bims-mitdis 2025-08-24 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2025–08–24
forty papers selected by
Catalina Vasilescu, Helmholz Munich

High tide or low tide: the transport and metabolism of mitochondrial nucleotides.
Mitochondrial transplants make healthy babies.
Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.
The mitochondrial trans-2-enoyl-coA reductase is necessary for mitochondrial homeostasis in C. elegans.
Loss of Drosophila ribosomal protein S6 kinase II causes mitochondrial dysfunction and cell death.
Canonical and alternate mechanisms that regulate ubiquitylation by the E3 ligase parkin.
Early-Onset Sensorimotor Axonal Neuropathy as Sole Manifestation of HADHA-Related Disorder/ Mitochondrial Trifunctional Protein Defect.
Mitochondrial Quality Control in Health and Disease.
Mitochondrial genome copy number variation across tissues in mice and humans.
Community-Driven Copy Number Variant Discovery at Scale: Results from a Rare Disease Genomics Hackathon.
Novel Compound Heterozygous Missense Variants in RPL3L Gene Associated With Neonatal Dilated Cardiomyopathy.
Significance of Mitochondrial Dynamics in Reproductive Physiology: Current and Emerging Horizons in Mitochondrial Therapy for Assisted Reproductive Technologies.
Mitochondrial hyper-acetylation induced by an engineered acetyltransferase promotes cellular senescence.
Mitochondrial protection role of oxidoreductase-like domain containing 1 in myocardial cells under hypoxia.
Low-frequency genetic variants in GAK enhance Golgi function and protect against Parkinson's disease.
Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.
Reasonable Design of Near-Infrared Boron Dipyrromethene with Cationic Pyridinium for Super-Resolution Imaging of Dynamic Voltages of Mitochondria in Living Cells.
A robust method for assessing mitochondrial function in healthy and diseased frozen cardiac tissue.
Patent highlights December 2023-January 2024.
Amphipathic Proline-Rich Cell Penetrating Peptides for Targeting Mitochondria.
Dehydration promotes intracellular lipid synthesis and accumulation.
Progress in stem cells mitochondrial proteomics research: A review.
Diagnosing Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Syndrome in a Young Adult Female Patient With Seizures and Lactic Acidosis.
The mevalonate pathway couples lipid metabolism to amino acid synthesis via ubiquinone-dependent redox control.
Gene editing enables islet transplantation without immunosuppression.
Beyond AlphaFold: how AI is decoding the grammar of the genome.
High-resolution quantification of metabolic heat output from individual live Drosophila brains.
Mitochondria as a Therapeutic Target in Neurodegeneration: Strategies for Restoring Cellular Homeostasis.
Functional evidence for G6PD variant classification from mutational scanning.
Novel Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors for the Treatment of Parkinson's Disease.
Unconventional myosin VI is involved in regulation of muscle energy metabolism.
The effect of rotenone contamination on high-resolution mitochondrial respiration experiments.
Mitochondrial neurogastrointestinal encephalomyopathy in china: a novel TYMP variant and comprehensive clinical-genetic insights.
Ataxia and oculomotor apraxia caused by a large-scale deletion in the senataxin gene.
Redefining druggable targets with artificial intelligence.
Spatiotemporally Traceable Peptide Self-Assemblies for Mitochondrial-Specific Dysfunction.
Delivering the Message: Translating mRNA Therapy for Liver Inherited Metabolic Diseases.
FUNDC1-dependent mitochondrial-ER membranes mediate mitochondrial dysfunction and melanocyte damage under oxidative stress.
Cyanide overproduction impairs cellular bioenergetics in Down syndrome.
A baby benefits from personalized gene editing in the clinic.

Biochem J. 2025 Aug 18. pii: BCJ20253237. [Epub ahead of print]482(16):

High tide or low tide: the transport and metabolism of mitochondrial nucleotides.

Thomas MacVicar.

  Mitochondria are multifaceted organelles that support numerous cellular metabolic pathways, including the biosynthesis of nucleotides required for cell growth and proliferation. Owing to an ancient endosymbiotic origin, mitochondria contain multiple copies of their own genome and therefore demand sufficient (deoxy)nucleotides in the mitochondrial matrix for DNA replication and transcription into RNA. Disturbed mitochondrial deoxynucleotide homeostasis can lead to a decline in mitochondrial DNA abundance and integrity, causing mitochondrial diseases with diverse and severe symptoms. Mitochondrial nucleotides are not only required for nucleic acid synthesis but also for bioenergetics and mitochondrial enzymatic activity. This review first explores how mitochondria supply energy and anabolic precursors for nucleotide synthesis and how the mitochondrial network influences the spatial control of cellular nucleotide metabolism. Then follows an in-depth discussion of the mechanisms that supply mitochondria with sufficient and balanced nucleotides and why these mechanisms are relevant to human mitochondrial disease. Lastly, the review highlights the emergence of regulated mitochondrial nucleotide supply in physiological processes including innate immunity and discusses the implications of dysregulated mitochondrial and cytosolic nucleotide homeostasis in pathophysiology.

Keywords:  metabolism; mitochondria; mitochondrial disease; nucleotide salvage; nucleotide transport; nucleotides

DOI:  https://doi.org/10.1042/10.1042/BCJ20253237
Nat Biotechnol. 2025 Aug 19.

Mitochondrial transplants make healthy babies.

Laura DeFrancesco.

DOI: https://doi.org/10.1038/s41587-025-02799-2
Brain. 2025 Aug 20. pii: awaf300. [Epub ahead of print]

Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.

Camila Armirola-Ricaurte, Laura Morant, Isabelle Adant, Sherifa Ahmed Hamed, Menelaos Pipis, Stephanie Efthymiou, Silvia Amor-Barris, Derek Atkinson, Liedewei Van de Vondel, Aleksandra Tomic, Sara Seneca, Els de Vriendt, Stephan Zuchner, Bart Ghesquiere, Michael Hanna, Henry Houlden, Michael P Lunn, Mary M Reilly, Vedrana Milic Rasic, Albena Jordanova.

  Defects in mitochondrial dynamics are a common cause of Charcot-Marie-Tooth disease (CMT), while primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this etiology. This study aims to report COX18 as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV (CIV) that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane. Exome sequencing was performed in four affected individuals from three families. The patients and available family members underwent thorough neurological and electrophysiological assessment. The impact of one of the identified variants on splicing, protein levels, and mitochondrial bioenergetics was investigated in patient-derived lymphoblasts. The functionality of the mutant protein was assessed using a Proteinase K protection assay and immunoblotting. Neuronal relevance of COX18 was assessed in a Drosophila melanogaster knockdown model. Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G in COX18 in two siblings with early-onset progressive axonal sensory-motor peripheral neuropathy. By querying external databases, we identified two additional families with rare deleterious biallelic variants in COX18. All eight affected individuals presented with axonal CMT and some patients also exhibited central nervous system symptoms, such as dystonia and spasticity. Functional characterization of the c.435-6A>G variant demonstrated that it leads to the expression of an alternative transcript that lacks exon 2, resulting in a stable but defective COX18 isoform. The mutant protein impairs CIV assembly and activity, leading to a reduction in mitochondrial membrane potential. Downregulation of the COX18 homolog in Drosophila melanogaster displayed signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons. Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without central nervous system involvement. These findings emphasize the significance of peripheral neuropathy within the spectrum of primary mitochondrial disorders and the role of mitochondrial CIV in the development of CMT. Our research has important implications for the diagnostic workup of CMT patients.

Keywords:  CMT; complex IV deficiency; cytochrome c oxidase assembly factor 18

DOI:  https://doi.org/10.1093/brain/awaf300
Genetics. 2025 Aug 19. pii: iyaf166. [Epub ahead of print]

The mitochondrial trans-2-enoyl-coA reductase is necessary for mitochondrial homeostasis in C. elegans.

Katherine Spilsbury, Jing Wu, Michael Reidy, Peter A Kropp.

