochondrial dynamics and respiratory function. Our results show that GSC loss reduces mitochondrial volume and respiratory function in young adulthood but preserves mitochondrial activity during aging and upon exposure to hypothermic stress, correlating with enhanced survival. We found that the transcription factor NHR-49/PPARα, but not DAF-16/ FOXO3A, was essential for preserving mitochondrial function and hypothermia resistance in these long-lived mutants. Together, these findings reveal the impact of germline signals on somatic mitochondrial health and underscore the intricate relationship between reproductive fitness and organismal health.
EMBO J. 2025 May 09.

Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.

Furkan E Oflaz, Alexander I Bondarenko, Michael Trenker, Markus Waldeck-Weiermair, Benjamin Gottschalk, Eva Bernhart, Zhanat Koshenov, Snježana Radulović, Rene Rost, Martin Hirtl, Johannes Pilic, Aditya Karunanithi Nivedita, Adlet Sagintayev, Gerd Leitinger, Bent Brachvogel, Susanne Summerauer, Varda Shoshan-Barmatz, Roland Malli, Wolfgang F Graier.

  Annexin A5 (AnxA5) is a Ca2+-dependent phospholipid-binding protein associated with the regulation of intracellular Ca2+ homeostasis. However, the precise role of AnxA5 in controlling mitochondrial Ca2+ signaling remains elusive. Here, we introduce a novel function of AnxA5 in regulating mitochondrial Ca2+ signaling. Our investigation revealed that AnxA5 localizes at and in the mitochondria and orchestrates intermembrane space Ca2+ signaling upon high Ca2+ elevations induced by ER Ca2+ release. Proximity ligation assays and co-immunoprecipitation revealed a close association but no direct contact of AnxA5 with the voltage-dependent anion channel (VDAC1) in the outer mitochondrial membrane (OMM). In single-cell mitochondrial Ca2+ measurements and electrophysiological recordings, AnxA5 was found to enhance Ca2+ flux through the OMM by promoting the Ca2+-permeable state of VDAC1. By modulating intermembrane space Ca2+ signaling, AnxA5 shapes mitochondrial ultrastructure and influences the dynamicity of the mitochondrial Ca2+ uniporter. Furthermore, by controlling VDAC1's oligomeric state, AnxA5 is protective against cisplatin and selenite-induced apoptotic cell death. Our study uncovers AnxA5 as an integral regulator of VDAC1 in physiological and pathological conditions.

Keywords:  Annexin-A5; Apoptotic Cell Death; Intermembrane Space Ca2⁺ Signaling; VDAC1 Ca2+ Permeability

DOI:  https://doi.org/10.1038/s44318-025-00454-9
Annu Rev Biophys. 2025 May;54(1): 209-226

Cryo-EM of Mitochondrial Complex I and ATP Synthase.

Werner Kühlbrandt, Luis A M Carreira, Özkan Yildiz.

  Cryo-electron microscopy (cryo-EM) is the method of choice for investigating the structures of membrane protein complexes at high resolution under near-native conditions. This review focuses on recent cryo-EM work on mitochondrial complex I and ATP synthase. Single-particle cryo-EM structures of complex I from mammals, plants, and fungi extending to a resolution of 2 Å show different functional states, indicating consistent conformational changes of loops near the Q binding site, clusters of internal water molecules in the membrane arm, and an α-π transition in a membrane-spanning helix that opens and closes the proton transfer path. Cryo-EM structures of ATP synthase dimers from mammalian, yeast, and Polytomella mitochondria show several rotary states at a resolution of 2.7 to 3.5 Å. The new structures of complex I and ATP synthase are important steps along the way toward understanding the detailed molecular mechanisms of both complexes. Cryo-electron tomography and subtomogram averaging have the potential to resolve their high-resolution structures in situ.

Keywords:  ATP synthase; complex I; cryo-electron microscopy; cryo-electron tomography; mitochondria; respiratory chain

DOI:  https://doi.org/10.1146/annurev-biophys-060724-110838
Int J Mol Sci. 2025 Apr 20. pii: 3892. [Epub ahead of print]26(8):

Isolated and Syndromic Genetic Optic Neuropathies: A Review of Genetic and Phenotypic Heterogeneity.

Marco Zeppieri, Caterina Gagliano, Marco Di Maita, Alessandro Avitabile, Giuseppe Gagliano, Edoardo Dammino, Daniele Tognetto, Maria Francesca Cordeiro, Fabiana D'Esposito.

