bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–07–27
47 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mutation of NDUFAF2 Linked to Mitochondrial Complex I Deficiency.
  2. PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.
  3. Molecule eases neurological symptoms of mitochondrial deficiency in coenzyme Q10.
  4. Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: Broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction.
  5. NDUFV1 mutation presenting as isolated progressive optic neuropathy: a unique manifestation of mitochondrial complex I deficiency.
  6. Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.
  7. Acute Bilateral Vision Loss in a Young Male: A Case of Leber's Hereditary Optic Neuropathy.
  8. Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism.
  9. NAD+-Boosters Improve Mitochondria Quality Control In Parkinson's Disease Models Via Mitochondrial UPR.
  10. Stressful situations: molecular insights on mitochondrial quality control pathways.
  11. The peculiar properties of mitochondrial carriers of the SLC25 family.
  12. PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson's disease.
  13. MitSorter: a standalone tool for accurate discrimination of mtDNA and NuMT ONT reads based on differential methylation.
  14. Amino Acid Metabolism in Liver Mitochondria: From Homeostasis to Disease.
  15. Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase.
  16. Meet the biotech-company founders driven by their child's rare disease.
  17. The mammalian protein MTCH1 can function as an insertase.
  18. Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease.
  19. LONP1 loss causes mitochondrial mayhem in β-cells.
  20. MITF promotes MFN2-dependent mitochondrial fusion to protect retinal pigment epithelial cells from mitochondrial damage.
  21. LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
  22. Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): A Case Report With a Complex Biochemical Profile.
  23. Pseudohypoxia-Stabilized HIF2α Transcriptionally Inhibits MNRR1, a Druggable Target in MELAS.
  24. Mitochondrial cardiomyopathies: pathogenesis, diagnosis, and treatment.
  25. Bilateral epilepsia partialis continua in POLG related mitochondrial disease.
  26. Ultra-Photostable Fluorescent Boron-Bridged Near-Infrared Probes to Reveal New Mode of Lipid Droplet-Mitochondria Interaction at STED Super-Resolution.
  27. Mitochondrial proteins go public and novel interactions: insights from surfaceome mapping.
  28. TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger.
  29. A protein-specific priority code in presequences determines the efficiency of mitochondrial protein import.
  30. Mitochondrial cardiovascular diseases: molecular mechanisms, multi-omics exploration and therapeutic strategies.
  31. Determination of Mitochondrial Morphology in Live Cells Using Confocal Microscopy.
  32. UCP2 MEDIATES MITOCHONDRIAL DYNAMICS TO INDUCE AgRP NEURONAL ACTIVITY.
  33. A rare de novo mutation, m.1630A>G, in the mitochondrial trnAVal (MT-TV) gene in a child with epilepsy.
  34. [A case of a spinal cord involvement in an adult mitochondrial disease with an m.3243A>G].
  35. Cell type-specific purifying selection of synonymous mitochondrial DNA variation.
  36. Mitochondrial Glycosylation in Neuroinflammation Models.
  37. Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis.
  38. Targeting ALDH2 to promote skeletal muscle health: A novel strategy against mitochondrial dysfunction.
  39. Mitochondrial dysfunction drives basal cell hyperplasia in eosinophilic oesophagitis.
  40. High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
  41. TANGO2 deficiency disorder in a 61-year-old male with episodic weakness, rhabdomyolysis, myotonia, and a novel missense variant.
  42. Acute-onset axonal neuropathy following infection in children with biallelic RCC1 variants: a case series.
  43. Accelerating the path towards a cure for Parkinson's disease.
  44. Triggering ferroptosis in neurodegenerative diseases.
  45. Inhibiting MARCH5/Mfn2 signaling as an alternative strategy to protect cardiomyocytes from hypoxia-induced mitochondrial dysfunction.
  46. A Brief History of Inherited Metabolic Diseases: A Personal 60 Years Clinical Flashback.
  47. PPA2 deficiency-a rare cause of genetic cardiomyopathy: a case report.
  1. Cureus. 2025 Jun;17(6): e86670
    Mutation of NDUFAF2 Linked to Mitochondrial Complex I Deficiency.
    Anwar R Alhamad, Aziza Mushiba, Huda Alkhawaja, AbdullabAli PeerZada, Shahad Bawazeer, Mohammed Saleh.
      Mitochondrial complex I deficiency is an autosomal recessive disorder caused by homozygous mutations in the reduced form of nicotinamide adenine dinucleotide (NADH). It is characterized by a wide range of signs and symptoms that affect numerous human systems and organs. This disease causes neurological issues, including encephalopathy, recurrent epilepsy, intellectual disability, ataxia, and involuntary movements. The initial step of the mitochondrial respiratory chain, during which protons are transported across the inner mitochondrial membrane along with electron transfer from NADH to ubiquinone, is catalyzed by NADH: ubiquinone oxidoreductase. In this case report, we describe a patient presenting with severe, rapidly progressive neurological loss who harbored a novel mutation in NDUFAF2 identified using exome sequencing. At six  months of age, her mother noticed delayed motor development. Thereafter, the patient developed metabolic acidosis and abnormal movements, mimicking seizures triggered by aspiration pneumonia, with elevated serum lactate levels. Genetic testing revealed a c.127G>A mutation in NDUFAF2, consistent with mitochondrial complex I deficiency. This case highlights the utility of exome sequencing as a powerful and cost-effective tool for diagnosing clinically heterogeneous disorders such as mitochondrial diseases. Mitochondrial complex I deficiency is an important differential diagnosis in patients with recurrent central hypoventilation. Our findings expand the mutational spectrum of this rare disease.
    Keywords:  case report; episodic respiratory failure; mitochondrial complex i deficiency; ndufaf2; recurrent encephalopathy
    DOI:  https://doi.org/10.7759/cureus.86670
  2. Clin Transl Med. 2025 Jul;15(7): e70404
    PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.
    Swagat Pradhan, Takayuki Mito, Nahid A Khan, Sofiia Olander, Aleksandra Zhaivoron, Thomas G McWilliams, Anu Suomalainen.
       BACKGROUND: Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual-extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles-respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.
    METHODS: We used a mouse model for mitochondrial myopathy ("deletor"), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors.
    RESULTS: In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.
    CONCLUSIONS: Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.
    Keywords:  integrated stress response; mitochondrial disease; mitochondrial myopathy; nutrient signaling; progressive external ophthalmoplegia; pyruvate dehydrogenase kinase
    DOI:  https://doi.org/10.1002/ctm2.70404
  3. Nature. 2025 Jul 23.
    Molecule eases neurological symptoms of mitochondrial deficiency in coenzyme Q10.
      
    Keywords:  Brain; Diseases; Health care
    DOI:  https://doi.org/10.1038/d41586-025-02289-0
  4. J Hum Genet. 2025 Jul 22.
    Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: Broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction.
    Kohta Nakamura, Yoshihito Kishita, Atsuko Imai-Okazaki, Taku Omata, Maki Nodera, Yukiko Yatsuka, Ayumu Sugiura, Naoyuki Matsumoto, Holger Prokisch, Hiroshi Matsumoto, Akira Ohtake, Kei Murayama, Yasushi Okazaki.
      Mitochondrial diseases are characterized by impaired energy production due to mitochondrial dysfunction. Despite advances in sequencing technologies, many cases remain genetically undiagnosed. We report two cases of mitochondrial disease harboring identical de novo variant in the non-coding RNA gene RNU4-2, previously associated with neurodevelopmental disorders. Re-analysis of whole genome sequencing data from 357 patients ascertained as possibly having mitochondrial disease (see Methods: Supplementary Data S1) identified two cases with a pathogenic RNU4-2 variant (GRCh38: chr.12:120291839: T > TA; NR_003137.2: n.64_65insT). Both patients exhibited decreased oxygen consumption rates and clinical features including developmental delay, microcephaly, short stature. This study provides the first evidence linking RNU4-2 variant to mitochondrial disease, expanding the phenotypic spectrum associated with this gene. Our findings highlight the importance of re-analyzing genomic data and considering non-coding RNA gene variants in mitochondrial disease diagnostics, potentially improving the diagnosis of previously unsolved cases.
    DOI:  https://doi.org/10.1038/s10038-025-01356-8
  5. BMJ Case Rep. 2025 Jul 18. pii: e266155. [Epub ahead of print]18(7):
    NDUFV1 mutation presenting as isolated progressive optic neuropathy: a unique manifestation of mitochondrial complex I deficiency.
    Parul Mittal, Samendra Karkhur, Vidhya Verma, Priti Singh.
      Mutations in the NDUFV1 gene, encoding a subunit of mitochondrial complex I, are typically associated with severe neurological disorders such as Leigh syndrome. We report a pre-teen girl with progressive bilateral optic atrophy and steady visual deterioration, without neurological findings or systemic involvement. Neuroimaging was unremarkable for white matter lesions or structural brain lesions. Whole-exome sequencing demonstrated a homozygous missense mutation (c.1156C>T, p. Arg386Cys) in NDUFV1, implying a nuclear-encoded complex I defect. Laboratory analysis revealed increased lactate levels, consistent with mitochondrial dysfunction. Despite treatment with coenzyme Q, riboflavin and idebenone, no significant visual improvement occurred. This case represents a novel phenotype of NDUFV1-associated disease isolated optic atrophy without systemic involvement expanding the clinical spectrum of NDUFV1 mutations. Recognising this unique mitochondrial optic neuropathy may aid early diagnosis and targeted management.