  Fatty acids function not only as signaling molecules and for energy storage, but also as essential cofactors for mitochondrial enzymes. These fatty acid cofactors are produced by the mitochondrial fatty acid synthesis pathway (mtFAS), the terminal enzyme of which is mitochondrial trans-2-enoyl-coA reductase (MECR). Dysfunction of MECR prevents the synthesis of fatty acids and is the monogenic cause of MEPAN syndrome, a rare mitochondrial disease characterized by dystonia, basal ganglia degeneration, and optic nerve atrophy. Given the necessity of mtFAS products for mitochondrial function, MECR should be essential. Yet, evidence from MEPAN individuals and model organisms with MECR loss of function indicate that mitochondrial function is not as severely impaired as would be expected. However, many of these studies have been limited to single cells or cell types. To better understand the role of MECR and its products in a multicellular system, we used CRISPR/Cas9 to knock out its two orthologs in C. elegans, MECR-1 and MECR-2. We found that only MECR-1 is necessary for normal mitochondrial function, germline development, and neuromuscular function. We thus establish a model in which further studies of MECR/MECR-1 can clarify its biochemical, developmental, and physiological roles.

Keywords:   C. elegans ; MECR; Mitochondria; Mitochondrial trans-2-Enoyl-CoA Reductase; mtFAS

DOI:  https://doi.org/10.1093/genetics/iyaf166
Dis Model Mech. 2025 Aug 01. pii: dmm052374. [Epub ahead of print]18(8):

Loss of Drosophila ribosomal protein S6 kinase II causes mitochondrial dysfunction and cell death.

Ting Deng, Lajos Kalmar, Samantha Loh, Olivier E Pardo, L Miguel Martins.

  Mitochondria are dynamic organelles that are critical for energy production in high-demand tissues, such as the brain and muscle, with fusion and fission maintaining network integrity. The dysregulation of these processes underlies pathologies, such as neurodegenerative diseases. Ribosomal S6 kinases (RSK1-4) are effectors of extracellular signal-regulated kinases (ERKs), with roles in cell survival and metabolism. Here, we show that RSKs are essential for mitochondrial health. In human cells, siRNAs targeting any RSK isoform (RSK1-4) induced mitochondrial fragmentation and reduced viability. In Drosophila melanogaster, CRISPR-mediated loss of S6kII (the sole RSK orthologue) caused mitochondrial dysfunction and tissue degeneration in high-energy-demand organs, including the indirect flight muscle and brain, accompanied by autophagic activation. Notably, we rescued these defects by expressing human RSK4, underscoring functional conservation. Our findings establish RSKs as critical regulators of mitochondrial integrity, linking ERK signalling to organelle dynamics. This work identifies RSKs as regulators of mitochondrial health in energy-demanding tissues, providing insights into the mechanisms underlying neurodegeneration and strategies to target ERK/RSK-driven mitochondrial dysfunction.

Keywords:   Drosophila ; Cell death; Kinase; Mitochondria

DOI:  https://doi.org/10.1242/dmm.052374
Biochem Soc Trans. 2025 Aug 18. pii: BST20253050. [Epub ahead of print]

Canonical and alternate mechanisms that regulate ubiquitylation by the E3 ligase parkin.

Nicoletta T Basilone, Viveka M Pimenta, Gary S Shaw.

  Parkin, a Ring-InBetweenRING-Rcat E3 ubiquitin ligase, plays a vital role in the clearance of damaged mitochondria (mitophagy) by ubiquitylating a broad spectrum of mitochondrial proteins. Mutations in the PRKN gene alter parkin ubiquitylation activity and are a leading cause of early-onset Parkinsonism, underlining its critical function in maintaining mitochondrial homeostasis. The structures, substrates, and ubiquitylation mechanisms used by parkin in mitophagy are well established. Yet, early studies as well as more recent proteomics studies identify alternative substrates that reside in the cytosol or other cellular compartments, suggesting potential roles for parkin beyond mitophagy. In addition to its well-documented activation via S65 phosphorylation, numerous other post-translational modifications (PTMs) have been identified in parkin. Some of these modifications have the potential to serve key regulatory mechanisms, perhaps fine-tuning parkin activity or potentially signaling the involvement in alternative cellular pathways beyond mitochondrial quality control. This review examines the canonical mechanism of parkin-mediated ubiquitylation while also exploring alternative regulatory influences that may modulate its enzyme activity. By analyzing emerging evidence on PTMs including phosphorylation, acetylation, ubiquitylation, oxidation, and interaction with alternative activating molecules, we highlight the broader functional landscape of parkin and its implications for cellular stress response.

Keywords:  Parkinson's disease; mitochondrial dysfunction; parkin; protein structure; ubiquitin ligases

DOI:  https://doi.org/10.1042/BST20253050
J Child Neurol. 2025 Aug 17. 8830738251356850

Early-Onset Sensorimotor Axonal Neuropathy as Sole Manifestation of HADHA-Related Disorder/ Mitochondrial Trifunctional Protein Defect.

Giulia Balletto, Giulia Barbagallo, Matteo Cataldi, Francesco Germano, Monica Traverso, Deborah Leuzzi, Marina Martinez Popple, Alessandro Geroldi, Fabio Gotta, Emilia Bellone, Marcello Scala, Federico Zara, Lino Nobili, Chiara Fiorillo.

  Pathogenic variants in the HADHA and HADHB genes are associated with impairment of mitochondrial trifunctional protein. Mitochondrial trifunctional protein deficiency is a disorder of long-chain fatty acid oxidation with different clinical presentations: the neonatal-onset form expressing with severe cardiac phenotype, the infantile-onset form with intermediate hepatic phenotype with metabolic crises, and the late-onset form with mild neuromyopathic phenotype. Long-term complications in patients with the intermediate and late-onset phenotypes include peripheral neuropathy and retinopathy. We report a patient harboring 2 compound heterozygous variants in the HADHA gene (p.Tyr724* and p.Gly319Ser) and presenting with an early-onset, progressive sensorimotor axonal polyneuropathy, without any other systemic manifestations typical of mitochondrial trifunctional protein deficiency. We also provide a literature review of HADHA mutated patients presenting with early-onset isolated neuropathy phenotype.

Keywords:  childhood; mitochondrial trifunctional protein; neuropathy

DOI:  https://doi.org/10.1177/08830738251356850
MedComm (2020). 2025 Aug;6(8): e70319

Mitochondrial Quality Control in Health and Disease.

Lin Ye, Xinzhi Fu, Qi Li.

  Mitochondria are central regulators of cellular energy metabolism, and their functional integrity is essential for maintaining cellular homeostasis. Mitochondrial quality control (MQC) encompasses a coordinated network of mitochondrial biogenesis, dynamics (fusion and fission), and selective autophagy (mitophagy), which together sustain mitochondrial structure and function. Under physiological conditions, MQC ensures the removal of dysfunctional mitochondria, restricts excessive reactive oxygen species production, and modulates apoptosis, thereby supporting the high energy demands of organs such as the heart and brain. Disruption of MQC contributes to the onset and progression of various diseases, including neurodegenerative disorders, cardiovascular pathologies, and metabolic syndromes, largely through accumulation of damaged mitochondria and impaired metabolic signaling. While the core components of MQC have been characterized, the mechanistic interplay among its modules and their disease-specific alterations remain incompletely defined. This review provides an integrated overview of the molecular pathways governing mitochondrial biogenesis, dynamics, and mitophagy, with a focus on their cross-talk in maintaining mitochondrial homeostasis. We further discuss how MQC dysfunction contributes to disease pathogenesis and examine emerging therapeutic approaches aimed at restoring mitochondrial quality. Understanding the regulatory logic of MQC not only elucidates fundamental principles of cellular stress adaptation but also informs novel strategies for disease intervention.

Keywords:  disease intervention; mitochondria; mitochondrial quality control; therapeutic strategies

DOI:  https://doi.org/10.1002/mco2.70319
Proc Natl Acad Sci U S A. 2024 Aug 13. 121(33): e2402291121

Mitochondrial genome copy number variation across tissues in mice and humans.

Sneha P Rath, Rahul Gupta, Ellen Todres, Hong Wang, Alexis A Jourdain, Kristin G Ardlie, Sarah E Calvo, Vamsi K Mootha.