  Nonsyndromic and syndromic hereditary optic neuropathies (HONs) encompass a variety of genetic illnesses that cause progressive optic nerve damage, resulting in considerable vision impairment. These disorders result from pathogenic variants in mitochondrial or nuclear DNA, impacting essential cellular processes like oxidative phosphorylation, mitochondrial dynamics, and neuroprotection. Advances in next-generation sequencing (NGS) have significantly improved the identification of genetic variations, enabling precise diagnoses and genotype-phenotype correlations. This review consolidates current knowledge regarding the classification, molecular pathogenesis, clinical manifestations, diagnostic methodologies, and emerging therapeutic strategies for HONs. The critical role of mitochondrial dysfunction in optic nerve degeneration highlights the necessity for multimodal therapeutic approaches. Recent clinical trials evaluating gene therapy for Leber hereditary optic neuropathy (LHON) and neuroprotective strategies in dominant optic atrophy (DOA) are discussed. Additionally, individualized therapeutic interventions, as demonstrated by recent case studies involving tailored gene therapies, are evaluated. The integration of molecular and imaging biomarkers in future personalized treatment strategies aims to enhance prognosis and therapeutic outcomes.

Keywords:  Leber hereditary optic neuropathy (LHON); dominant optic atrophy (DOA); gene therapy; hereditary optic neuropathy; mitochondrial DNA; optic atrophy; wolfram syndrome

DOI:  https://doi.org/10.3390/ijms26083892
Am J Med Genet A. 2025 May 02. e64105

A Novel Presentation and Variable Phenotypic Spectrum of Homozygous Start-Loss Variant in LYRM7-Associated Mitochondrial Complex III Deficiency.

Noel Deep Luke, Aditya Vijayakrishnan Nair, Ajith Sivadasan, Karthik Muthusamy, Maya Mary Thomas, Sangeetha Yoganathan, Rekha Aaron, Anitha Jasper, Pavithra Mannam, Roshan Daniel, Sumita Danda.

  LYRM7-associated mitochondrial complex III deficiency has classically been described in the literature as a childhood-onset episodic leukoencephalopathy with neuroimaging findings of cavitating periventricular and subcortical white matter loss. We describe the heterogeneous clinical and neuroimaging profile of six individuals from south India with the specific homozygous pathogenic variant in the LYRM7 gene (c.2T>C, (p.Met1?)). This is a retrospective case series featuring six cases (four pediatric, one adult, and one adolescent-onset) with the pathogenic start loss LYRM7 variant. The spectrum of neurologic manifestations and brain imaging findings documented over multiple clinic visits was analyzed and described. Vision loss and lactic acidosis were seen in all but one individual. A novel phenotype with adult-onset isolated bilateral simultaneous optic neuropathy was noted. Characteristic cavitating leukoencephalopathy in supratentorial white matter was seen in the brain MRI of three out of six individuals. A comprehensive description of our cases along with the previously published cases is provided in the table highlighting the clinical and imaging variability and the disease course. The phenotype of adult-onset isolated acute optic neuropathy can be a manifestation of LYRM7-related mitochondrial disorder. LYRM7-associated Mitochondrial Complex III deficiency should be considered in the differential diagnosis of para- and post-infectious demyelinating/inflammatory disorders, especially if there is a background of variable developmental delay, recurrence of the episodes, family history, cystic changes in cerebral white matter on imaging, or poor response to immunomodulation. The case series also exemplifies the intra-and inter-familial variability seen with this rare disorder.

Keywords:  LYRM7 gene; leukoencephalopathy; mitochondrial complex III deficiency; optic atrophy; start‐loss variant

DOI:  https://doi.org/10.1002/ajmg.a.64105
iScience. 2025 May 16. 28(5): 112390

Agent-based modeling of neuronal mitochondrial dynamics using intrinsic variables of individual mitochondria.

Garrett M Fogo, Francisco J Torres Torres, Reagan L Speas, Anthony R Anzell, Thomas H Sanderson.

  Mitochondrial networks undergo remodeling to regulate form and function. The dynamic nature of mitochondria is maintained by the dueling processes of mitochondrial fission and fusion. Dysfunctional mitochondrial dynamics have been linked to debilitating diseases and injuries, suggesting mitochondrial dynamics as a promising therapeutic target. Increasing our understanding of the factors influencing mitochondrial dynamics will help inform therapeutic development. Utilizing live imaging of primary neurons, we analyzed how intrinsic properties of individual mitochondria influence their behavior. We found that size, shape, mitochondrial membrane potential, and protein oxidation predict mitochondrial fission and fusion. We constructed an agent-based model of mitochondrial dynamics, the mitochondrial dynamics simulation (MiDyS). In silico experiments of neuronal ischemia/reperfusion injury and antioxidant treatment illustrate the utility of MiDyS for testing hypothesized mechanisms of injury progression and evaluating therapeutic strategies. We present MiDyS as a framework for leveraging in silico experimentation to inform and improve the design of therapeutic trials.