    Keywords:  Genetics; Neuroimaging; Neuroopthalmology; Retina; Visual pathway
    DOI:  https://doi.org/10.1136/bcr-2025-266155
  6. Nat Commun. 2025 Jul 21. 16(1): 6700
    Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.
    Yingyuan Sun, Yaru Wang, Zheng Xing, Dongyu Li, Rong Wang, Baozhi Chen, Ning Zhou, Alyssa Ayala, Benjamin P Tu, Xiaofeng Qi.
      The Mitochondrial Pyruvate Carrier (MPC) bridges cytosolic and mitochondrial metabolism by transporting pyruvate into mitochondria for ATP production and biosynthesis of various essential molecules. MPC functions as a heterodimer composed of MPC1 and MPC2 in most mammalian cells. Here, we present the cryogenic electron microscopy (cryo-EM) structures of the human MPC1-2 complex in the mitochondrial intermembrane space (IMS)-open state and the inhibitor-bound in the mitochondrial matrix-open state. Structural analysis shows that the transport channel of MPC is formed by the interaction of transmembrane helix (TM) 1 and TM2 of MPC1 with TM2 and TM1 of MPC2, respectively. UK5099, a potent MPC inhibitor, shares the same binding site with pyruvate at the matrix side of the transport channel, stabilizing MPC in its matrix-open conformation. Notably, a functional W82F mutation in MPC2 leads to the complex in an IMS-open conformation. Structural comparisons across different conformations, combined with yeast rescue assays, reveal the mechanisms of substrate binding and asymmetric conformational changes in MPC during pyruvate transport across the inner mitochondrial membrane (IMM) as well as the inhibitory mechanisms of MPC inhibitors.
    DOI:  https://doi.org/10.1038/s41467-025-61939-z
  7. Cureus. 2025 Jun;17(6): e86607
    Acute Bilateral Vision Loss in a Young Male: A Case of Leber's Hereditary Optic Neuropathy.
    Zineb Hilali, Oumaima El Korno, Younes Laarif, Noureddine Boutimzine, Lalla Ouafae Cherkaoui.
      Leber's Hereditary Optic Neuropathy (LHON) is a rare mitochondrial genetic disorder that primarily affects young adult males, leading to acute or subacute painless central vision loss. The condition results from point mutations in mitochondrial DNA, most commonly affecting the ND1, ND4, or ND6 genes, which impair the function of complex I in the mitochondrial respiratory chain. This leads to selective degeneration of retinal ganglion cells and the optic nerve, causing severe and often irreversible visual impairment. We present the case of a 24-year-old male farmer who consulted for rapidly progressive bilateral visual acuity loss. Visual acuity was measured at 1/10 in the right eye and "counting fingers at near" in the left eye, with a left relative afferent pupillary defect (RAPD). An extensive etiological workup for optic neuropathy was conducted. Genetic testing of the MT-ND4 gene identified the 11778/ND4 mutation, confirming the diagnosis of LHON.
    Keywords:  gene therapy; genetic disease; leber’s hereditary optic neuropathy; optic neuropathy; sudden vision loss
    DOI:  https://doi.org/10.7759/cureus.86607
  8. Cell Chem Biol. 2025 Jul 17. pii: S2451-9456(25)00201-6. [Epub ahead of print]32(7): 902-904
    Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism.
    Riley J Wedan, Sara M Nowinski.
      Mitochondrial NADPH is abundant, but the reason why was uncertain. In a study published in Nature Cell Biology, Kim et al.1 identified an important role of NADK2-derived mitochondrial NADPH in mitochondrial fatty acid synthesis (mtFAS) through direct quantification of the products built by mtFAS. This work opens the door to understanding how NADK2, mitochondrial NADPH, and mtFAS regulate mitochondrial function.
    DOI:  https://doi.org/10.1016/j.chembiol.2025.06.006
  9. Adv Sci (Weinh). 2025 Jul 20. e08503
    NAD+-Boosters Improve Mitochondria Quality Control In Parkinson's Disease Models Via Mitochondrial UPR.
    Shuoting Zhou, Xi Xiong, Jialong Hou, Qi Duan, Yi Zheng, Tao Jiang, Jiani Huang, Haijun He, Jiaxue Xu, Keke Chen, Wenwen Wang, Jinlai Cai, Jingjing Qian, Huijun Chen, Weihong Song, XinShi Wang, Chenglong Xie.
      Serving as a pivotal hub for cellular metabolism and intracellular signaling, the mitochondrion has emerged as a crucial organelle whose dysfunction is linked to many human diseases, including neurodegenerative disorders, particularly Parkinson's disease (PD). However, whether mitochondrial quality control (MQC) can be targeted for therapeutic interventions remains uncertain. This study uses clinical samples, molecular biology techniques, pharmacological interventions, and genetic approaches to investigate the significance of NAD+ levels in cross-species models of PD. These results reveal that treatment of rotenone-incubated cells with NAD+ boosters (such as NMN, siCD38, and NAT) increases UPRmt/mitophagy-related MQC, reduces pro-inflammatory cytokine expression, inhibits apoptosis, and strengthen redox reactions. In vivo, NMN supplementation inhibits motor deficit and forestalls the neuropathological phenotypes of MPTP-induced PD mice, which are required for the atf4-related mitochondrial UPR pathway. Notably, bulk omics signatures and metabolomic profiling analyses of the striatum reveal NMN-induced transcriptional changes in genes and proteins involved in mitochondrial homeostasis. Thus, these findings demonstrate that the accelerated pathology in PD models is probably mediated by impaired MQC and that bolstering cellular NAD+ levels alleviates mitochondrial proteotoxic stress and mitigate PD phenotypes.
    Keywords:  NAD+‐boosters; Parkinson's disease; mitochondria quality control; mitochondrial unfolded protein response; nicotinamide mononucleotide
    DOI:  https://doi.org/10.1002/advs.202408503
  10. J Biol Chem. 2025 Jul 16. pii: S0021-9258(25)02333-6. [Epub ahead of print] 110483
    Stressful situations: molecular insights on mitochondrial quality control pathways.
    Sabrina Romanelli, Jean-François Trempe.
      Mitochondrial quality control has emerged as an important area of research over the past decade, with more than 2,000 publications exploring the molecular pathways that regulate it. Mitochondria are essential for energy production and various cellular functions but are highly susceptible to damage from stressors such as protein misfolding, reactive oxygen species, and chemicals that disrupt the electron transport chain. If left unresolved, mitochondrial dysfunction can lead to health complications, including neurodegenerative disorders, cardiovascular diseases, and cancer. To maintain cellular health, cells evolved quality control pathways to remove damaged mitochondrial components. This review focuses on three key quality control responses: the PINK1-Parkin pathway, the DELE1-HRI pathway, and the mitochondrial unfolded protein response (UPRmt). While these pathways have distinct functions, there is ongoing debate about how they overlap and which responds first in different contexts. In this review, we discuss the physiological and structural mechanisms behind each pathway, explore how they interconnect, and highlight their differences and relevance to disease. By summarizing this information in a single review, we aim to enhance the molecular understanding of mitochondrial quality control, which can help highlight avenues for novel therapeutics for diseases associated to dysfunctional mitochondria.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110483
  11. Biochem J. 2025 Jul 23. pii: BCJ20253171. [Epub ahead of print]482(15):
    The peculiar properties of mitochondrial carriers of the SLC25 family.
    Edmund R S Kunji, Vasiliki Mavridou, Martin S King, Camila Cimadamore-Werthein, Stephany Jaiquel Baron, Scott A Jones, Alannah C King, Roger Springett, Deepak Chand, Shane M Palmer, Denis Lacabanne, Sotiria Tavoulari, Jonathan J Ruprecht.
      With 53 members, the SLC25 mitochondrial carriers form the largest solute carrier family in humans. They transport a wide variety of substrates across the mitochondrial inner membrane to generate chemical energy and to supply molecules and ions for growth and maintenance of cells. They are among the smallest transporters in nature, yet they translocate some of the largest molecules without proton leak. With one exception, they are monomeric and have an unusual three-fold pseudo-symmetric structure. These carriers also have a unique transport mechanism, which is facilitated by six structural elements, meaning that all transmembrane helices move separately, but in a co-ordinated way. In addition, there are three functional elements that are an integral part of the alternating access mechanism, which opens and closes the carrier to the mitochondrial matrix or the intermembrane space. The first is a matrix gate, comprising the matrix salt bridge network and glutamine braces on transmembrane helices H1, H3 and H5. The second is a cytoplasmic gate, containing the cytoplasmic salt bridge network and tyrosine braces on transmembrane helices H2, H4 and H6. The third functional element is a single central substrate-binding site, the access to which is controlled by the opening and closing of the two gates in an alternating way. The electrostatic properties of the binding site facilitate the exchange of charged substrates across the inner membrane in the presence of a high membrane potential. Here, we discuss the extraordinary features of mitochondrial carriers, providing new insights into one of the most complex and dynamic transport mechanisms in nature.
    Keywords:  bioenergetics; mitochondria; oxidative phosphorylation; translocases; translocators; transport mechanism
    DOI:  https://doi.org/10.1042/BCJ20253171
  12. Cell Rep. 2025 Jul 20. pii: S2211-1247(25)00802-2. [Epub ahead of print]44(8): 116031
    PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson's disease.