  The mammalian mitochondrial genome (mtDNA) is multicopy and its copy number (mtCN) varies widely across tissues, in development and in disease. Here, we systematically catalog this variation by assaying mtCN in 52 human tissues across 952 donors (10,499 samples from the Genotype-Tissue Expression project) and 20 murine tissues using qPCR, capturing 50- and 200-fold variation, respectively. We also estimate per cell mtCN across 173 human cell lines from the Cancer Cell Line Encyclopedia using whole-genome sequencing data and observe >50-fold variation. We then leverage the vast amount of genomics data available for these repositories to credential our resource and uncover mtDNA-related biology. Using already existing proteomics data, we show that variation in mtCN can be predicted by variation in TFAM, histone, and mitochondrial ribosome protein abundance. We also integrate mtCN estimates with the CRISPR gene dependency measurements to find that cell lines with high mtCN are resistant to loss of GPX4, a glutathione phospholipid hydroperoxidase. Our resource captures variation in mtCN across mammalian tissues and should be broadly useful to the research community.

Keywords:  GPX4; TFAM; histone; mitochondrial ribosome; mtDNA

DOI:  https://doi.org/10.1073/pnas.2402291121
medRxiv. 2025 Aug 12. pii: 2025.08.08.25333317. [Epub ahead of print]

Community-Driven Copy Number Variant Discovery at Scale: Results from a Rare Disease Genomics Hackathon.

Ming Yin Lun, Jennifer E Posey, Jesse D Bengtsson, Haowei Du, Rituparna Sinha Roy, Lei Yang, Sebastian Ochoa, Bo Yuan, Maddie Gillentine, Anna Lindstrand, Claudia M B Carvalho.

Purpose: Copy number variants (CNVs) are a major contributor to rare genetic diseases, but their detection and interpretation from short-read genome sequencing (srGS) data remain challenging, especially at scale. Large amounts of existing srGS data remain under-analyzed for clinically relevant CNVs.
Methods: During a collaborative Hackathon, we developed and applied scalable CNV analysis workflows to srGS data from three unsolved, exome-negative, rare disease cohorts: Primary Immunodeficiency (N = 39), Turkish developmental disorders (N = 31), and data from the Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) (N = 1437). We employed Parliament2 for structural variant (SV) calling, Mosdepth and SLMSuite for read-depth-based quality control and CNV detection, and R Shiny-based visualization tools. We also constructed an SV/CNV variant database with population frequency and pathogenicity annotations, applied DBSCAN clustering for internal allele frequency estimation, and used a 3-way annotation strategy to aid interpretation.
Results: Our pipelines identified high-confidence CNVs and streamlined interpretation across cohorts. Within 2 days, the Hackathon yielded 39 candidate pathogenic SVs. The tools and workflows enabled rapid filtering, prioritization, and visualization of clinically relevant variants.
Conclusion: This community-driven effort demonstrates the feasibility and utility of scalable CNV analysis for accelerating diagnosis and discovery in rare disease cohorts using srGS data.

DOI: https://doi.org/10.1101/2025.08.08.25333317
Am J Med Genet A. 2025 Aug 17. e64225

Novel Compound Heterozygous Missense Variants in RPL3L Gene Associated With Neonatal Dilated Cardiomyopathy.

Xianghong Zhang, Tingting Wen, Hongyu Chen, Ziyi Jiang, Weizhong Gu, Weihua Yuan, Fengxia Li, Shanshan Shi, Qiang Shu, Lan Yu.

  Dilated cardiomyopathy type 2D (CMD2D) is a rare autosomal recessive disorder characterized by neonatal-onset severe cardiomyopathy, rapid progression to cardiac decompensation, and high mortality, with heart transplantation being the only life-saving intervention. Although mutations in RPL3L, a muscle-specific ribosomal protein gene critical for cardiac and skeletal muscle function, are known to cause CMD2D, this disorder remains genetically and clinically undercharacterized. To date, only 13 patients with RPL3L-related CMD2D have been reported, with nearly all of whom are attributed to compound missense mutations. Using whole exome sequencing, we identified an infant with fulminant DCM and severe acute heart failure who carried compound heterozygous RPL3L variants: c.346C>T (p.R116C) and c.605A>G (p.E202G). Histopathological analysis revealed cardiomyocyte death, collagen deposition, disturbed mitochondrial structure, and deregulated sarcomeres. Computational protein modeling demonstrated these mutations induce conformational changes in RPL3L, suggesting potential functional relevance. This case expands the mutational spectrum of CMD2D and emphasizes the need for further genotype-phenotype correlations to elucidate the pathogenesis of this lethal disorder.

Keywords:   RPL3L ; dilated cardiomyopathy; genetics; mitochondrial disorganization

DOI:  https://doi.org/10.1002/ajmg.a.64225
Reprod Med Biol. 2025 Jan-Dec;24(1):24(1): e12672

Significance of Mitochondrial Dynamics in Reproductive Physiology: Current and Emerging Horizons in Mitochondrial Therapy for Assisted Reproductive Technologies.

Sanath Udayanga Kankanam Gamage, Yoshiharu Morimoto.

   Background: Mitochondria play a critical role in cellular bioenergetics and signaling, with particular importance in the context of reproductive biology. This review summarizes their role in reproduction and explores current and emerging mitochondrial therapies for fertility treatment.
Methods: A comprehensive literature search using terms like mitochondria, infertility, reproduction, gametes, mitochondrial replacement, and mitochondrial transplantation identified relevant studies on mitochondria's role in gametogenesis, fertilization, and early embryonic development in relevant databases. Selected publications were reviewed and summarized to present current and future mitochondrial therapies for fertility.
Main Findings: Mitochondrial dynamics and functions are critical for meeting the energy requirements of essential reproductive processes, including gametogenesis, fertilization, and early embryonic development. Dysregulation of mitochondrial function has been associated with a range of reproductive disorders, such as infertility, recurrent pregnancy loss, and maternally inherited mitochondrial diseases. Emerging therapeutic strategies, such as mitochondrial replacement therapy, antioxidant supplementation, and mitochondrial transplantation, offer promising avenues for overcoming these challenges and improving reproductive outcomes.
Conclusions: Utilizing mitochondrial-based therapies represents a promising and innovative approach in the advancement of fertility treatments. Ongoing research and clinical development in this area hold significant potential to enhance reproductive outcomes and improve the quality of life for individuals and couples facing fertility challenges.

Keywords:  ascent; infertility; mitochondria; mitochondrial dysfunction; mitochondrial therapies for infertility; mitochondrial transplantation; reproductive aging

DOI:  https://doi.org/10.1002/rmb2.12672
iScience. 2025 Sep 19. 28(9): 113233

Mitochondrial hyper-acetylation induced by an engineered acetyltransferase promotes cellular senescence.

Tadahiro Shimazu, Ayane Kataoka, Takehiro Suzuki, Naoshi Dohmae, Yoichi Shinkai.

  Protein acetylation plays crucial roles in diverse biological functions, including mitochondrial metabolism. Although SIRT3 catalyzes the removal of acetyl groups in mitochondria, the addition of the acetyl groups is thought to be primarily controlled in an enzyme-independent manner due to the absence of potent acetyltransferases. In this study, we developed an engineered mitochondria-localized acetyltransferase, named engineered mitochondrial acetyltransferase (eMAT). eMAT localized in the mitochondrial matrix and introduced robust global protein lysine acetylation, including 413 proteins with 1,119 target lysine residues. Notably, 74% of the acetylated proteins overlapped with previously known acetylated proteins, indicating that the eMAT-mediated acetylation system is physiologically relevant. Functionally, eMAT negatively regulated mitochondrial energy metabolism, inhibited cell growth, and promoted cellular senescence, suggesting that mitochondrial hyper-acetylation drives metabolic inhibition and cellular senescence. SIRT3 counteracted eMAT-induced acetylation and metabolic inhibition, restored cell growth, and protected cells from senescence, highlighting the contribution of SIRT3 in maintaining energy metabolism and preventing cellular senescence.

Keywords:  Metabolic flux analysis; Metabolomics; Protein

DOI:  https://doi.org/10.1016/j.isci.2025.113233
Med Gas Res. 2026 Jun 01. 16(2): 116-124

Mitochondrial protection role of oxidoreductase-like domain containing 1 in myocardial cells under hypoxia.

Yan Yan, Min Dong, Liuyang Tian, Chao Zhu, Xiaojing Zhao.