Keywords:  Cell biology; Molecular biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2025.112390
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
Nat Commun. 2025 May 08. 16(1): 4266

A nuclear-encoded endonuclease governs the paternal transmission of mitochondria in Cucumis plants.

Jia Shen, Xiaolong Lyu, Xinyang Xu, Zheng Wang, Yuejian Zhang, Chenhao Wang, Eduardo D Munaiz, Mingfang Zhang, Michael J Havey, Weisong Shou.

Non-Mendelian transmission of mitochondria has been well established across most eukaryotes, however the genetic mechanism that governs this uniparental inheritance remains unclear. Plants in the genus Cucumis, specifically melon and cucumber, exhibit paternal transmission of the mitochondrial (mt) DNA, making them excellent models for exploring the molecular mechanisms underlying mitochondrial transmission. Here, we develop a toolkit to screen for mutants in mitochondrial inheritance (mti), and use fine mapping to successfully identify a mitochondrially targeted endonuclease gene (MTI1) controlling mitochondrial transmission. Knockout of MTI1 results in a shift from paternal to bi-parental inheritance of the mtDNA, confirming the crucial role of MTI1 in uniparental inheritance of mitochondria. Moreover, we demonstrate that MTI1 exhibits robust endonuclease activity both in vitro and in vivo, specifically expresses in mitochondria of the fertilized ovule within 24 h of pollination. Collectively, this study reveals that a nuclear-encoded but mitochondria-targeted gene plays a causative role in governing the non-Mendelian mitochondrial inheritance, revolutionizing our knowledge about mitochondrial DNA transmission.

DOI: https://doi.org/10.1038/s41467-025-59568-7
Curr Cardiol Rev. 2025 May 06.

Mitochondrial Dysfunction in Cardiac Diseases: Insights into Pathophysiology and Clinical Outcomes.

Syed Shadab Ahmad, Javed Akhtar Ansari, Tarique Mahmood Ansari, Syed Mehdi Hasan Zaidi.

  Mitochondrial dysfunction plays a crucial role in the pathogenesis of various cardiac diseases, including heart failure, ischemic cardiomyopathy, and drug-induced cardiotoxicity. Mitochondria are essential for cellular energy production, calcium homeostasis, redox balance, and apoptotic regulation, making their proper function vital for cardiac health. Dysfunctional mitochondria contribute to excessive reactive oxygen species (ROS) production, impaired ATP synthesis, and disruption of mitochondrial dynamics, leading to cardiomyocyte damage and cell death. Emerging research highlights mitochondrial dynamics, including fission, fusion, mitophagy, and biogenesis, as critical determinants of cardiac homeostasis. Perturbations in these processes exacerbate myocardial injury and heart failure progression. Additionally, chemotherapy-induced cardiotoxicity, primarily from anthracyclines, is closely linked to mitochondrial damage, underscoring the need for targeted therapeutic strategies. Pharmacological interventions, such as antioxidants, mitochondrial-targeted drugs, and cardioprotective agents, have shown promise in mitigating mitochondrial dysfunction-related cardiac toxicity. Furthermore, lifestyle modifications, including exercise and dietary interventions, are being explored to enhance mitochondrial resilience in cardiac tissues. Advanced imaging techniques and biomarker-based diagnostics are improving the early detection of mitochondrial dysfunction in cardiac diseases. Emerging therapeutic strategies, such as mitochondrial transplantation, gene therapy, and precision medicine approaches, hold potential for targeted intervention. Despite these advances, challenges remain in translating mitochondrial-targeted therapies into clinical practice due to complexities in mitochondrial regulation and inter-organ communication. Future research should focus on optimizing mitochondrial-targeted interventions, improving diagnostic precision, and exploring novel molecular pathways to mitigate cardiac mitochondrial dysfunction. A comprehensive understanding of mitochondrial pathophysiology in cardiac diseases will pave the way for innovative treatment strategies aimed at preserving cardiac function and reducing the burden of heart failure.

Keywords:  Mitochondrial dysfunction; cardiac toxicity; cardiomyopathy; cardiovascular diseases; disease.; health

DOI:  https://doi.org/10.2174/011573403X379197250417061904
ACS Sens. 2025 May 09.

Ratiometric Covalent Fluorescent Probes for Dynamic Super-Resolution Imaging of Mitochondrial HClO.

Xiangpeng Lin, Meng Zhang, Huimin Feng, Yunfei Wei, Xinxin Duan, Peng Xu, Yu-Hui Zhang.