    Global Parkinson’s Genetics Program (GP2)
      Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking, and LRRK2-activating mutations are linked to Parkinson's disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including protein phosphatase, Mg2+/Mn2+ dependent 1H (PPM1H), which acts on phosphorylated Rab 8A (phosphoRab8A) and phosphoRab10. Here, we report a phosphatome-wide small interfering RNA (siRNA) screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cultured cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of Ppm1m leads to primary cilia loss in striatal cholinergic and parvalbumin interneurons. We also identified a rare PPM1M mutation in patients with Parkinson's disease that is catalytically inactive when tested in vitro and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinson's disease.
    Keywords:  CP: Cell biology; CP: Neuroscience; LRRK2 kinase; Parkinson’s disease; Rab GTPase; phosphatase; primary cilia
    DOI:  https://doi.org/10.1016/j.celrep.2025.116031
  13. Bioinform Adv. 2025 ;5(1): vbaf135
    MitSorter: a standalone tool for accurate discrimination of mtDNA and NuMT ONT reads based on differential methylation.
    Sharon Natasha Cox, Angelo Sante Varvara, Graziano Pesole.
       Motivation: The accurate differentiation between mitochondrial DNA (mtDNA) and nuclear mitochondrial DNA segments (NuMTs) is a critical challenge in studies involving mitochondrial disorders. Mapping the mtDNA mutation spectrum and quantifying heteroplasmy are complex tasks when using next-generation sequencing methods, mostly due to NuMTs contamination in data analysis.
    Results: Here, we present a novel, easy-to-use standalone command-line tool designed to reliably discriminate long reads originated by either mtDNA or NuMTs and generated by Oxford Nanopore Technologies (ONT) sequencing based on the known lack of CpG methylation in human mtDNA. MitSorter aligns the reads to the mitochondrial genome incorporating base modification calls directly from raw POD5 files. The resulting BAM file is then partitioned into two separate BAM files: one containing unmethylated reads and the other containing methylated reads. We show that MitSorter analysis can provide a more accurate landscape of the mtDNA mutation profile. We describe here the tool's features, computational framework, validation approach, and its potential applications in other genomic research areas.
    Availability and implementation: Source code and documentation, are available at https://github.com/asvarvara/MitSorter.
    DOI:  https://doi.org/10.1093/bioadv/vbaf135
  14. Metabolites. 2025 Jul 02. pii: 446. [Epub ahead of print]15(7):
    Amino Acid Metabolism in Liver Mitochondria: From Homeostasis to Disease.
    Ranya Erdal, Kıvanç Birsoy, Gokhan Unlu.
      Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics. These functions depend on tightly regulated mitochondrial processes, including amino acid catabolism, ammonia clearance via the urea cycle, and transport through specialized solute carriers. Genetic disruptions in these pathways underlie a range of inborn errors of metabolism, often resulting in systemic toxicity and neurological dysfunction. Here, we review the physiological functions of hepatic mitochondrial amino acid metabolism, with a focus on subcellular compartmentalization, disease mechanisms, and therapeutic strategies. We discuss how emerging genetic and metabolic interventions-including dietary modulation, cofactor replacement, and gene therapy-are reshaping treatment of liver-based metabolic disorders. Understanding these pathways offers mechanistic insights into metabolic homeostasis and reveals actionable vulnerabilities in metabolic disease and cancer.
    Keywords:  amino acids; cancer; inborn errors of metabolism; liver; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/metabo15070446
  15. J Clin Invest. 2025 Jul 22. pii: e190215. [Epub ahead of print]
    Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase.
    Chao-Chieh Lin, Yi-Tzu Lin, Ssu-Yu Chen, Yasaman Setayeshpour, Yubin Chen, Denise E Dunn, Taylor Nguyen, Alexander A Mestre, Adrija Banerjee, Lalitha Guruprasad, Erik J Soderblom, Guo-Fang Zhang, Chen-Yong Lin, Valeriy Filonenko, Suh Young Jeong, Scott R Floyd, Susan J Hayflick, Ivan Gout, Jen-Tsan Chi.
      The cystine-xCT transporter-glutathione (GSH)-GPX4 axis is the canonical pathway protecting cells from ferroptosis. While GPX4-targeting ferroptosis-inducing compounds (FINs) act independently of mitochondria, xCT-targeting FINs require mitochondrial lipid peroxidation, though the mechanism remains unclear. Since cysteine is also a precursor for coenzyme A (CoA) biosynthesis, here, we demonstrated that CoA supplementation selectively prevented ferroptosis triggered by xCT inhibition by regulating the mitochondrial thioredoxin system. Our data showed that CoA regulated the in vitro enzymatic activity of mitochondrial thioredoxin reductase (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolished its enzymatic activity and ability to protect cells against ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2. Furthermore, the fibroblasts from patients with disrupted CoA metabolism demonstrated increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis led to an oxidized thioredoxin system, increased mitochondrial lipid peroxidation, and loss of cell viability, which were all rescued by ferrostatin-1. These findings identified CoA-mediated post-translational modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.
    Keywords:  Amino acid metabolism; Cell biology; Cell stress; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/JCI190215
  16. Nature. 2025 Jul;643(8073): 1143-1145
    Meet the biotech-company founders driven by their child's rare disease.
    Rachel Brazil.
      
    Keywords:  Biotechnology; Careers; Drug discovery; Industry
    DOI:  https://doi.org/10.1038/d41586-025-02262-x
  17. J Cell Sci. 2025 Jul 24. pii: jcs.263736. [Epub ahead of print]
    The mammalian protein MTCH1 can function as an insertase.
    Anna Roza Dimogkioka, Anni Elias, Doron Rapaport.
      The outer mitochondrial membrane (OMM) hosts a variety of proteins such as import machineries, enzymes, fission/fusion factors, and pore proteins. In Saccharomyces cerevisiae, the MIM complex, consisting of Mim1 and Mim2, mediates the insertion of α-helical proteins into the OMM. Until recently, it was unclear which proteins serve this function in higher eukaryotes. Recent studies identified MTCH2 as the insertase of α-helical proteins into the OMM in mammals. MTCH1 is a paralogue of MTCH2 but its general function and contribution to the biogenesis process are not clear. To better characterize MTCH1, we explored whether MTCH1 or MTCH2 could functionally replace Mim1/Mim2 in yeast. Expression of MTCH1 and MTCH2 in yeast cells lacking Mim1, Mim2, or both revealed that MTCH1, but not MTCH2, could compensate the growth defects upon deleting the MIM complex. Furthermore, MTCH1 could restore the biogenesis of MIM substrates, TOM complex stability, and morphology of mitochondria. These findings indicate that MTCH1 by itself has insertase activity and is a functional homologue of the MIM complex, despite the absence of any evolutionary relation between the mammalian and yeast insertases.
    Keywords:  Insertase; MIM; MTCH1; MTCH2; Mitochondria; Outer membrane
    DOI:  https://doi.org/10.1242/jcs.263736
  18. N Engl J Med. 2025 Jul 16.
    Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease.
    Robert McFarland, Louise A Hyslop, Catherine Feeney, Rekha N Pillai, Emma L Blakely, Eilis Moody, Matthew Prior, Anita Devlin, Robert W Taylor, Mary Herbert, Meenakshi Choudhary, Jane A Stewart, Douglass M Turnbull.
      Pathogenic variants in mitochondrial DNA (mtDNA) are a common cause of severe, often fatal, inherited metabolic disease. A reproductive care pathway was implemented to provide women carrying pathogenic mtDNA variants with reproductive options. A total of 22 women with pathogenic mtDNA variants have commenced or completed pronuclear transfer (and thus receipt of a mitochondrial donation), and there have been 8 live births. All 8 children were healthy at birth, with no or low levels of mtDNA heteroplasmy in blood. Hyperlipidemia and cardiac arrhythmia developed in a child whose mother had hyperlipidemia during pregnancy; both of the child's conditions responded to treatment. Infant myoclonic epilepsy developed in another child, with spontaneous remission. At the time of this report, all the children have made normal developmental progress. (Funded by the U.K. National Health Service and others.).
    DOI:  https://doi.org/10.1056/NEJMoa2503658
  19. Nat Metab. 2025 Jul 21.
    LONP1 loss causes mitochondrial mayhem in β-cells.
    Kok Lim Kua, Carmella Evans-Molina.
      
    DOI:  https://doi.org/10.1038/s42255-025-01328-4
  20. Free Radic Biol Med. 2025 Jul 16. pii: S0891-5849(25)00840-8. [Epub ahead of print]239 27-42
    MITF promotes MFN2-dependent mitochondrial fusion to protect retinal pigment epithelial cells from mitochondrial damage.
    Ying-Ao Chen, Wan-Ni Lu, Pingping Li, Tianyin Nie, Yan Li, Rui Zeng, Sen Lin, Meiling Gao, J Fielding Hejtmancik, Ling Hou, Xiaoyin Ma.