  JOURNAL/mgres/04.03/01612956-202606000-00006/figure1/v/2025-08-18T154854Z/r/image-tiff Although mitochondria and related proteins are essential for mitochondrial preservation, the functions of some of these proteins remain unknown. The novel protein oxidoreductase-like domain containing 1 (OXLD1/C17orf90, UniProtKB Q5BKU9) have attracted our attention because of its correlation with mitochondria. This study revealed a decrease in OXLD1 levels in cardiomyocytes cultured in 1% oxygen for 24 hours. Suppressing OXLD1 increases mitochondrial injury under both normoxic and hypoxic conditions. This is evidenced by decreased mitochondrial membrane potential and increased reactive oxygen species production. Meanwhile, suppressing OXLD1 decreased mitochondrial oxidative phosphorylation. Overexpression of OXLD1 decreased mitochondrial injury under normoxia and hypoxia, as indicated by an increase in the mitochondrial membrane potential and a decrease in reactive oxygen species production. Moreover, overexpression of OXLD1 enhanced mitochondrial oxidative phosphorylation. Additionally, we found that OXLD1 regulates mitochondrial oxidative phosphorylation by affecting mitochondrial complexes I and V. OXLD1 plays a crucial role in protecting cardiomyocytes by improving mitochondrial function under low-oxygen conditions. OXLD1 achieves this protection through interactions with mitochondrial complexes I and V. Therefore, OXLD1 may serve as a new and important regulator of mitochondrial function.

Keywords:  C17orf90; MMP; OXLD1; ROS; cardiomyocytes; hypoxia; mitochondria; mitochondrial complex I; mitochondrial complex V; oxidative phosphorylation

DOI:  https://doi.org/10.4103/mgr.MEDGASRES-D-24-00117
medRxiv. 2025 Aug 15. pii: 2025.08.13.25333123. [Epub ahead of print]

Low-frequency genetic variants in GAK enhance Golgi function and protect against Parkinson's disease.

C Calatayud, I Fernandez-Carasa, N Spataro, C Mussolino, Y Richaud-Patin, A Faella, R Fernández-Santiago, M Ezquerra, T Courtin, S Bandres-Ciga, A Miguez, J M Canals, M Chiritoiu, V Malhotra, A Garrido, M J Marti, E Tolosa, E Bosch, T Cathomen, F H Gage, A Raya, A Consiglio.

Genome-wide association studies (GWAS) have contributed significantly to unraveling the genetic bases of complex diseases such as Parkinson's disease (PD); yet experimental evidence for causation is often elusive. Here, we hypothesized that non-manifesting carriers of a PD-causing mutation in the LRRK2 gene could express genetic modifiers conferring disease protection. Using a pluripotent stem cell-based model, we showed that dopaminergic neurons derived from these individuals were partially protected from the disease in vitro, and that this protective effect is genetically driven. Whole-exome sequencing identified a previously unreported low-frequency variant in cyclin G-associated kinase (GAK) that was associated with a nearly nine-year delay in age at onset among LRRK2 mutation carriers in a local cohort, although replication in additional cohorts was inconclusive. To rule out inter-cohort heterogeneity, we used CRISPR/Cas9-mediated gene editing to isolate the effect of the mutation. We found that the candidate protective variant prevented neuron loss in vitro along with an improvement of several indicators endocytic-mediated transport. Together, our findings provide mechanistic insights into PD pathogenesis and actionable genetic information for the prognosis of PD patients.
One Sentence Summary: Investigating genetic protection against Parkinson's disease in non-manifesting carriers of LRRK2 mutations by CRISPR/Cas9-based genome edition.

DOI: https://doi.org/10.1101/2025.08.13.25333123
J Biomed Sci. 2025 Aug 19. 32(1): 77

Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.

Fasih A Rahman, Mackenzie Q Graham, Alex Truong, Joe Quadrilatero.

   BACKGROUND: Postnatal skeletal muscle development leads to increased muscle mass, strength, and mitochondrial function, but the role of mitochondrial remodeling during this period is unclear. This study investigates mitochondrial remodeling during postnatal muscle development and examines how constitutive autophagy deficiency impacts these processes.
METHODS: We initially performed a broad RNA-Seq analysis using a publicly available GEO database of skeletal muscle from postnatal day 7 (P7) to postnatal day 112 (P112) to identify differentially expressed genes. This was followed by investigation of postnatal skeletal muscle development using the mitophagy report mouse line (mt-Kiema mice), as well as conditional skeletal muscle knockout (Atg7f/f:Acta1-Cre) mice.
RESULTS: Our study observed rapid growth of body and skeletal muscle mass, along with increased fiber cross-sectional area and grip strength. Mitochondrial maturation was indicated by enhanced maximal respiration, reduced electron leak, and elevated mitophagic flux, as well as increased mitochondrial localization of autophagy and mitophagy proteins. Anabolic signaling was also upregulated, coinciding with increased mitophagy and fusion signaling, and decreased biogenesis signaling. Despite the loss of mitophagic flux in skeletal muscle-specific Atg7 knockout mice, there were no changes in body or skeletal muscle mass; however, hypertrophy was observed in type IIX fibers. This lack of Atg7 and loss of mitophagy was associated with the activation of mitochondrial apoptotic signaling as well as ubiquitin-proteasome signaling, suggesting a shift in degradation mechanisms. Inhibition of the ubiquitin-proteasome system (UPS) in autophagy-deficient skeletal muscle led to significant atrophy, increased reactive oxygen species production, and mitochondrial apoptotic signaling.
CONCLUSION: These results highlight the role of mitophagy in postnatal skeletal muscle development and suggest that autophagy-deficiency triggers compensatory degradative pathways (i.e., UPS) to prevent mitochondrial apoptotic signaling and thus preserve skeletal muscle integrity in developing mice.

Keywords:  Apoptosis; Autophagy; BNIP3; Development; Mitochondria; Mitophagy; Skeletal muscle; UPS

DOI:  https://doi.org/10.1186/s12929-025-01153-7
ACS Sens. 2025 Aug 17.

Reasonable Design of Near-Infrared Boron Dipyrromethene with Cationic Pyridinium for Super-Resolution Imaging of Dynamic Voltages of Mitochondria in Living Cells.

Jiang-Lin Wang, Lu Zhang, Huan He, Pengfei Zhang, Feng-Lei Jiang.

  Mitochondrial membrane potential (ΔΨm) is a critical regulator of cellular homeostasis and an established biomarker in mitochondrial dysfunction. While super-resolution fluorescence imaging reveals intrinsic links between mitochondrial ultrastructure and function, prolonged monitoring of the dynamic ΔΨm remains constrained by the scarcity of photostable voltage-sensitive probes. Here, we designed and synthesized three water-soluble near-infrared boron dipyrromethene (BODIPY) probes (o/m/pMePy-BDP). These cationic pyridinium-functionalized probes exhibit specific mitochondria localization (Pearson's colocalization coefficient >0.93), high photostability (<15% intensity loss after 15 min laser irradiation), and exceptional biocompatibility. When integrated with structured illumination microscopy (SIM), they resolved mitochondrial cristae ultrastructure at 0.24 μm resolution and captured real-time ΔΨm fluctuations during fusion/fission (∼15 mV shifts) and mitochondria-lysosome contact (MLC). Semiquantitative submitochondrial models further revealed voltage gradients (150-170 mV) across cristae junctions, challenging the classical "homogeneous ΔΨm" paradigm. The probes' compatibility with multiplexed imaging enabled continuous ΔΨm tracking during mitophagy, uncovering transient bioenergetic hotspots. This work bridges nanoscale mitochondrial dynamics to disease mechanisms, providing tools to dissect pathologies from neurodegeneration to cancer.

Keywords:  BODIPY; SIM; fluorescent probes; organelle dynamics; voltage-sensitive imaging

DOI:  https://doi.org/10.1021/acssensors.5c01636
Commun Biol. 2025 Aug 19. 8(1): 1249

A robust method for assessing mitochondrial function in healthy and diseased frozen cardiac tissue.

Liangyu Hu, Alexia van Rinsum, Rocco Caliandro, Xi Qi, Shuxiu Fan, Xinyi Jiang, Jur Massop, Melissa Bekkenkamp-Grovenstein, Christiane Ott, Tilman Grune, Melissa A E van de Wal, Werner J H Koopman, Marcel Giesbers, Monika Gladka, Jaap Keijer, Deli Zhang.