  Dynamic monitoring of hypochlorous acid (HClO) in mitochondria is crucial for elucidating the molecular pathogenesis of ferroptosis-related diseases. Super-resolution microscopy, which surpasses the optical diffraction limit, has emerged as a powerful tool for subcellular dynamic imaging. However, the lack of mitochondrial HClO fluorescent probes with high specificity, stable labeling, low environmental interference, and negligible spectral crosstalk presents a significant challenge for achieving dynamic super-resolution imaging. Here, we designed and screened a series of HClO fluorescent probes, ultimately obtaining a novel HClO probe, YM-P. The combination of a triphenylphosphine group and a chloroacetyl chloride group enables YM-P to achieve specific, covalent mitochondrial labeling, thereby overcoming off-target labeling during ferroptosis. The ratiometric fluorescence response of YM-P to HClO and its detection limit of as low as 35 nM allow it to resist interferences from environmental factors and ensure accurate detection of HClO. The ultralarge Stokes shift of 210 nm exhibited by YM-P also minimizes spectral crosstalk. Using YM-P, we achieved dynamic super-resolution imaging of mitochondrial HClO during ferroptosis. Notably, we observed for the first time that changes in mitochondrial cristae numbers precede alterations in HClO concentration, with an initial increase followed by a decrease, suggesting that mitochondrial cristae are more sensitive to the occurrence of ferroptosis than HClO concentration. This study provides a robust tool for dynamic monitoring of mitochondrial HClO during ferroptosis, as well as potential support for other mitochondrial HClO-related processes.

Keywords:  HClO fluorescent probe; dynamic detection; ferroptosis; mitochondrial covalent labeling; super-resolution imaging

DOI:  https://doi.org/10.1021/acssensors.5c00640
FEBS J. 2025 May 09.

Msp1 and Pex19-Pex3 cooperate to achieve correct localization of Pex15 to peroxisomes.

Shunsuke Matsumoto, Yoshiki Kogure, Suzuka Ono, Tomoyuki Numata, Toshiya Endo.

  Yeast Msp1 is a dual-localized AAA-ATPase on the mitochondrial outer membrane (OM) and peroxisomal membrane. We previously showed that Msp1 transfers mistargeted tail-anchored (TA) proteins from mitochondria to the endoplasmic reticulum (ER) for degradation or delivery to their original destinations. However, the mechanism by which Msp1 in mitochondria and peroxisomes handles authentic peroxisomal TA proteins remains unclear. We show that newly synthesized Pex15 is targeted to peroxisomes primarily via the Pex19- and Pex3-dependent pathway. Mistargeted Pex15 on the mitochondrial OM is extracted by mitochondrial Msp1 and transferred to the ER via the guided-entry of TA proteins pathway for degradation or to peroxisomes via the Pex19-Pex3 pathway. Intriguingly, endogenous Pex15 localized in peroxisomes is also extracted from the membranes by peroxisomal Msp1 but returns to peroxisomes via the Pex19-Pex3 pathway. These results suggest that correct Pex15 localization to peroxisomes relies on not only the initial targeting by Pex19-Pex3 but also the constant re-routing by Msp1 and Pex19-Pex3.

Keywords:  Msp1; Pex15; Pex19‐Pex3; mitochondria; peroxisome

DOI:  https://doi.org/10.1111/febs.70132
Bioessays. 2025 May 04. e70016

Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases.

Seiji Watanabe, Koji Yamanaka.

  Recent evidence indicates that the mitochondria-endoplasmic reticulum (ER) contact site is a novel microdomain essential for cellular homeostasis. Various proteins are accumulated at the mitochondria-associated membrane (MAM), an ER subcomponent closely associated with the mitochondria, contributing to Ca2+ transfer to the mitochondria, lipid synthesis, mitochondrial fission/fusion, and autophagy. These functions are disrupted in the diseases, particularly in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In this review, we summarize the disruption of protein homeostasis in various neurodegenerative diseases, present recent works on the mechanisms of MAM aberration, including ours mainly focused on ALS, and then discuss challenges and prospects for future MAM-targeted therapies in neurodegenerative diseases.

Keywords:  mitochondria‐associated membranes; neurodegenerative diseases; protein homeostasis

DOI:  https://doi.org/10.1002/bies.70016
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
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
Cell Rep Med. 2025 May 02. pii: S2666-3791(25)00189-2. [Epub ahead of print] 102116

Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males.