      There is growing indication that protecting the retinal pigment epithelium (RPE) against mitochondrial damage is crucial for preventing RPE cell dysfunction and retinal degeneration. However, the molecular mechanisms remain largely unknown. Here, we show that microphthalmia-associated transcription factor (MITF), a potent antioxidant inducer in RPE, promotes mitochondrial fusion in RPE cells and protects them from mitochondrial uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced mitochondrial damage in ARPE-19 or mouse primary RPE cells ex vivo and Mitf heterozygous mice (Mitf-/+), Mitf-overexpressing transgenic mice (Dct-Mitf) or AAV mediated MITF overexpression mice in vivo. Mechanistically, MITF directly binds to the promoter of Mitofusin 2 (MFN2), a mitochondrial membrane protein that participates in mitochondrial fusion, and activates its transcription. Conversely, the knockdown of MFN2 neutralized the effects of MITF on mitochondrial fusion and mitochondrial damage protection. Intravitreal injection of mitochondria-targeted SkQ-1 nanoparticles effectively protects RPE cells from CCCP-induced damage in the Mitf-/+ mice in vivo. These findings suggest that MITF has an important role in regulating mitochondrial fusion in RPE cells and provides new insights into understanding the mechanisms of MITF deficiency induced RPE abnormalities and retinal degeneration.
    Keywords:  MITF; Mitochondria; Mitochondrial fusion; RPE; Retinal degeneration
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.07.025
  21. Nat Metab. 2025 Jul 21.
    LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
    Jin Li, Yamei Deng, Marie Gasser, Jie Zhu, Emily M Walker, Vaibhav Sidarala, Emma C Reck, Dre L Hubers, Mabelle B Pasmooij, Chun-Shik Shin, Khushdeep Bandesh, Eftyhmios Motakis, Siddhi Nargund, Romy Kursawe, Venkatesha Basrur, Alexey I Nesvizhskii, Michael L Stitzel, David C Chan, Guy A Rutter, Scott A Soleimanpour.
      Protein misfolding is a contributor to the development of type 2 diabetes (T2D), but the specific role of impaired proteostasis is unclear. Here we show a robust accumulation of misfolded proteins in the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability through the mitochondrial matrix protease LONP1. Quantitative proteomics studies of protein aggregates reveal that islets from donors with T2D have a signature resembling mitochondrial rather than endoplasmic reticulum protein misfolding. Loss of LONP1, a vital component of the mitochondrial proteostatic machinery, with reduced expression in the β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, leading to β cell apoptosis and hyperglycaemia. LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival after glucolipotoxicity via a protease-independent effect requiring LONP1-mitochondrial HSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycaemia by facilitating mitochondrial protein folding. These observations provide insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D, which could be considered as future therapeutic targets.
    DOI:  https://doi.org/10.1038/s42255-025-01333-7
  22. JIMD Rep. 2025 Jul;66(4): e70035
    Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): A Case Report With a Complex Biochemical Profile.
    Romain Penicaud, Jean-Baptiste Ferron, Xavier Valette, Pierrick Bauduin, Maxime Faisant, Manuel Schiff, Alexandre Nguyen, Fanny Fontaine, Stéphane Allouche.
      Three clinical entities of multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM#231680) can be differentiated: two severe neonatal forms and one later-onset form that can manifest in adulthood. The latter typically presents with muscle-related symptoms, such as exercise intolerance and muscle weakness, with an increase in all chain-length acylcarnitine species on the acylcarnitine profile. Here, we report the case of a 33-year-old woman who experienced severe psychiatric issues complicated by an eating disorder resulting in a significant malnutrition a few months before presenting with a profound muscle weakness, fatigue, intermittent ptosis, and a major rhabdomyolysis (creatine kinase (CK) > 15 000 IU/L). Biochemical blood tests, including acylcarnitine profile, urinary organic acid analysis, and in vitro beta-oxidation, were not suggestive of a metabolic disease. Given the absence of an etiology and the worsening health condition of the patient, whole exome sequencing (WES) was performed and revealed two pathogenic variants in the electron transfer flavoprotein dehydrogenase (ETFDH) gene, whose association has not been reported before. Unlike other beta oxidation deficiencies, which have a typical biochemical signature, the diagnosis of MADD was made by genetic analyses, which allowed the introduction of vitamin B2 supplementation and the rapid improvement of symptoms.
    Keywords:  acylcarnitine profile; beta‐oxidation; electron transfer flavoprotein dehydrogenase (ETFDH); mitochondrial disease; multiple acyl‐CoA dehydrogenase deficiency (MADD); rhabdomyolysis
    DOI:  https://doi.org/10.1002/jmd2.70035
  23. Cells. 2025 Jul 15. pii: 1078. [Epub ahead of print]14(14):
    Pseudohypoxia-Stabilized HIF2α Transcriptionally Inhibits MNRR1, a Druggable Target in MELAS.
    Neeraja Purandare, Vignesh Pasupathi, Yue Xi, Vikram Rajan, Caleb Vegh, Steven Firestine, Tamas Kozicz, Andrew M Fribley, Lawrence I Grossman, Siddhesh Aras.
      The mitochondrial regulator MNRR1 is reduced in several pathologies, including the mitochondrial heteroplasmic disease MELAS, and genetic restoration of its level normalizes the pathological phenotype. Here, we investigate the upstream mechanism that reduces MNRR1 levels. We have identified the hypoxic regulator HIF2α to bind the MNRR1 promoter and inhibit transcription by competing with RBPJκ. In MELAS cells, there is a pseudohypoxic state that transcriptionally induces HIF2α and stabilizes HIF2α protein. MELAS cybrids harboring the m.3243A > G mutation display reduced levels of prolyl hydroxylase 3 (PHD3), which contributes to the HIF2α stabilization. These results prompted a search for compounds that could increase MNRR1 levels pharmacologically. The screening of a 2400-compound library uncovered the antifungal drug nitazoxanide and its metabolite tizoxanide as enhancers of MNRR1 transcription. We show that treating MELAS cybrids with tizoxanide restores cellular respiration, enhances mitophagy, and, importantly, shifts heteroplasmy toward wild-type mtDNA. Furthermore, in fibroblasts from MELAS patients, the compound improves mitochondrial biogenesis, enhances autophagy, and protects from LPS-induced inflammation. Mechanistically, nitazoxanide reduces HIF2α levels by increasing PHD3. Chemical activation of MNRR1 is thus a potential strategy to improve mitochondrial deficits seen in MELAS. Finally, our data suggests a broader physiological pathway wherein two proteins, induced under severe (1% O2; HIF2α) and moderate (4% O2; MNRR1) hypoxic conditions, regulate each other inversely.
    Keywords:  drug repurposing; heteroplasmy; hypoxia
    DOI:  https://doi.org/10.3390/cells14141078
  24. Eur Heart J. 2025 Jul 24. pii: ehaf491. [Epub ahead of print]
    Mitochondrial cardiomyopathies: pathogenesis, diagnosis, and treatment.
    Christoph Maack, Jan Dudek, Edoardo Bertero, Emmanouil Tampakakis, Hilary J Vernon.
      Mitochondrial cardiomyopathies are a heterogeneous group of disorders caused by dysfunction of mitochondrial energy production due to genetic mutations affecting mitochondrial or nuclear DNA. Mitochondrial cardiomyopathies can include a wide range of cardiac manifestations and are frequently associated with other multisystemic symptoms, including skeletal myopathy, neurological deficits, and metabolic disturbances. Advances in genetic testing have improved diagnostic accuracy, but early identification remains challenging due to the variable clinical presentation and clinical overlap with other cardiomyopathies. Therapeutic strategies are still evolving, with current management focusing on symptom control and mitigation of mitochondrial dysfunction. This review aims to provide a comprehensive overview of the pathophysiology, clinical features, diagnostic approaches, and treatment options for mitochondrial cardiomyopathies, highlighting the ongoing need for research into effective therapies and improved patient outcomes.
    Keywords:  Bioenergetics; Heart failure; Mitochondrial cardiomyopathy; mtDNA
    DOI:  https://doi.org/10.1093/eurheartj/ehaf491
  25. Seizure. 2025 Jul 07. pii: S1059-1311(25)00176-1. [Epub ahead of print]131 200-202
    Bilateral epilepsia partialis continua in POLG related mitochondrial disease.
    Thuppanattumadam Ananthasubramanian Sangeeth, L G Viswanathan, Seshagiri Dv, Shilpa Rao, Madhu Nagappa, Jitender Saini, Sanjib Sinha.
      
    Keywords:  Epilepsia partialis continua; Mitochondrial encephalopathy; POLG-related disorder
    DOI:  https://doi.org/10.1016/j.seizure.2025.07.004
  26. Anal Chem. 2025 Jul 22.
    Ultra-Photostable Fluorescent Boron-Bridged Near-Infrared Probes to Reveal New Mode of Lipid Droplet-Mitochondria Interaction at STED Super-Resolution.
    Mingyue Cao, Xiaoming Zhu, Yunting Liu, Yangang Su, Xinru Hu, Zhiqiang Liu, Xiaoqiang Yu.
      Interactions between lipid droplets (LDs) and mitochondria are vital for maintaining the cellular metabolism and energy homeostasis. However, visualizing these interaction dynamics at a high resolution in live cells is still very challenging. Here, a boron-bridged near-infrared probe (QI-BF) was developed specifically for low-power stimulated emission depletion (STED) super-resolution imaging of LDs. QI-BF exhibited excellent photostability and enabled continuous scanning of 1000+ frames using a STED laser (0.96 MW cm-2, 775 nm), without significant fluorescence decay. Furthermore, dynamic dual-color STED super-resolution visualization of the morphological interactions between LDs and mitochondria was achieved with the aid of commercial mitochondrial dyes. For the first time, the dynamic process of mitochondrial wrapping around the LDs and LD-mediated mitochondria tubulation were successfully captured. This study sheds light on developing ultraphotostable organic fluorescent probes for versatile low-power STED nanoscopy.