Cardiovascular diseases are often associated with impairment in mitochondrial function. However, existing respirometry measuring mitochondrial function are limited by the necessity of fresh tissue samples. This study develops a method with tailored substrate-inhibitor titration (TSIT) of mitochondrial electron transport complexes (ETC) to measure mitochondrial function in frozen cardiac samples using high-resolution respirometry. Briefly, acetyl-CoA is added to fuel the tricarboxylic acid (TCA) cycle for NADH production, enabling complex I (CI)-linked respiratory assessment. NADH is then added to measure maximum CI-linked respiratory capacity, followed by rotenone and succinate to assess complex II (CII)-linked respiratory capacity. TSIT detects mitochondrial functional differences between frozen atrial and ventricular tissue, with comparable results as measured in fresh samples. It also detects cardiac mitochondrial dysfunction across various (patho)physiological mouse models and in human frozen cardiac samples, highlighting its clinical potential. Furthermore, we provides the first evidence for SC formation between the ETC-SCs and the TCA cycle metabolon using blue native electrophoresis, underpinning why TSIT is feasible in frozen tissue. In conclusion, we establish a novel, robust, sensitive and translational method (TSIT) for assessing mitochondrial (dys)function in frozen cardiac samples from various species, enabling flexible analysis of mitochondrial function in both laboratory and clinical settings.

DOI: https://doi.org/10.1038/s42003-025-08608-5
Pharm Pat Anal. 2024 ;13(4-6): 105-110

Patent highlights December 2023-January 2024.

Hermann Am Mucke.

  A snapshot of noteworthy recent developments in the patent literature of relevance to pharmaceutical and medical research and development.

Keywords:  G-quadruplexes; cell cycle proteins; machine learning; memory T-cells; mitochondrial diseases; neuroglobin

DOI:  https://doi.org/10.1080/20468954.2024.2390353
ACS Chem Biol. 2025 Aug 18.

Amphipathic Proline-Rich Cell Penetrating Peptides for Targeting Mitochondria.

Adeline Schmitt, Helma Wennemers.

Cell-penetrating peptides (CPPs) offer a platform for targeted intracellular delivery. Here, we developed amphipathic oligoprolines for targeting mitochondria. The rigid peptides feature cationic guanidinium and hydrophobic cyclohexyl groups aligned along the edges of the polyproline II (PPII) helical backbone. Systematic variations of the hydrophobicity through C-terminal and backbone modifications provided CPPs with enhanced cellular uptake and mitochondrial selectivity. Comparative studies with conformationally more flexible analogs revealed the benefit of aligned cationic and hydrophobic residues on a rigid backbone for mitochondria targeting. Notably, the amphipathic peptides undergo time-dependent intracellular redistribution, leading to selective and prolonged mitochondrial residency. Our findings established design principles for optimizing CPPs to target mitochondria.

DOI: https://doi.org/10.1021/acschembio.5c00479
bioRxiv. 2025 Aug 11. pii: 2025.08.07.669190. [Epub ahead of print]

Dehydration promotes intracellular lipid synthesis and accumulation.

Joshua S Carty, Jazlyn Selvasingh, Yvonne Zuchowski, Hyuck-Jin Nam, Clothilde Pénalva, Gayani Nanayakkara, Erin Q Jennings, Kelsey Voss, Edith T Adame, John T Tossberg, Wei Sheng Yap, Meiling Melzer, Olga Viquez, A Scott McCall, Elizabeth R Piotrowski, Ryoichi Bessho, Shirong Cao, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, Simona G Codreanu, Stacy D Sherrod, John A McLean, Jonathan B Trapani, Matthew A Cottam, Ma Wan, Deepti Shrivastava, Don Delker, Matthew H Wilson, Clinton M Hasenour, Louise Lantier, Irene Chernova, Jamey D Young, Volker H Haase, Jose Pablo Vazquez-Medina, Dylan K Kosma, Peter Kim, Jean-Philippe Cartailler, Mingzhi Zhang, Roy Zent, Raymond C Harris, Jason A Watts, Andrew S Terker, Fabian Bock, Jeffrey C Rathmell, Aylin R Rodan, Juan P Arroyo.

Lipids can be considered a water reservoir used to offset dehydration stress as their oxidation by the mitochondria generates water. However, whether dehydration directly regulates lipid synthesis is unknown, which is the focus of this study. We found that dehydration stress decreases cellular oxygen consumption, increases intracellular lipid synthesis, and favors glutamine oxidation as a carbon precursor for lipid synthesis via remodeling mitochondrial metabolism. These findings provide a mechanism whereby cellular dehydration leads to intracellular lipid accumulation, functionally linking water availability to lipid storage.

DOI: https://doi.org/10.1101/2025.08.07.669190
Adv Clin Exp Med. 2025 Aug 19.

Progress in stem cells mitochondrial proteomics research: A review.

Weidong Yao, Xinyi Yu, Yameng Wang, Liang Xia.

  This review summarizes the latest advancements in stem cell (SC) mitochondrial proteomics. With the rapid development of biotechnology, mitochondrial proteomics has emerged as a pivotal area in SC research. The research methods used in mitochondrial proteomics include mass spectrometry (MS), with pre-MS sample processing, MS data acquisition employing both qualitative and quantitative approaches, and bioinformatics analysis to annotate and explore protein functions. In recent years, mitochondrial proteomics research has contributed to the establishment and expansion of our understanding of the roles of various mitochondrial proteins involved in regulating SC differentiation, metabolism and aging, including Drp1, Mfn1/2, OPA1, SIRT3, Bcl-2, YME1L, and PGC-1α. This multidisciplinary approach, combining qualitative and quantitative proteomics with bioinformatics, sheds light on the intricate regulatory mechanisms of mitochondrial proteins in SC. These findings provide a scientific basis for developing novel therapeutic targets and strategies, thereby advancing the field of regenerative medicine and personalized treatment paradigms.

Keywords:  bioinformatics; mass spectrometry; mitochondria; proteomics; stem cells

DOI:  https://doi.org/10.17219/acem/203862
Cureus. 2025 Jul;17(7): e88031

Diagnosing Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Syndrome in a Young Adult Female Patient With Seizures and Lactic Acidosis.

Ishan A Sane, Jessica R Gupte.

  The aim of this case report is to highlight the diagnostic challenges and clinical presentation of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, which is a rare, maternally inherited mitochondrial disorder. MELAS typically manifests with a constellation of neurological and systemic symptoms, including seizures, lactic acidosis, stroke-like episodes, and progressive cognitive decline. Mutations in mitochondrial DNA impair oxidative phosphorylation and result in widespread cellular dysfunction. We report the case of a 33-year-old female patient who presented with seizures, altered mental status, and focal neurological deficits. Laboratory evaluation revealed elevated serum lactate, and neuroimaging demonstrated stroke-like lesions not confined to vascular territories. A muscle biopsy showed abnormal mitochondrial accumulation, and electron microscopy detected ragged red fibers, which is confirmatory of mitochondrial cytopathy. The patient was managed symptomatically in the intensive care unit with antiepileptics, corticosteroids, and a mitochondrial cocktail comprising coenzyme Q10, L-arginine, L-carnitine, and B-complex vitamins. Plasmapheresis was also performed during initial management due to diagnostic uncertainty. The patient showed gradual clinical improvement and was discharged on supportive therapy. This case emphasizes the importance of early recognition of atypical stroke-like presentations and metabolic derangements in young patients. MELAS syndrome should be considered in the differential diagnosis of stroke mimics, especially in the absence of vascular risk factors. Timely diagnosis, supportive care, and long-term follow-up, including genetic counselling, are essential for optimizing outcomes in these patients.

Keywords:  encephalomyopathy; lactic acidosis; melas syndrome; mitochondrial disorder; red ragged fibers; stroke-like episodes

DOI:  https://doi.org/10.7759/cureus.88031
bioRxiv. 2025 Aug 12. pii: 2025.08.10.669191. [Epub ahead of print]

The mevalonate pathway couples lipid metabolism to amino acid synthesis via ubiquinone-dependent redox control.

Thi Thinh Nguyen, Mohit Bansal, Jane Ding, Sunil Sudarshan, Han-Fei Ding.