Zhenqi Zhou, Timothy M Moore, Alexander R Strumwasser, Vicent Ribas, Hirotaka Iwasaki, Noelle Morrow, Alice Ma, Peter H Tran, Jonathan Wanagat, Thomas Q de Aguiar Vallim, Bethan Clifford, Zhengyi Zhang, Tamer Sallam, Brian W Parks, Karen Reue, Orian Shirihai, Rebeca Acin-Perez, Marco Morselli, Matteo Pellegrini, Sushil K Mahata, Frode Norheim, Mingqi Zhou, Marcus M Seldin, Aldons J Lusis, Cathy C Lee, Mark O Goodarzi, Jerome I Rotter, Joshua R Hansen, Ben Drucker, Tyler J Sagendorf, Joshua N Adkins, James A Sanford, Francesco J DeMayo, Sylvia C Hewitt, Kenneth S Korach, Andrea L Hevener.

  Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood, especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor α [ERα]) is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain-of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in the skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.

Keywords:  estrogen action; exercise adaptation; insulin sensitivity; mitochondrial cristae architecture; mitochondrial function; mtDNA replication; oxidative metabolism

DOI:  https://doi.org/10.1016/j.xcrm.2025.102116
Autophagy. 2025 May 06. 1-3

SNX10 at the crossroad of endocytosis and piecemeal mitophagy.

Laura Trachsel-Moncho, Benan John Mathai, Chiara Veroni, Anne Simonsen.

  Mitophagy targets damaged or dysfunctional mitochondria for lysosomal degradation. While canonical mitophagy pathways target the whole mitochondria for lysosomal degradation, it has become clear that selected mitochondrial components can be targeted for lysosomal degradation via other pathways, such as piecemeal mitophagy or mitochondria-derived vesicles. In a recent study, we identified the PX domain-containing endosomal protein SNX10 as a negative modulator of piecemeal mitophagy. Endosomal SNX10-positive vesicles dynamically interact with mitochondria and acquire selected mitochondrial proteins upon hypoxia. Zebrafish larvae lacking Snx10 show elevated Cox-IV degradation, increased levels of reactive oxygen species (ROS), and ROS-dependent neuronal death.

Keywords:  SNX10; endosomal sorting; mitophagy; oxidative stress; zebrafish

DOI:  https://doi.org/10.1080/15548627.2025.2499641
Int J Mol Sci. 2025 Apr 11. pii: 3624. [Epub ahead of print]26(8):

The Role of N6-Methyladenosine in Mitochondrial Dysfunction and Pathology.

Wenxin Yan, Saqirile, Ke Li, Kexin Li, Changshan Wang.

  Mitochondria are indispensable in cells and play crucial roles in maintaining cellular homeostasis, energy production, and regulating cell death. Mitochondrial dysfunction has various manifestations, causing different diseases by affecting the diverse functions of mitochondria in the body. Previous studies have mainly focused on mitochondrial-related diseases caused by nuclear gene mutations or mitochondrial gene mutations, or mitochondrial dysfunction resulting from epigenetic regulation, such as DNA and histone modification. In recent years, as a popular research area, m6A has been involved in a variety of important processes under physiological and pathological conditions. However, there are few summaries on how RNA methylation, especially m6A RNA methylation, affects mitochondrial function. Additionally, the role of m6A in pathology through influencing mitochondrial function may provide us with a new perspective on disease treatment. In this review, we summarize several manifestations of mitochondrial dysfunction and compile examples from recent years of how m6A affects mitochondrial function and its role in some diseases.

Keywords:  N6-methydenosine; cancer; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/ijms26083624
Adv Sci (Weinh). 2025 May 08. e2503579

Neuronal FGF13 Inhibits Mitochondria-Derived Damage Signals to Prevent Neuroinflammation and Neurodegeneration in a Mouse Model of Parkinson's Disease.

Nanshan Song, Xiangxu Wang, Luqing Ha, Lamei Hu, Shuyuan Mei, Yue Liang, Yujie Zhao, Xingyin Yang, Qingyu Zhang, Yuanzhang Zhou, Jianhua Ding, Yan Liu, Qigang Zhou, Feng Han, Gang Hu, Ming Lu.

  Fibroblast growth factor homologous factors (FHFs) are highly expressed in the central nervous system (CNS). It is demonstrated that the FHFs subfamily plays cardinal roles in several neuropathological diseases, while their involvement in Parkinson's disease (PD) has been so far scarcely investigated. From the publicly available Gene Expression Omnibus (GEO) datasets, FHF2 (also known as fibroblast growth factor 13, FGF13) alterations are described in PD patients. Fgf13 gene is significantly decreased in several PD mouse models, and its overexpression alleviates the PD-like pathological phenotype. Although FGF13 is highly expressed in neurons, it functions by preventing glia-dependent inflammatory processes. Mechanistically, FGF13 combines mitochondrial proteins such as MCHT2 (a protein localized on the mitochondrial outer membrane), to anchor mitochondria within the cytoplasm. Under PD-related stress, decreased neuronal FGF13 levels induce the release of the damaged mitochondria, which in turn activate microglia and astrocytes, thereby promoting neurodegeneration. Abacavir, an FDA-applied anti-retroviral drug, is identified to prevent excessive gliosis and neuron loss in both glia-neuron co-cultures and PD mouse models by rejuvenating FGF13 signaling. Collectively, neuronal FGF13 inhibits the transfer of stressed mitochondria to glia, thereby impeding neuroinflammation and neurodegeneration. Abacavir is a promising neuroprotectant and sets a brake to PD progression.