    DOI:  https://doi.org/10.1021/acs.analchem.5c02739
  27. Nat Rev Immunol. 2025 Jul 23.
    Mitochondrial proteins go public and novel interactions: insights from surfaceome mapping.
    Adam J Grippin, Wen Jiang.
      
    DOI:  https://doi.org/10.1038/s41577-025-01216-8
  28. Nat Cell Biol. 2025 Jul 21.
    TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger.
    Jim Lu Zhang, Yu-Chen Chang, Po-Hsuan Lai, Han-I Yeh, Chen-Wei Tsai, Yu-Lun Huang, Tsung-Yun Liu, I-Chi Lee, North Foulon, Yan Xu, Bing Rao, Hsiu-Man Shih, Yung-Chi Tu, Andres V Reyes, Shou-Ling Xu, Liang Feng, Ming-Feng Tsai.
      Mitochondria export Ca2+ via Na+/Ca2+ exchange machinery (mito-NCX) to regulate intracellular Ca2+ signalling and mitochondrial Ca2+ homeostasis. TMEM65 has recently been implicated as essential for mito-NCX, but its mechanisms and roles remain unclear. Here we show that TMEM65 depletion severely impairs mito-NCX. TMEM65 is highly expressed in the heart and brain but absent in the liver, correlating with mito-NCX activity in these tissues. Biochemical and functional analyses reveal that TMEM65 forms a homodimer, containing plausible ion-coordinating residues critical for function. Heterologous expression of TMEM65 induces Na+/Ca2+ exchange in cells lacking native mito-NCX activity. Moreover, purified, liposome-reconstituted TMEM65 exhibits key mito-NCX features. We further identify the binding site for CGP-37157, a potent, widely used mito-NCX inhibitor. Finally, TMEM65 deletion elevates mitochondrial Ca2+ and primes mitochondria to permeability transition. These findings firmly establish TMEM65 as the protein mediating mito-NCX, offering a new therapeutic target for diseases associated with mitochondrial Ca2+ dysregulation.
    DOI:  https://doi.org/10.1038/s41556-025-01721-x
  29. PLoS Biol. 2025 Jul 21. 23(7): e3003298
    A protein-specific priority code in presequences determines the efficiency of mitochondrial protein import.
    Saskia Rödl, Yasmin Hoffman, Felix Jung, Annika Egeler, Annika Nutz, Oliver Šimončík, Martin Jung, Markus Räschle, Petr Muller, Zuzana Storchova, Timo Mühlhaus, Johannes M Herrmann.
      The biogenesis of mitochondria relies on the import of hundreds of different precursor proteins from the cytosol. Most of these proteins are synthesized with N-terminal presequences which serve as mitochondrial targeting signals. Presequences consistently form amphipathic helices, but they considerably differ with respect to their primary structure and length. Here we show that presequences can be classified into seven different groups based on their specific features. Using a test set of different presequences, we observed that group A presequences endow precursor proteins with improved in vitro import characteristics. We developed IQ-Compete (for Import and de-Quenching Competition assay), a novel assay based on fluorescence de-quenching, to monitor the import efficiencies of mitochondrial precursors in vivo. With this assay, we confirmed the increased import competence of group A presequences. Using mass spectrometry, we found that the presequence of the group A protein Oxa1 specifically recruits the tetratricopeptide repeat (TPR)-containing protein TOMM34 to the cytosolic precursor protein. TOMM34, and the structurally related yeast co-chaperone Cns1, apparently serve as a presequence-specific targeting factor which increases the import efficiency of a specific subset of mitochondrial precursor proteins. Our results suggest that presequences contain a protein-specific priority code that encrypts the targeting mechanism of individual mitochondrial precursor proteins.
    DOI:  https://doi.org/10.1371/journal.pbio.3003298
  30. J Adv Res. 2025 Jul 16. pii: S2090-1232(25)00546-6. [Epub ahead of print]
    Mitochondrial cardiovascular diseases: molecular mechanisms, multi-omics exploration and therapeutic strategies.
    Zhengyang Zhang, Xingwang Zhao, Xu Zhang, Sitong Wan, Peng An, Yinhua Zhu, Yongting Luo, Junjie Luo.
       BACKGROUND: Recent research highlights that abnormal mitochondrial function is a key feature in several cardiovascular diseases (CVDs), including aortic dissection, aortic aneurysm, atherosclerosis, pulmonary hypertension, and heart failure. We propose a novel concept termed mitochondrial cardiovascular diseases (Mito-CVDs) to define these conditions, which involve heart and vascular disorders directly driven by mitochondrial impairments, with the aim of highlighting the critical role of mitochondria in CVDs.
    AIM OF REVIEW: This review aims to explore the complex relationship between mitochondrial impairments and Mito-CVDs, offering insights into potential molecular mechanisms and therapeutic strategies to address these diseases.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: The role of mitochondrial impairments in CVDs is expounded upon in detail, encompassing aspects such as excessive production of Reactive Oxygen Species (ROS), diminished Oxidative Phosphorylation (OXPHOS) capacity, and perturbations in Ca2+ transport. We also recapitulate the application of mitochondrial multi-omics, incorporating genomics, transcriptomics, proteomics, and metabolomics, within the realm of CVDs research. Additionally, single-cell mtDNA sequencing technology unfolds novel vistas for disclosing mitochondrial heterogeneity and status functional in Mito-CVDs. To enhance the understanding of Mito-CVDs, we present advanced diagnostic tools and categorize specific subtypes within each class of these disorders. Additionally, we propose Predictive, Preventive, and Personalized Medicine (PPPM) strategies designed to address mitochondrial impairments. Emerging therapeutic approaches are also discussed, including small-molecule modulators targeting key metabolic pathways, precision-based mtDNA editing technologies, and mitochondrial transplantation. A profound and exhaustive analysis of the mechanisms and therapeutic avenues associated with Mito-CVDs holds the potential to engender novel perspectives and opportunities for the prevention and treatment of CVDs.
    Keywords:  Mito-CVDs; Mito-CVDs therapy; Mitochondrial impairment; Mitochondrial multi-omics; Predictive approach; Single-cell mtDNA sequencing; Treatments tailored to individualised patient profiles
    DOI:  https://doi.org/10.1016/j.jare.2025.07.021
  31. J Vis Exp. 2025 Jul 03.
    Determination of Mitochondrial Morphology in Live Cells Using Confocal Microscopy.
    Manna Lin, Jiakang Wang, Zihong Xian, Chunyuan Zeng, Jiangping Xu.
      The dynamic balance of mitochondrial fusion and fission directly contributes to mitochondrial homeostasis, which influences numerous cellular functions in addition to adenosine triphosphate (ATP) homeostasis. Therefore, assessing mitochondrial morphology under stress conditions is essential for mechanistic research. This study describes a detailed protocol for analyzing mitochondrial morphology, encompassing the preparation of a MitoTracker solution, staining of mitochondria, optimization of imaging parameters, and detection of morphological features. MitoTrackers are commonly used, cost-effective mitochondrion-specific dyes. However, some changes in mitochondrial morphology may occur owing to inappropriate handling, which can be unperceivable and fail to reflect the true state of mitochondria. Therefore, it is necessary to understand how to analyze changes in mitochondrial morphology using MitoTrackers. The protocol utilized SH-SY5Y cells stimulated with 1-methyl-4-phenylpyridinium iodide (MPP+) to illustrate the protocol of mitochondrial morphological analysis. Compared with control cells, MPP+-stimulated cells exhibited smaller and more fragmented mitochondria, with morphological parameters indicating decreased mitochondrial footprint. These results suggest that MitoTracker staining is an effective and feasible method for mitochondrial morphological analysis that (with minor modifications) can be applied to study various conditions.
    DOI:  https://doi.org/10.3791/68167
  32. Mol Metab. 2025 Jul 17. pii: S2212-8778(25)00122-X. [Epub ahead of print] 102215
    UCP2 MEDIATES MITOCHONDRIAL DYNAMICS TO INDUCE AgRP NEURONAL ACTIVITY.
    Sungho Jin, Nal Ae Yoon, Zhong-Wu Liu, Ciro Menale, Jung Dae Kim, Nadia Diano, Sabrina Diano.
       OBJECTIVE: The hypothalamic agouti-related protein (AgRP)- expressing neurons regulate feeding and whole-body energy homeostasis. A growing body of evidence indicates that changes in mitochondrial dynamics, such as fission and fusion, play a crucial role in regulating AgRP neuronal activity. However, the mechanisms underlying this process remain to be elucidated. Here, we showed a role of mitochondrial UCP2-mediated mitochondrial dynamics in AgRP neurons in regulating AgRP neuronal activity and fasting-induced feeding behavior.
    METHODS: We analyzed mitochondrial morphology, expression of activated dynamin-related protein 1 (DRP1), and mRNA expression levels of uncoupling protein 2 (Ucp2) in AgRP neurons of mice that were either in fed or fasted states. We then generated a mouse model in which Ucp2 was selectively deleted from adult AgRP neurons to assess the role of this mitochondrial protein in feeding behavior and whole-body energy metabolism.