The mevalonate pathway produces sterols and isoprenoids that support cancer cell growth, yet its broader metabolic functions remain incompletely defined. Here, we show that this pathway sustains amino acid biosynthesis by promoting mitochondrial NAD⁺ regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impairs oxidative phosphorylation, lowers the NAD⁺/NADH ratio, and suppresses de novo serine and aspartate synthesis, thereby activating the GCN2-eIF2α-ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limits purine and pyrimidine nucleotide production. Expression of the bacterial NADH oxidase LbNOX or the alternative oxidase AOX restores NAD⁺ levels and rescues statin-induced growth inhibition. These findings suggest that impaired NAD⁺ regeneration is a key mechanism contributing to the anti-proliferative activity of statins, linking the mevalonate pathway to mitochondrial electron transport- dependent control of amino acid metabolism.
Significance: This study identifies the mevalonate pathway as a regulator of amino acid biosynthesis through mitochondrial electron transport-dependent NAD⁺ regeneration and reveals redox disruption as a key mechanism contributing to the anti-proliferative effects of statins.

DOI: https://doi.org/10.1101/2025.08.10.669191
Nat Med. 2025 Aug 18.

Gene editing enables islet transplantation without immunosuppression.

Karen O'Leary.



Keywords:  Diabetes; Stem cells; Transplantation

DOI:  https://doi.org/10.1038/d41591-025-00053-5
Nature. 2025 Aug;644(8077): 829-832

Beyond AlphaFold: how AI is decoding the grammar of the genome.

Jeffrey M Perkel.



Keywords:  Genomics; Machine learning; Synthetic biology; Technology

DOI:  https://doi.org/10.1038/d41586-025-02621-8
bioRxiv. 2025 Aug 12. pii: 2025.08.08.669302. [Epub ahead of print]

High-resolution quantification of metabolic heat output from individual live Drosophila brains.

Kanishka Panda, Rohith Mittapally, Qianqian Chen, Akshay Bhaskaran, Pramod Reddy, Edgar Meyhofer, Swathi Yadlapalli.

Quantitative insights into brain metabolism are essential for advancing our understanding of the energy dynamics in the brain. However, current approaches to tracking brain metabolism, such as metabolic profiling, offer only static snapshots of metabolite levels and fall short in capturing real-time energy fluxes. Here, we present the first direct, quantitative measurement of metabolic output from individual, live explanted brains of Drosophila melanogaster using a high-resolution biocalorimeter capable of detecting nanowatt-scale metabolic changes, while maintaining brain viability via continuous buffer perfusion. Using this platform, we measured an average metabolic output of ∼256 nW per brain in female, 10-day-old Drosophila flies. Notably, female brains exhibited significantly higher metabolic activity than male brains at a young age (10-day-old). Furthermore, in parkin mutants-used to model Parkinson's disease-homozygous mutant brains showed a ∼15% reduction in metabolic output relative to heterozygous controls, consistent with impaired mitochondrial function. We further extended our measurements to other Drosophila tissues, demonstrating that mass-normalized metabolic rates of ovaries and testes are ∼2.5-fold lower compared to brains in Drosophila , highlighting the brain's exceptional energy demands. This platform enables real-time, quantitative brain bioenergetics studies and is adaptable to tissue organoids and drug screening, offering new avenues for investigating aging, neurodegeneration, and metabolism-driven disease mechanisms.

DOI: https://doi.org/10.1101/2025.08.08.669302
Curr Neuropharmacol. 2025 Aug 12.

Mitochondria as a Therapeutic Target in Neurodegeneration: Strategies for Restoring Cellular Homeostasis.

Bartosz Twarowski, Iwona Piątkowska-Chmiel, Mariola Herbet.

  Ageing is a complex biological process marked by a gradual decline in bodily functions at the cellular, tissue, and organ levels, resulting from molecular damage and environmental influences. It increases disease risk, particularly in older adults with neurodegenerative conditions characterized by progressive neuronal loss and neurological symptoms such as cognitive and motor impairments. Key mechanisms include abnormal protein accumulation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Disruption of cellular homeostasis prevents the maintenance of internal conditions such as pH and glucose levels. Mitochondria, known as the cell's "powerhouses," are essential for ATP production, DNA protection, and metabolic regulation, supporting cellular structures. Their dysfunction plays a crucial role in the progression of neurodegenerative diseases. Factors like chronic inflammation, ATP deficiency, excessive production of reactive oxygen species (ROS), and calcium imbalance leads to oxidative stress and neuronal damage, exacerbating neurodegeneration. Current therapies mainly focus on symptom relief, emphasizing the urgent need for new treatment strategies. Given the key role of mitochondrial dysfunction, therapies aiming to restore mitochondrial homeostasis are gaining increasing attention. Mitochondrial antioxidants such as MitoQ, MitoTEMPO, and SkQ1 have shown neuroprotective, anti-inflammatory, and antioxidant properties. Research into their therapeutic potential may lead to the development of effective drugs that restore mitochondrial function and improve quality of life of the patienst.

Keywords:  Mitochondrial antioxidants; mitochondrial dysfunction.; neurodegenerative diseases; neuropharmacology; toxicology

DOI:  https://doi.org/10.2174/011570159X389970250727031306
bioRxiv. 2025 Aug 14. pii: 2025.08.11.669723. [Epub ahead of print]

Functional evidence for G6PD variant classification from mutational scanning.

Renee C Geck, Melinda K Wheelock, Rachel L Powell, Ziyu R Wang, Daniel L Holmes, Shawn Fayer, Gabriel E Boyle, Allyssa J Vandi, Clara J Amorosi, Nick Moore, Alan F Rubin, Douglas M Fowler, Maitreya J Dunham.

G6PD deficiency is the most common enzyme deficiency worldwide, and increases the likelihood of adverse reactions to certain drugs and foods. Identifying people at risk is challenging, since most are asymptomatic until they encounter a trigger. This is further complicated since over 60% of 1,548 known genetic variants in G6PD are variants of uncertain significance and thus cannot guide drug prescribing and dosing. To resolve which variants are clinically meaningful and avoid harm from adverse drug reactions, we conducted two high-throughput functional assays: one for G6PD activity, and one for abundance. We measured the function of 10,674 missense, nonsense, and synonymous G6PD variants. The patterns of variant effect on activity and abundance confirmed the importance of structural NADP + for G6PD activity and abundance, and G6PD dimerization for G6PD activity. Based on the ability of our functional assay scores to accurately classify G6PD variants of known clinical effect, we generated evidence that 4,883 missense variants contribute to G6PD deficiency and 2,768 are unlikely to contribute to G6PD deficiency. Our data can be used to deepen our understanding of G6PD as a protein, and to close the gap in classification for variants of uncertain significance to improve implementation of genetic medicine for G6PD deficiency.

DOI: https://doi.org/10.1101/2025.08.11.669723
ACS Med Chem Lett. 2025 Aug 14. 16(8): 1511-1512

Novel Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors for the Treatment of Parkinson's Disease.

Zhendong Song, Steven H Liang.

This patent describes novel leucine-rich repeat kinase 2 (LRRK2) inhibitors featuring a 2,4,12,13-tetrahydro-11H-5,7-(azenometheno)-dipyrazolo-[3,4-b:5',1'-g]-[1]-oxa-[4,6,8]-triazacycloundecine scaffold. These LRRK2 inhibitors exhibit therapeutic potential for the treatment of Parkinson's disease.

DOI: https://doi.org/10.1021/acsmedchemlett.5c00438
Am J Physiol Cell Physiol. 2025 Aug 18.

Unconventional myosin VI is involved in regulation of muscle energy metabolism.

Dominika Wojton, Dorota Dymkowska, Damian Matysniak, Malgorzata Topolewska, Maria Jolanta Rędowicz, Lilya Lehka.

  Mitochondria are essential for the regulation of the metabolic state of skeletal muscle, making their structure and function crucial for muscle performance. Myosin VI (MVI), an unconventional minus-end-directed motor, is expressed in skeletal muscle and myogenic cells. To explore its role in mitochondrial function and muscle metabolism, we used MVI knockout mice (Snell's waltzer, SV, MVI-KO) and their heterozygous littermates. We analyzed muscle samples from newborn (P0) and adult mice (3- and 12-months-old) and found that both MVI mRNA and protein levels were highest in newborn muscles and decreased with age. MVI expression also varied by muscle type, being highest in the slow-twitch soleus muscle (SOL) of adult mice. Loss of MVI had the most significant effects on SOL, which contains the highest number of mitochondria compared to fast-twitch muscles. MVI loss resulted in reduced respiratory capacity and ATP production in myogenic cells, indicating impaired mitochondrial function. Furthermore, MVI deficiency caused a shift from glycolytic to oxidative fiber types, especially in SOL. We also observed increased phospho-AMPK levels in MVI-KO SOL across all time points, along with downregulation of the mTOR pathway and upregulation of proteins involved in lipolysis. These findings highlight MVI as a novel regulator of metabolic processes in skeletal muscle.