Keywords:  FGF13; MTCH2; mitochondrial transfer; neuroinflammation; parkinson's disease

DOI:  https://doi.org/10.1002/advs.202503579
PLoS One. 2025 ;20(5): e0323136

Small-scale protocols to characterize mitochondrial Complex V activity and assembly in peripheral blood mononuclear cells.

Kai-Yin Chau, Jan-Willem Taanman, Anthony H V Schapira.

Complex V of the mitochondrial oxidative phosphorylation system is an ATP synthase that plays a pivotal role in the cell's energy transduction. Mutations in genes encoding the multiple protein subunits that constitute complex V cause severe metabolic and neurodegenerative diseases. We present here three complementary assays to assess Complex V activity and assembly in peripheral blood mononuclear cells (PBMCs). The assays involve spectrophotometric and in-gel activity measurements, cytochemical assessment of the mitochondrial transmembrane electrochemical gradient (∆Ѱm) to determine if the enzyme acts forward as an ATP synthase or in reverse as an ATPase, and western blot analysis of clear native gels to evaluate Complex V assembly. The whole process can be performed with 2 × 106 PBMCs isolated from ~2 ml of blood. Our study suggests that PBMCs can serve as a platform for small-scale, minimally invasive investigations of patients suspected of Complex V deficiency or in biomarker research of mitochondrial function.

DOI: https://doi.org/10.1371/journal.pone.0323136
Nat Aging. 2025 May 09.

Stem cell therapies for Parkinson's disease.

Yahyah Aman.

DOI: https://doi.org/10.1038/s43587-025-00885-3
J Physiol. 2025 May 05.

NAD replenishment restores mitochondrial function and thermogenesis in the brown adipose tissue of mice with obesity.

Renata R Braga, Matheus B Rocha, Ana P Morelli, Raul G da Costa, Marcelo A S Mori, Adelino S R da Silva, José R Pauli, Dennys E Cintra, Eduardo R Ropelle.

  Brown adipose tissue (BAT) is a highly specialized thermogenic tissue and plays a critical role in controlling energy expenditure and metabolic homeostasis. BAT dysfunction is associated with body weight gain and metabolic disorders in mice models. Here, we investigated the influence of the NAD-biosynthesis pathway in the control of BAT metabolism and function. Using a wide multi-omics and phenotypic panel of isogenic strains of BXD mice, we found that the NAD-biosynthesis pathway in BAT is closely associated with body weight gain, adiposity, insulin resistance, oxygen consumption, exercise capacity and mitochondrial metabolism. Interestingly, the high-fat diet (HFD) treatment disrupted the NAD-biosynthesis pathway, reducing Nampt and NMNat3 protein contents and inducing severe mitochondrial dysfunction in BAT of mice. Finally, the oral treatment with nicotinamide riboside (NR), an NAD+ precursor, significantly boosted NAD+ levels and preserved the morphofunctional mitochondria aspects of mitochondria, and the thermogenesis capacity of BAT in HFD-fed mice. These data point to the NAD synthesis pathway as a promising therapeutic adjuvant target in body thermogenesis management. KEY POINTS: Obesity impairs the NAD+ biosynthesis pathway, leading to mitochondrial dysfunction and reduced thermogenic capacity. NAD+ metabolism enzymes Nampt and NMNat3 are crucial for mitochondrial function in BAT. Nicotinamide riboside treatment increases the expression of key thermogenic proteins and NAD+-related enzymes in BAT, optimizing adaptive thermogenesis and mitochondria function.

Keywords:  BAT; NAD; mitochondria; obesity

DOI:  https://doi.org/10.1113/JP288453
Dis Model Mech. 2025 May 06. pii: dmm.052077. [Epub ahead of print]

A murine model of Barth syndrome with cardiac and skeletal muscle selective inactivation of tafazzin.

Erika Yazawa, Erin M Keating, Suya Wang, Mason E Sweat, Qing Ma, Yang Xu, Michael Schlame, William T Pu.