    RESULTS: We show fasting-induced AgRP neuronal activation is associated with UCP2-mediated mitochondrial fission and mitochondrial fatty acid utilization in AgRP neurons. In line with this, mice lacking UCP2 in AgRP neurons (Ucp2AgRPKO) show attenuated fasting- or ghrelin-induced AgRP neuronal activation and feeding behaviors and exhibited a significant decrease in body weight and fat mass accompanied by a significant increase in energy expenditure.
    CONCLUSIONS: Altogether, our data revealed that UCP2-mediated mitochondrial dynamics and fatty acids oxidation in the hypothalamic AgRP neurons is necessary for AgRP neuronal function and fasting-induced food intake.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102215
  33. Transl Pediatr. 2025 Jun 27. 14(6): 1385-1386
    A rare de novo mutation, m.1630A>G, in the mitochondrial trnAVal (MT-TV) gene in a child with epilepsy.
    Qiong Wang, Yan Chen, Jun Li, Baomin Li.
      
    DOI:  https://doi.org/10.21037/tp-2025-258
  34. Rinsho Shinkeigaku. 2025 Jul 24.
    [A case of a spinal cord involvement in an adult mitochondrial disease with an m.3243A>G].
    Ken-Ichi Shibata, Tatsuya Mukai, Hideaki Nakagaki, Sukehisa Nagano.
      A 44-year-old woman had weakness in her right lower limb, a right Babinski reflex, paresthesia in her left lower leg, hypoesthesia at and below the T6 dermatome, and abnormality of the vibrational perception in both legs after prolonged exertion. Her medical history comprised sensorineural hearing loss and diabetes. Furthermore, her child had mitochondrial disease with an m.3243A>G. The patient was diagnosed with maternally inherited diabetes and deafness (MIDD), and the disease-causing variant was identified as m.3243A>G. Cerebrospinal fluid analysis revealed the presence of oligoclonal bands. T2-weighted magnetic resonance imaging showed hyperintensity of the right side of the spinal cord at the level of the 4th thoracic vertebra. This paper examines spinal cord lesions that occur in patients with mitochondrial diseases.
    Keywords:  Spinal cord; m.3243A>G; maternally inherited diabetes and deafness (MIDD); mitochondrial disease
    DOI:  https://doi.org/10.5692/clinicalneurol.cn-002071
  35. Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2505704122
    Cell type-specific purifying selection of synonymous mitochondrial DNA variation.
    Caleb A Lareau, Patrick Maschmeyer, Yajie Yin, Jacob C Gutierrez, Ryan S Dhindsa, Anne-Sophie Gribling-Burrer, Sebastian Zielinski, Yu-Hsin Hsieh, Lena Nitsch, Veronika Dimitrova, Benan Nalbant, Frank A Buquicchio, Tsion Abay, Robert R Stickels, Jacob C Ulirsch, Patrick Yan, Fangyi Wang, Zhuang Miao, Katalin Sandor, Bence Daniel, Vincent Liu, Paul L Mendez, Petra Knaus, Manpreet Meyer, William J Greenleaf, Anshul Kundaje, Redmond P Smyth, Mathias Munschauer, Leif S Ludwig, Ansuman T Satpathy.
      While somatic variants are well-characterized drivers of tumor evolution, their influence on cellular fitness in nonmalignant contexts remains understudied. We identified a mosaic synonymous variant (m.7076A > G) in the mitochondrial DNA (mtDNA)-encoded cytochrome c-oxidase subunit 1 (MT-CO1, p.Gly391=), present at homoplasmy in 47% of immune cells from a healthy donor. Single-cell multiomics revealed strong, lineage-specific selection against the m.7076G allele in CD8+ effector memory T cells, but not other T cell subsets, mirroring patterns of purifying selection of pathogenic mtDNA alleles. The limited anticodon diversity of mitochondrial tRNAs forces m.7076G translation to rely on wobble pairing, unlike the Watson-Crick-Franklin pairing used for m.7076A. Mitochondrial ribosome profiling confirmed stalled translation of the m.7076G allele. Functional analyses demonstrated that the elevated translational and metabolic demands of short-lived effector T cells (SLECs) amplify dependence on MT-CO1, driving this selective pressure. These findings suggest that synonymous variants can alter codon syntax, impacting mitochondrial physiology in a cell type-specific manner.
    Keywords:  immunology; mitochondria; selection; single-cell
    DOI:  https://doi.org/10.1073/pnas.2505704122
  36. Cells Tissues Organs. 2025 Jul 24. 1-25
    Mitochondrial Glycosylation in Neuroinflammation Models.
    Meghana Madabhushi, Rachel Erin Murphy, Md Akkas Ali, Muthuvel Paneerselvam, Mallikarjun Hanamantagouda Patil, Daniel J Tyrrell, Juhi Samal.
       INTRODUCTION: Mitochondria are cellular energy factories, but their function declines with age in many tissues as well as disease pathophysiology. Mitochondrial proteins have sugar modifications called glycans, which regulate their function and localization. There is a knowledge gap on the impact of mitochondrial protein glycosylation on mitochondrial function and mediating neuroinflammation. We hypothesize that stimuli-specific neuroinflammatory treatments in microglia induce pathological changes in mitochondrial protein glycosylation and compromise mitochondrial function.
    METHODS: The aim of this study was to establish a detailed microglial mitochondrial glycoprofile in different models of inflammation using lectins to identify the glycan-based markers of mitochondrial dysfunction. We use three different pathways of microglial activation: lipopolysaccharide (LPS), cytokines, and oxygen-glucose deprivation (OGD), revealing differences in mitochondrial glycosylation in different models of inflamed microglia. Mitochondrial lectin blots and lectin flow analysis were used to quantify the glycosylation changes due to different neuroinflammatory conditions. Seahorse Mito Stress assay was performed to assess mitochondrial function in each of these conditions.
    RESULTS: Lectin immunoblots of mitochondrial proteins and lectin flow studies with intact mitochondria were performed in three different neuroinflammation models using BV-2 microglial cells, revealing considerable stimuli-specific, differential mitochondrial glycosylation between these models and healthy controls. It was found that several glycans associated with mitochondria were differentially regulated during microglial activation. The observed changes in glycosylation trends were more drastic in OGD treatment as compared to other treatments, especially for complex and sialylated glycans.
    CONCLUSION: This study represents the first functional investigation of mitochondrial glycosylation in microglial inflammation models towards identifying glycosylation-based therapeutic targets.
    DOI:  https://doi.org/10.1159/000547463
  37. Cell Rep. 2025 Jul 21. pii: S2211-1247(25)00803-4. [Epub ahead of print]44(8): 116032
    Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis.
    Louise Nuyttens, Marah Heyerick, Geike Heremans, Elise Moens, Maxime Roes, Céline Van Dender, Liesbet De Bus, Johan Decruyenaere, Jan Dewaele, Jolien Vandewalle, Claude Libert.
      Sepsis, killing 11 million people yearly, is associated with increased production of lactate-a metabolite mechanistically linked to mortality-complicating glucose administration in sepsis. To understand the mechanism behind hyperlactatemia, we applied the cecal ligation and puncture (CLP) model and studied all pyruvate processing routes in liver mitochondria during acute sepsis. Our data suggest that mitochondrial pyruvate-driven respiration is nearly nonexistent in sepsis, not due to insufficient pyruvate uptake or carboxylation, but due to a dysfunctional pyruvate dehydrogenase complex (PDC). Septic mitochondria compensate via glutamate-mediated tricarboxylic acid (TCA) anaplerosis, simultaneously converting some pyruvate into alanine via enhanced mitochondrial glutamic pyruvate transaminase (GPT2) activity. PDC dysfunction is not caused by PDC inactivation per se but by a shortage of its cofactor, thiamine pyrophosphate (TPP). TPP supplementation restores pyruvate oxidation and protects mice from sepsis. TPP also allows safe glucose administration in mice, leading to a robust TPP-plus-glucose therapy.
    Keywords:  CP: Metabolism; CP: Microbiology; lactate; mitochondria; pyruvate; sepsis; thiamine
    DOI:  https://doi.org/10.1016/j.celrep.2025.116032
  38. J Physiol. 2025 Jul 20.
    Targeting ALDH2 to promote skeletal muscle health: A novel strategy against mitochondrial dysfunction.
    Katia S G Andrade, Jianming Liu, Dimitrius Santiago P S F Guimarães, Julio C B Ferreira, Zhigao Wang, Da-Zhi Wang, Leonardo R Silveira.
      The maintenance of skeletal muscle relies on several cellular signalling pathways directly linked to mitochondrial function. Mitochondria support skeletal muscle bioenergetics and are known as a primary source of reactive oxygen species (ROS). Indeed, mitochondrial dysfunction-induced excessive ROS accumulation leads to irreversible molecular damage caused by lipid peroxidation by product 4-hydroxy-trans-2-nonenal (4-HNE), this is able to directly inactivate proteins and DNA, causing mitochondrial and cellular dysfunction. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme responsible for counteracting this deleterious cycle by detoxifying aldehydes and converting them into less harmful molecules. In this context, ALDH2 is essential for functional skeletal muscle maintenance. In fact, studies published in the last decade show that ALDH2 overexpression downregulates atrophic genes; meanwhile, the lack of this protein is associated with muscle weakness and atrophy, demonstrating its relevance for maintaining muscle mass. In this context, interventions capable of increasing ALDH2 levels and/or activity are considered promising therapeutic strategies for mitigating oxidative damage, enhancing mitochondrial function, and preserving muscle integrity under adverse conditions.