Keywords:  Energy metabolism; mitochondria; myogenic cell; skeletal muscle; unconventional myosin VI

DOI:  https://doi.org/10.1152/ajpcell.00300.2025
PeerJ. 2025 ;13 e19879

The effect of rotenone contamination on high-resolution mitochondrial respiration experiments.

Dale F Taylor, Jia Li, Nicholas J Saner, Jia Wei, Xu Yan, Elizabeth G Reisman, Hanzhe Li, Matthew J-C Lee, Navabeh Zare, Andrew Garnham, Jujiao Kuang, David J Bishop.

   Background: High-resolution respirometry is commonly used in skeletal muscle research and exercise science to measure mitochondrial respiratory function in both permeabilized muscle fibers and isolated mitochondria. Due to the low throughput and high cost of the most used respirometer, the Oroboros 2k (O2k), multiple experiments are often conducted within the same chamber in short succession. Despite this, no methodological consideration has been given for the potential contamination of inhibitors, used to investigate the contribution of specific complexes within the electron transport chain, between experiments.
Methods: We first assessed the potential effect of inhibitor contamination on mitochondrial respiration experiments by evaluating the ability of the currently recommended wash protocol to remove rotenone and compared its efficacy against a simplified wash protocol of sequential rinses. Secondly, we assessed the potential effect of inhibitor contamination on mitochondrial respiration measured before and after a single session of high-intensity interval exercise, with and without the use of rotenone between experiments.
Results: The currently recommended protocol for washing chambers was insufficient for removing rotenone. Following exercise, a decrease in mitochondrial respiration was observed exclusively in chambers exposed to rotenone between experiments.
Discussion: Our findings highlight an important methodological consideration regarding the measurement of mitochondrial respiratory function using high-resolution respirometry, with inhibitor contamination potentially affecting the conclusions derived from experiments conducted in close succession. Future studies investigating mitochondrial respiratory function should assess the necessity of using inhibitors such as rotenone, ensure thorough wash procedures between experiments, and explicitly report the washing protocols used.

Keywords:  Bioenergetics; Exercise; Exercise-induced adaptation; Mitochondria; Oroboros O2k; Permeabilized fibers; Protocol development; Respiration; Rotenone

DOI:  https://doi.org/10.7717/peerj.19879
Orphanet J Rare Dis. 2025 Aug 18. 20(1): 439

Mitochondrial neurogastrointestinal encephalomyopathy in china: a novel TYMP variant and comprehensive clinical-genetic insights.

Xuebi Xu, Junhui Xia, Fei Xu, Mingshan Wang, Lihong Yang, Xiaoli Chen.

   BACKGROUND: Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare autosomal recessive disorder caused by variants in the TYMP gene, which encodes thymidine phosphorylase (TP). It is characterized by multisystem involvement, with prominent gastrointestinal, neurological, and systemic manifestations that typically exhibit progressive worsening over time.
METHODS: We characterized a multigenerational MNGIE family through comprehensive proband analysis, identifying compound heterozygous TYMP variants (c.131G > C, p.Arg44Pro and c.1268T>G, p.Leu423Arg in trans) as the molecular basis of disease. Extended family testing for genetic counseling confirmed no secondary pathogenic variants. Muscle biopsies were analyzed using comprehensive staining techniques. Genomic analysis involved next-generation sequencing (NGS) of the proband's DNA and Sanger sequencing of family members' DNA to confirm variants. In silico analysis utilized bioinformatics tools and protein modeling to predict pathogenicity and assess structural impacts, with variant classification adhering to American College of Medical Genetics and Genomics(ACMG) guidelines. Additionally, a literature review of Chinese MNGIE cases was conducted to contextualize the findings.
RESULTS: The proband exhibited characteristic MNGIE features, including gastrointestinal dysmotility, diffuse leukoencephalopathy on brain MRI (magnetic resonance imaging), and electrophysiologically confirmed peripheral neuropathy. Muscle biopsy revealed ragged red fibers, cytochrome c oxidase-deficient fibers, and enhanced succinate dehydrogenase activity in blood vessels, consistent with mitochondrial dysfunction. Genetic analysis identified a novel TYMP variant (c.1268T > G, p.Leu423Arg) and a known variant (c.131G > C, p.Arg44Pro) in the proband, both classified as likely pathogenic according to ACMG guidelines. Molecular analysis of other 11 family members detected heterozygous carriers of either the c.1268T > G or c.131G > C variant in six asymptomatic individuals. In silico analysis confirmed that both variants are highly conserved and likely pathogenic. Protein modeling revealed that both variants compromise structural integrity and conformation, impairing TP function. Homozygous or compound heterozygous missense variants were identified as the predominant genetic alterations in 16 Chinese MNGIE cases, with gastrointestinal and neurological symptoms being the most common clinical manifestations.
CONCLUSIONS: This study enriches the variant spectrum in Chinese patients, highlights the importance of early diagnosis prior to the onset of cachexia and irreversible tissue damage, and enhances the understanding of genetic heterogeneity.

Keywords:   TYMP ; ACMG; Compound heterozygous; MNGIE; TP

DOI:  https://doi.org/10.1186/s13023-025-03962-3
J Appl Genet. 2025 Aug 20.

Ataxia and oculomotor apraxia caused by a large-scale deletion in the senataxin gene.

Joanna M Rusecka, Biruta Kierdaszuk, Iwona Stępniak, Małgorzata Rydzanicz, Piotr Stawiński, Tomasz Gambin, Damian Loska, Magdalena M Kacprzak, Magdalena Kaliszewska, Dorota Piekutowska-Abramczuk, Anna M Kamińska, Ewa Pronicka, Ewa Bartnik, Anna Kostera-Pruszczyk, Rafał Płoski, Agnieszka Sobczyńska-Tomaszewska, Katarzyna Tońska.

  Senataxin, an RNA/DNA helicase, is a key protein providing genome stability and one of the best characterized R-loop-binding factors playing an important role in transcription and DNA repair processes. Pathogenic SETX gene variants cause autosomal recessive spinocerebellar ataxia with axonal neuropathy (AOA2, MIM #606002) and autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4, MIM #602433), rare neurodegenerative disorders characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, combined upper and lower motor neuron symptoms, and increased serum alpha-fetoprotein (AFP; specific for AOA2). We report two cases of adult patients presenting with cerebellar syndrome, scanned speech, and exercise intolerance which started in the second/third decade of life and were followed by muscle weakness and impaired gait coordination. Whole exome sequencing (WES) was performed to analyze single nucleotide and copy number variants. A decreased coverage of a genomic region of around 16 kb on chromosome 9 (chr9:132,295,852-132,311,876), suggesting a deletion encompassing 5 exons of the SETX gene (exons 11-15, NM_015046.7) was observed. This homozygous SETX (9q34.13) deletion leads to a frame shift and consequently truncation of the helicase domain in the protein. Loss-of-function variants in the SETX gene are known to be pathogenic. Statistical analysis of NGS data from the Polish population identified a few heterozygous carriers, suggesting its region-specific origin.

Keywords:   SETX ; AOA2; CNV; MtDNA; Neurodegenerative disorder; R-loop; WES

DOI:  https://doi.org/10.1007/s13353-025-01001-2
Nat Biotechnol. 2025 Aug 19.

Redefining druggable targets with artificial intelligence.

Karen Akinsanya, Mohammed AlQuraishi, Ann Boija, John Chodera, Anna Cichońska, Marzyeh Ghassemi, Martha Head, Wengong Jin, Warren A Kibbe, Nevan Krogan, Michael V LeVine, John Moult, Lynda Stuart, Georgia Tourassi, James Zou, Regina Barzilay, Olivier Elemento.

DOI: https://doi.org/10.1038/s41587-025-02770-1
Anal Chem. 2025 Aug 19.