  Barth syndrome is a mitochondrial disorder with hallmarks of cardiac and skeletal muscle weakness. Barth syndrome is caused by mutation of the X-linked gene Taz, required for cardiolipin remodeling. Previously described germline and conditional Taz knockout models are not ideal for therapeutic development because they lack the combination of robust survival to adulthood, cardiomyopathy, and skeletal muscle weakness. We characterized a cardiac and skeletal muscle-specific Taz knockout model (TazmKO) in which Cre recombinase is expressed from the muscle creatine kinase promoter (mCK-Cre). TazmKO mice survived normally. Cardiolipin composition was abnormal in both heart and skeletal muscle. TazmKO had reduced heart function by 2 months of age, and function progressively declined thereafter. Reduced treadmill endurance and diminished peak oxygen consumption were evident by three months of age, suggesting reduced skeletal muscle function. Electron microscopy showed abnormalities in mitochondrial structure and distribution. Overall, TazmKO mice display diminished cardiac function and exercise capacity while maintaining normal survival. This model will be useful for studying the effects of Taz deficiency in striated muscles and for testing potential therapies for Barth Syndrome.

Keywords:  Barth syndrome; Cardiomyopathy; Skeletal myopathy; Tafazzin

DOI:  https://doi.org/10.1242/dmm.052077
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
Nat Biotechnol. 2025 May 07.

Evolution-guided protein design of IscB for persistent epigenome editing in vivo.

Soumya Kannan, Han Altae-Tran, Shiyou Zhu, Peiyu Xu, Daniel Strebinger, Rachel Oshiro, Guilhem Faure, Lukas Moeller, Julie Pham, Kepler S Mears, Heyuan M Ni, Rhiannon K Macrae, Feng Zhang.

Naturally existing enzymes have been adapted for a variety of molecular technologies, with enhancements or modifications to the enzymes introduced to improve the desired function; however, it is difficult to engineer variants with enhanced activity while maintaining specificity. Here we engineer the compact Obligate Mobile Element Guided Activity (OMEGA) RNA-guided endonuclease IscB and its guiding RNA (ωRNA) by combining ortholog screening, structure-guided protein domain design and RNA engineering, and deep learning-based structure prediction to generate an improved variant, NovaIscB. We show that the compact NovaIscB achieves up to 40% indel activity (~100-fold improvement over wild-type OgeuIscB) on the human genome with improved specificity relative to existing IscBs. We further show that NovaIscB can be fused with a methyltransferase to create a programmable transcriptional repressor, OMEGAoff, that is compact enough to be packaged in a single adeno-associated virus vector for persistent in vivo gene repression. This study highlights the power of combining natural diversity with protein engineering to design enhanced enzymes for molecular biology applications.

DOI: https://doi.org/10.1038/s41587-025-02655-3
Mol Cell. 2025 Apr 30. pii: S1097-2765(25)00361-2. [Epub ahead of print]

DNA methyltransferase 1 modulates mitochondrial function through bridging m5C RNA methylation.

Jing Wang, Xiaoqian Deng, Tianshen Jian, Shanshan Yin, Linzhi Chen, Laurent Vergnes, Zhehao Li, Huoyuan Liu, Ryan Lee, Sin Yee Lim, Jae Hoon Bahn, Xinshu Xiao, Xianmin Zhu, Ganlu Hu, Karen Reue, Yizhi Liu, Guoping Fan.

  DNA methyltransferase 1 (DNMT1) is an enzyme known for DNA methylation maintenance. Point mutations in its replication focus targeting sequence (RFTS) domain lead to late-onset neurodegeneration, such as autosomal dominant cerebellar ataxia-deafness and narcolepsy (ADCA-DN) disorder. Here, we demonstrated that DNMT1 has the capability to bind to mRNA transcripts and facilitate 5-methylcytosine (m5C) RNA methylation by recruiting NOP2/Sun RNA methyltransferase 2 (NSUN2). RNA m5C methylation, in turn, promotes RNA stability for those genes modulating mitochondrial function. When the DNMT1 RFTS domain is mutated in mice, it triggers aberrant DNMT1-RNA interaction and significantly elevated m5C RNA methylation and RNA stability for a portion of metabolic genes. Consequently, increased levels of metabolic RNA transcripts contribute to cumulative oxidative stress, mitochondrial dysfunction, and neurological symptoms. Collectively, our results reveal a dual role of DNMT1 in regulating both DNA and RNA methylation, which further modulates mitochondrial function, shedding light on the pathogenic mechanism of DNMT1 mutation-induced neurodegeneration.

Keywords:  DNA methylation; DNMT1; RNA methylation; mitochondrial dysfunction; neurodegeneration

DOI:  https://doi.org/10.1016/j.molcel.2025.04.019
Nat Commun. 2025 May 04. 16(1): 4151

Design of diverse, functional mitochondrial targeting sequences across eukaryotic organisms using variational autoencoder.