    Keywords:  aldehydic load; antioxidant; cachexia; sarcopenia; skeletal muscle; therapy
    DOI:  https://doi.org/10.1113/JP288882
  39. Gut. 2025 Jul 23. pii: gutjnl-2024-334561. [Epub ahead of print]
    Mitochondrial dysfunction drives basal cell hyperplasia in eosinophilic oesophagitis.
    Masaki Morimoto, Kento Kawasaki, Niamh McNamee, Samuel Flashner, Rieko Shimonosono, Masataka Shimonosono, Norihiro Matsuura, Yasuto Tomita, Wataru Hirose, Ryugo Teranishi, Takefumi Itami, Manti Guha, Pavithra Rajagopalan, Cecilia Martin, Hailey Golden, Diya Dhakal, Benjamin J Wilkins, Andres J Klein-Szanto, Kirk J Wangensteen, Julian A Abrams, Sydney Pomenti, David A Katzka, Jianwen Que, Kelly A Whelan, Amanda B Muir, Hirohito Kita, Benjamin L Wright, Alfred D Doyle, Hiroshi Nakagawa, Uma M Sachdeva.
       BACKGROUND: Eosinophilic oesophagitis (EoE) is a food allergen-induced inflammatory disorder characterised by interleukin (IL)-13-mediated oesophageal inflammation and epithelial basal cell hyperplasia (BCH). The role of mitochondria in EoE pathogenesis remains elusive.
    DESIGN: Prompted by single cell transcriptomics data, we interrogated the role of mitochondria in EoE pathobiology using patient biopsies, EoE-mouse models and oesophageal epithelial cells grown in monolayer and three-dimensional (3D) organoid cultures treated with EoE-relevant cytokines. 3D organoids and EoE-bearing mice were treated with omeprazole-a proton-pump inhibitor used as first-line EoE therapy. We performed CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) interference in mouse organoids to identify the key mitochondrial regulatory genes whose depletion may lead to BCH. We analysed mitochondrial membrane potential, mass and superoxide production by flow cytometry, cellular oxygen consumption by respirometry, mitochondrial structures and perturbation of cellular energy homeostasis by immunoblotting.  RESULTS : Mitochondrial dysfunction appeared to be a hallmark of EoE-related BCH where mitochondrial structural damage was associated with impaired oxidative respiratory capacity, elevation of mitochondrial superoxide and decreased adenosine triphosphate (ATP) production, as corroborated by activation of the adenosine monophosphate (AMP) -activated protein kinase and suppression of mammalian target-of-rapamycin signalling. Depletion of PGC1A, the master regulator of mitochondria biogenesis, recapitulated EoE-related BCH, suggesting that mitochondrial dysfunction drives BCH. Further, omeprazole alleviated mitochondrial damage and dysfunction in EoE-related BCH modelled in mice and patient-derived organoids.  CONCLUSION: Mitochondrial dysfunction is tightly linked to perturbation of redox homeostasis in EoE-related BCH, which is promoted by IL-13 and reversible with omeprazole treatment.
    Keywords:  GASTROINTESTINAL IMMUNE RESPONSE; INFLAMMATORY DISEASES; OESOPHAGITIS
    DOI:  https://doi.org/10.1136/gutjnl-2024-334561
  40. Science. 2025 Jul 24. eadx3800
    High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
    Luke W Koblan, Kathryn E Yost, Pu Zheng, William N Colgan, Matthew G Jones, Dian Yang, Arhan Kumar, Jaspreet Sandhu, Alexandra Schnell, Dawei Sun, Can Ergen, Reuben A Saunders, Xiaowei Zhuang, William E Allen, Nir Yosef, Jonathan S Weissman.
      Charting the spatiotemporal dynamics of cell fate determination in development and disease is a long-standing objective in biology. Here we present the design, development, and extensive validation of PEtracer, a prime editing-based, evolving lineage tracing technology compatible with both single-cell sequencing and multimodal imaging methodologies to jointly profile cell state and lineage in dissociated cells or while preserving cellular context in tissues with high spatial resolution. Using PEtracer coupled with MERFISH spatial transcriptomic profiling in a syngeneic mouse model of tumor metastasis, we reconstruct the growth of individually-seeded tumors in vivo and uncover distinct modules of cell-intrinsic and cell-extrinsic factors that coordinate tumor growth. More generally, PEtracer enables systematic characterization of cell state and lineage relationships in intact tissues over biologically-relevant temporal and spatial scales.
    DOI:  https://doi.org/10.1126/science.adx3800
  41. Mol Genet Metab Rep. 2025 Sep;44 101241
    TANGO2 deficiency disorder in a 61-year-old male with episodic weakness, rhabdomyolysis, myotonia, and a novel missense variant.
    Henry Skocy, Amber McFerren, Daniel Cairns, H Mark Kenney, Eran Tallis, Amit S Dhamoon, Ellie Garbade, Samuel J Mackenzie.
      TANGO2 Deficiency Disorder (TDD) is an autosomal recessive condition, most commonly diagnosed in childhood. Clinical features may include episodic movement disorders, seizures, cognitive impairment, hypothyroidism, and metabolic crises marked by rhabdomyolysis and life-threatening cardiac symptoms. A small number of adults, thought to largely represent the milder end of the phenotypic spectrum, have received a diagnosis of TDD in their 30's or 40's, though no genotype-phenotype correlations have been established to date. In this case report, we present a 61-year-old man with mild intellectual disability and recurrent muscle weakness who was diagnosed with TDD during an inpatient hospitalization for diverticulitis, prostatitis, and muscle weakness, ultimately attributed to rhabdomyolysis. Genetic testing revealed a deletion of exons 3-9 in TANGO2 along with a novel missense variant (c.187G > T; p.Gly63Cys) on the other allele. The patient was started on vitamin B-complex with additional pantothenic acid (500 mg daily) and subsequently noted improvement in his speech and energy levels. To our knowledge, this case describes the oldest known individual living with TDD by two decades. Additionally, the patient's relatively mild symptom profile and previously unreported missense variant in TANGO2 may represent the first known example of genotype-phenotype correlation in TDD.
    Keywords:  Genotype-phenotype correlation; Mitochondrial disease; Muscle; Neurometabolic; Rhabdomyolysis; TANGO2
    DOI:  https://doi.org/10.1016/j.ymgmr.2025.101241
  42. Lancet Neurol. 2025 Aug;pii: S1474-4422(25)00198-X. [Epub ahead of print]24(8): 667-680
    Acute-onset axonal neuropathy following infection in children with biallelic RCC1 variants: a case series.
    J Robert Harkness, John H McDermott, Shea Marsden, Peter Jamieson, Kay A Metcalfe, Naz Khan, William L Macken, Robert D S Pitceathly, Christopher J Record, Reza Maroofian, Kleopas Kleopa, Kyproula Christodoulou, Ataf Sabir, Lily Islam, Saikat Santra, Enise Avci Durmusalioglu, Tahir Atik, Esra Isik, Ozgur Cogulu, Jill E Urquhart, Glenda M Beaman, Leigh A Demain, Adam Jackson, Alexander J M Blakes, Helen J Byers, Hayley Bennett, Wei-Hsiang Lin, Antony Adamson, Sanjai Patel, Wyatt W Yue, Robert W Taylor, Janine Reunert, Thorsten Marquardt, Rebecca Buchert, Tobias Haack, Heike Losch, Lukas Ryba, Petra Lassuthova, Radka Valkovičová, Jana Haberlová, Barbora Lauerová, Eva Trúsiková, Kiran Polavarapu, Ozge Aksel Kilicarslan, Hanns Lochmüller, Mina Zamani, Niloofar Chamanrou, Gholamreza Shariati, Saeid Sadeghian, Reza Azizimalamiri, Sateesh Maddirevula, Muhammad AlMuhaizea, Fowzan S Alkuraya, Rita Horvath, Serdal Gungor, Adnan Manzur, Pinki Munot, Rachael Matthews, Siddharth Banka, Mary M Reilly, Daimark Bennett, Raymond T O'Keefe, William G Newman.
       BACKGROUND: The reasons why some individuals have severe neuropathy following an infection are not known. Through the agnostic screening of children with acute axonal neuropathy after an infection, we identified several families with biallelic variants in RCC1. We aimed to describe the clinical phenotype of these patients, and the molecular and cellular pathology associated with the genetic variants identified in these families.
    METHODS: For this case series, we identified children affected by a severe, acute-onset axonal neuropathy following infection through an international research consortium of paediatric neurologists and clinical geneticists from nine countries (Canada, Cyprus, Czechia, Germany, Iran, Saudi Arabia, Slovakia, Türkiye, and the UK). Clinical assessments included nerve conduction studies and neuroimaging. We did exome or genome sequencing in DNA samples from all patients. We characterised the proteins encoded by the genetic variants by use of thermal stability and enzymatic assays, using recombinantly expressed proteins. We assessed cellular protein transport under heat or oxidative stress by use of immunofluorescence in primary fibroblasts, obtained from patients. We generated a humanised Drosophila knock-in model to assess the effects of stress on the in vivo function of RCC1.