Spatiotemporally Traceable Peptide Self-Assemblies for Mitochondrial-Specific Dysfunction.

Xia Wu, Hao Zhang, Mingxuan Li, Xiaoding Lou, Fan Xia, Jun Dai.

Peptide self-assembly has emerged as a highly regarded strategy for developing functional agents to control cellular fate. However, due to the complexity of intracellular environments, achieving spatiotemporally traceable organelle localization and functional perturbation through peptide self-assembly remains a challenge. In this study, we developed T-FFVLK, a fluorescent peptide probe that integrates a red-emitting mitochondria-targeted molecule with a self-assembling peptide for visual tracking. This probe sequentially enters cellular compartments, ultimately targeting mitochondria to form disruptive self-assembled structures while reporting mitochondrial dysfunction. Once endocytosed into the cell, T-FFVLK initially forms short fibers that promote lysosomal escape, subsequently entering the mitochondria, where it further forms long fibers, all accompanied by a gradual increase in fluorescence and self-reporting of probe localization and mitochondrial dysfunction. T-FFVLK achieves mitochondrial enrichment within 6 h and induces morphological and functional changes within 12 h, leading to microtubule damage and cell cycle arrest. Thus, T-FFVLK is an invaluable tool for the observation of mitochondrial dysfunction in living cells, offering great potential for subcellular imaging and disease treatment.

DOI: https://doi.org/10.1021/acs.analchem.5c02577
J Inherit Metab Dis. 2025 Sep;48(5): e70078

Delivering the Message: Translating mRNA Therapy for Liver Inherited Metabolic Diseases.

Sonam Gurung, Dany Perocheau, Roopkatha Ghosh, Stephen L Hart, Julien Baruteau.

  mRNA encapsulated in lipid nanoparticles (LNPs) provides a dual revolution in the field of gene therapy. mRNA brings fleeting efficacy and the possibility to adjust the therapy to clinical needs. LNP, as a non-viral vehicle with flexible organ-targeting, overcomes most immune complications of viral gene therapy. mRNA-LNP has rapidly progressed from preventive medicine and vaccine applications to therapeutic use, especially in inherited metabolic diseases (IMDs). Given their natural tropism for liver uptake, this platform has been utilised successfully in numerous preclinical programmes. Early phase clinical trials are recruiting to assess safety and efficacy in liver IMDs. Here, we provide the latest update on mRNA and LNP technologies, preclinical studies and clinical trials targeting IMDs, safety considerations with a spotlight on infusion-related reactions and safety modelling. We discuss the future directions of therapeutic mRNA-LNP in IMDs and the right clinical use of this adjustable therapy, still to be defined. The versatility of this technology is appealing, with multiple clinical applications as bridge, long-term cure, rescue, or adjuvant therapy. mRNA-LNP for gene editing/insertion is an alternative approach for one-off cure. Translating various successful preclinical programmes in patients remains an unsolved limitation. mRNA-LNP can be tuned according to the patient's needs and is the next step in personalised medicine and individualised gene therapy.

Keywords:  gene therapy; inherited metabolic diseases; lipid nanoparticle; liver; mRNA

DOI:  https://doi.org/10.1002/jimd.70078
Free Radic Biol Med. 2025 Aug 15. pii: S0891-5849(25)00906-2. [Epub ahead of print]240 108-123

FUNDC1-dependent mitochondrial-ER membranes mediate mitochondrial dysfunction and melanocyte damage under oxidative stress.

Jingjing Ma, Mengsha Yuan, Sen Guo, Tianwen Gao, Chunying Li, Ling Liu.

   BACKGROUND: Mitochondria play a pivotal role in oxidative stress-induced melanocyte destruction in vitiligo. FUN14 domain containing 1 (FUNDC1), a mitochondrial outer-membrane protein, has an important role in mitochondrial function by regulating mitophagy and mitochondria-associated endoplasmic reticulum membranes (MAM). However, the role of FUNDC1 in melanocyte damage under oxidative remains unclear.
OBJECTIVES: To determine the contribution of FUNDC1 to oxidative stress-triggered melanocyte damage in vitiligo.
METHODS: We treated human melanocyte cell line PIG1 with H2O2 to establish an oxidative stress model. Cell viability, mitochondrial function and dynamics as well as mitophagy were detected. The transmission electron microscopy was used to assess MAM structure. FUNDC1 was then knocked down to examine its effects on MAM structure and mitochondrial function under H2O2 treatment. Additionally, we compared FUNDC1 expression, MAM structure and mitochondrial function between PIG1 cells and human vitiligo melanocyte cell line PIG3V. Finally, FUNDC1 expression and MAM structure were analyzed in vitiligo lesions and healthy control skin.
RESULTS: H2O2 treatment significantly increased intracellular H2O2 level, mitochondrial superoxide and lipid peroxide (LPO), while decreased glutathione (GSH) level in PIG1 cells. Impaired cell viability and mitochondrial function as well as excessive mitochondrial fission in PIG1 cells were observed after H2O2 incubation. However, H2O2 treatment didn't induce mitophagy but enhanced FUNDC1 expression and altered MAM structure. FUNDC1 knockdown inhibited H2O2-induced changes of MAM structure, mitochondrial calcium overloading, mitochondrial dysfunction, and recovered cell viability under oxidative stress. Interestingly, persistent H2O2 exposure reduced FUNDC1 expression, leading to MAM formation deficiency, excessive mitochondrial fusion and compromised mitochondrial function in the human vitiligo melanocyte cell line PIG3V. Finally, the decreased FUNDC1 expression and dysregulated MAM formation were confirmed in vitiligo lesions.
CONCLUSIONS: FUNDC1-dependent MAM structure mediates oxidative stress-induced mitochondrial dysfunction and melanocytes damage in vitiligo, suggesting that FUNDC1 and its associated MAM structure are potential targets for vitiligo treatment.

Keywords:  FUNDC1; MAM structure; Melanocytes; Mitochondria; Oxidative stress; Vitiligo

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.027
Neurotherapeutics. 2025 Aug 18. pii: S1878-7479(25)00197-7. [Epub ahead of print] e00719

Cyanide overproduction impairs cellular bioenergetics in Down syndrome.

Maria Petrosino, Karim Zuhra, Anna Kieronska-Rudek, Lucia Janickova, Olivier Bremer, Moustafa Khalaf, Brian A Logue, Csaba Szabo.

  Cyanide exerts its toxic effects primarily by inhibiting mitochondrial Complex IV (Cytochrome c oxidase, CCOx). Recent studies have shown that mammalian cells can endogenously produce cyanide from glycine via a lysosomal pathway. At low concentrations, cyanide may play regulatory roles, but at higher levels, it causes metabolic inhibition. Here we show that Down syndrome (DS) cells and tissues exhibit significant overproduction of cyanide, contributing to cellular metabolic suppression. DS rats show elevated blood cyanide levels, and their tissues generate more cyanide than wild-type controls-both under basal conditions and following glycine supplementation. Similarly, human DS fibroblasts produce higher levels of cyanide than healthy control cells. We attribute this increased cyanide production in DS to the marked downregulation of thiosulfate sulfurtransferase (TST, also known as rhodanese), the key enzyme responsible for cyanide detoxification. Importantly, suppression of lysosomal cyanide production in DS cells (through cyanide scavengers, lysosomal deacidification, or inhibition of serine/glycine conversion) improves cellular bioenergetics and/or enhances cell proliferation rates. Previous work has implicated excessive hydrogen sulfide (H2S) production, another endogenous gaseous signaling molecule that inhibits CCOx, in DS-associated metabolic suppression. Our current findings indicate that cyanide overproduction may also contribute to this dysfunction. Cyanide and H2S may act cooperatively on the same molecular target. These results open the possibility of developing therapeutic strategies that target cyanide or both cyanide and H2S to counteract DS-associated metabolic impairment.

Keywords:  Bioenergetics; Gasotransmitters; Mitochondria

DOI:  https://doi.org/10.1016/j.neurot.2025.e00719
Nature. 2025 Aug;644(8078): 884-885

A baby benefits from personalized gene editing in the clinic.

Laura Sepp-Lorenzino.



Keywords:  Genetics; Medical research; Metabolism

DOI:  https://doi.org/10.1038/d41586-025-02590-y