Aashutosh Girish Boob, Shih-I Tan, Airah Zaidi, Nilmani Singh, Xueyi Xue, Shuaizhen Zhou, Teresa A Martin, Li-Qing Chen, Huimin Zhao.

Mitochondria play a key role in energy production and metabolism, making them a promising target for metabolic engineering and disease treatment. However, despite the known influence of passenger proteins on localization efficiency, only a few protein-localization tags have been characterized for mitochondrial targeting. To address this limitation, we leverage a Variational Autoencoder to design novel mitochondrial targeting sequences. In silico analysis reveals that a high fraction of the generated peptides (90.14%) are functional and possess features important for mitochondrial targeting. We characterize artificial peptides in four eukaryotic organisms and, as a proof-of-concept, demonstrate their utility in increasing 3-hydroxypropionic acid titers through pathway compartmentalization and improving 5-aminolevulinate synthase delivery by 1.62-fold and 4.76-fold, respectively. Moreover, we employ latent space interpolation to shed light on the evolutionary origins of dual-targeting sequences. Overall, our work demonstrates the potential of generative artificial intelligence for both fundamental research and practical applications in mitochondrial biology.

DOI: https://doi.org/10.1038/s41467-025-59499-3
Nat Genet. 2025 May 07.

Toward clinical long-read genome sequencing for rare diseases.

Jesper Eisfeldt, Marlene Ek, Magnus Nordenskjöld, Anna Lindstrand.

Genetic diagnostics is driven by technological advances, forming a tight interface between research, clinic and industry, which enables rapid implementation of new technologies. Short-read genome and exome sequencing, the current state of the art in clinical genetics, can detect a broad spectrum of genetic variants across the genome. However, despite these advancements, more than half of individuals with rare diseases remain undiagnosed after genomic investigations. Long-read whole-genome sequencing (LR-WGS) is a promising technology that identifies previously difficult-to-detect variants while also enabling phasing and methylation analysis and has the potential of generating complete personal assemblies. To pave the way for clinical use of LR-WGS, the clinical genomic community must establish standardized protocols and quality parameters while also developing innovative tools for data analysis and interpretation. In this Perspective, we explore the key challenges and benefits in integrating LR-WGS into routine clinical diagnostics.

DOI: https://doi.org/10.1038/s41588-025-02160-y
Genome Med. 2025 May 07. 17(1): 47

Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variants.

Maria Gridina, Timofey Lagunov, Polina Belokopytova, Nikita Torgunakov, Miroslav Nuriddinov, Artem Nurislamov, Lyudmila P Nazarenko, Anna A Kashevarova, Maria E Lopatkina, Stanislav Vasilyev, Andrey Zuev, Elena O Belyaeva, Olga A Salyukova, Aleksandr D Cheremnykh, Natalia N Sukhanova, Marina E Minzhenkova, Zhanna G Markova, Nina A Demina, Yana Stepanchuk, Anna Khabarova, Alexandra Yan, Emil Valeev, Galina Koksharova, Elena V Grigor'eva, Natalia Kokh, Tatiana Lukjanova, Yulia Maximova, Elizaveta Musatova, Elena Shabanova, Andrey Kechin, Evgeniy Khrapov, Uliana Boyarskih, Oxana Ryzhkova, Maria Suntsova, Alina Matrosova, Mikhail Karoli, Andrey Manakhov, Maxim Filipenko, Evgeny Rogaev, Nadezhda V Shilova, Igor N Lebedev, Veniamin Fishman.

BACKGROUND: Effective molecular diagnosis of congenital diseases hinges on comprehensive genomic analysis, traditionally reliant on various methodologies specific to each variant type-whole exome or genome sequencing for single nucleotide variants (SNVs), array CGH for copy-number variants (CNVs), and microscopy for structural variants (SVs).
METHODS: We introduce a novel, integrative approach combining exome sequencing with chromosome conformation capture, termed Exo-C. This method enables the concurrent identification of SNVs in clinically relevant genes and SVs across the genome and allows analysis of heterozygous and mosaic carriers. Enhanced with targeted long-read sequencing, Exo-C evolves into a cost-efficient solution capable of resolving complex SVs at base-pair accuracy.
RESULTS: Applied to 66 human samples Exo-C achieved 100% recall and 73% precision in detecting chromosomal translocations and SNVs. We further benchmarked its performance for inversions and CNVs and demonstrated its utility in detecting mosaic SVs and resolving diagnostically challenging cases.
CONCLUSIONS: Through several case studies, we demonstrate how Exo-C's multifaceted application can effectively uncover diverse causative variants and elucidate disease mechanisms in patients with rare disorders.

DOI: https://doi.org/10.1186/s13073-025-01471-3