    FINDINGS: Between Nov 2, 2011, and July 10, 2024, we identified 24 individuals from 12 families who had severe, acute-onset axonal neuropathy following infection (13 female and 11 male patients, with a mean age at diagnosis of 1 year 10 months [SD 2·27]). Eight biallelic missense variants in RCC1 were identified in affected individuals with autosomal recessive inheritance. Patients had variable phenotypes, ranging from rapidly progressive fatal axonal neuropathy to mild motor neuropathy with impaired walking. Neurological presentation was often secondary to an infection, resulting in initial misdiagnoses of Guillain-Barré syndrome in several patients. 15 children had disease recurrence. The disease was fatal in 15 patients. The RCC1 variants in these patients code for proteins that alter GDP-to-GTP exchange activity and have reduced thermal stability in vitro. In primary fibroblasts, heat shock or oxidative stress revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model of the disease revealed a fatal intolerance to oxidative stress.
    INTERPRETATION: We describe an autosomal recessive, acute-onset paediatric axonal neuropathy, seemingly triggered by infection, that affects individuals with biallelic RCC1 variants. In these children, the disease can mimic Guillain-Barré syndrome. The pathological mechanisms underlying this novel axonal neuropathy might overlap with those of amyotrophic lateral sclerosis. Cellular studies indicate that RCC1 variants affect nucleocytoplasmic transport, which is crucial for healthy axonal function. Future studies should be directed at pre-symptomatic treatment by exploring ways to maintain nucleocytoplasmic transport.
    FUNDING: National Institute for Health and Care Research, LifeArc, and Wellcome Trust.
    DOI:  https://doi.org/10.1016/S1474-4422(25)00198-X
  43. Lancet Neurol. 2025 Aug;pii: S1474-4422(25)00243-1. [Epub ahead of print]24(8): 625
    Accelerating the path towards a cure for Parkinson's disease.
    The Lancet Neurology.
      
    DOI:  https://doi.org/10.1016/S1474-4422(25)00243-1
  44. Trends Neurosci. 2025 Jul 21. pii: S0166-2236(25)00138-9. [Epub ahead of print]
    Triggering ferroptosis in neurodegenerative diseases.
    Triet P M Nguyen, Francesca Alves, Darius J R Lane, Ashley I Bush, Scott Ayton.
      Neuronal death is a defining feature of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and motor neuron diseases, and is accordingly a priority drug target. Among the various cell death pathways, ferroptosis, a form of regulated necrosis driven by iron-dependent lipid peroxidation, has emerged as a prominent candidate underlying neurodegeneration. Despite its potential significance, putative triggers initiating lipid peroxidation cascades that lead to ferroptosis in neurodegenerative diseases remain poorly characterized. This poses significant challenges for developing targeted and disease-specific therapies. We review evidence of ferroptosis in neurodegenerative diseases and examine potential disease-relevant triggers of ferroptosis. We propose that ferroptosis, rather than being initiated by a single triggering event, emerges due to a cumulative erosion of anti-ferroptosis defense systems. This process is likely driven by context-dependent interplay between common hallmarks of neurodegenerative diseases, including neuroinflammation, protein aggregation, mitochondrial dysfunction, altered lipid metabolism, and iron accumulation.
    Keywords:  iron accumulation; lipid metabolism; mitochondrial dysregulation; neuroinflammation; oxidative stress; protein aggregates
    DOI:  https://doi.org/10.1016/j.tins.2025.06.008
  45. Comput Struct Biotechnol J. 2025 ;27 3045-3065
    Inhibiting MARCH5/Mfn2 signaling as an alternative strategy to protect cardiomyocytes from hypoxia-induced mitochondrial dysfunction.
    Faten Habrat Zoabi, Mulate Zerihun, Roy Lizarovich, Chiara Dalla Torre, Liron Davis, Offir Ertracht, Michal Barsheshet, Shaul Atar, Deborah E Shalev, Marta De Zotti, Hanoch Senderowitz, Nir Qvit.
      The mitochondrial E3 ubiquitin ligase membrane-associated RING-CH-type finger 5 (MARCH5) and the GTPase Mitofusin 2 (Mfn2) both play crucial roles in regulating mitochondrial dynamics, which are essential for cellular homeostasis. Dysregulation of the MARCH5/Mfn2 signaling has been implicated in mitochondrial dysfunction, a key factor in cardiovascular diseases (CVDs). To investigate the therapeutic potential of targeting this interaction, we developed a novel peptide, CVP-220, designed to specifically disrupt the MARCH5/Mfn2 protein interaction. Using a hypoxia-reoxygenation (H/R) injury model in rat cardiomyocyte cell lines, CVP-220 demonstrated significant cardioprotective effects. Treatment with CVP-220 enhanced cell viability by 30 % compared to untreated controls and reduced reactive oxygen species (ROS) production by 45 %, suggesting improved mitochondrial function. Notably, CVP-220 selectively modulated MARCH5-mediated ubiquitination of Mfn2 without affecting other MARCH5 interactions, thereby preserving mitochondrial fusion and preventing fragmentation under stress conditions. A plausible binding mode of CVP-220 on Mfn2 was suggested through a combination of molecular docking and molecular dynamics simulations and was experimentally validated by mutational analysis. These findings highlight CVP-220 as a promising tool for modulating mitochondrial dynamics and mitigating mitochondrial damage in cardiac cells, with potential implications for therapeutic strategies targeting mitochondrial dysfunction in CVDs. Further investigation into the role of MARCH5/Mfn2 signaling in cardiac pathology could pave the way for novel peptide-based treatments.
    Keywords:  Cardiovascular diseases; Docking; Fission; Fusion; MARCH5; Mfn2; Mitochondria; Mitophagy; Molecular dynamics simulations; Peptide; Peptidomimetic; Protein-Protein Interaction
    DOI:  https://doi.org/10.1016/j.csbj.2025.07.001
  46. J Inherit Metab Dis. 2025 Jul;48(4): e70063
    A Brief History of Inherited Metabolic Diseases: A Personal 60 Years Clinical Flashback.
    Jean-Marie Saudubray, Manuel Schiff.
      The concept of IMDs has evolved over a century from rare deficits in amino acid catabolism diagnosed by the accumulation of biochemical markers such as phenylketonuria (PKU) to diseases affecting organelle metabolism, synthesis of complex molecules, and cellular trafficking. Small-molecule accumulation disorders form the major group of treatable IMDs. Do not miss these metabolic emergencies! IMDs currently number over 1800 and include all medical specialties. The specificity of true "molecular internists," metabolic specialists, lies in the in-depth knowledge of metabolic pathways and the understanding of the pathophysiology of the deficits underlying the treatments ("precision medicine"). Neurology is massively impacted, but cerebral metabolism remains largely misunderstood. Genetic analyses are becoming increasingly important for diagnosis but must be complemented by biochemical investigations, which sometimes have greater diagnostic specificity and provide functional information at the phenotype level. Biochemical analyses remain essential for monitoring treatment or even for diagnosis. Finally, contrary to early expectations, newborn screening such as that for phenylketonuria, leading to preventive therapy, could be extended to a significant though limited number of IMDs. Currently, there are numerous initiatives that include genetic screening combined with biochemical testing or that extend screening to lysosomal diseases potentially treatable by enzyme or gene therapy.
    Keywords:  Inborn metabolic diseases; Inherited metabolic diseases; Metabolic disorders; Precision medicine; inborn errors of metabolism
    DOI:  https://doi.org/10.1002/jimd.70063
  47. Eur Heart J Case Rep. 2025 Jul;9(7): ytaf307
    PPA2 deficiency-a rare cause of genetic cardiomyopathy: a case report.
    Sanchaya Khetrapal, Aakash Tuli, Yochitha Pulipati, Victor Farah, Indu Poornima.
       Background: PPA2 deficiency is a rare mitochondrial disorder associated with non-ischemic cardiomyopathy, recurrent rhabdomyolysis, and sudden cardiac death (SCD). This case attempts to highlight the diagnostic and management challenges and contribute to the growing literature on mitochondrial disorders.
    Case summary: A 21-year-old female with lupus presented with chest pain that developed after hospitalisation for rhabdomyolysis during a viral illness. A cardiac MRI showed patchy late gadolinium enhancement suggestive of myocarditis. She was started on colchicine, but her symptoms persisted. Subsequent imaging revealed persistent myocardial inflammation without troponin elevation. She experienced further episodes of muscle aches and chest pain, prompting additional hospitalisations. Her sibling's diagnosis of non-ischemic cardiomyopathy and need for cardiac transplantation raised suspicion for a genetic aetiology. Genetic testing confirmed compound heterozygosity for pathogenic PPA2 variants (c.380G > T and c.514G > A). She was managed with rhythm monitoring, alcohol avoidance, and genetic counseling.
    Discussion: PPA2 deficiency should be suspected in patients with unexplained cardiomyopathy, recurrent muscle involvement, and family history of SCD. Cardiac MRI findings of subepicardial and mid-myocardial fibrosis without troponin elevation are characteristic. Early identification allows for lifestyle modifications and consideration of preventive measures like an implantable cardioverter-defibrillator to mitigate the risk of SCD. This case highlights the importance of recognising PPA2 cardiomyopathy in young patients with recurrent cardiac and muscle symptoms. Comprehensive diagnostic evaluation, including genetic testing, is crucial for identifying this rare but life-threatening condition.
    Keywords:  Case report; Genetic testing; Late gadolinium enhancement; Mitochondrial cardiomyopathy; PPA2 deficiency; Sudden cardiac death
    DOI:  https://doi.org/10.1093/ehjcr/ytaf307
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