bims-cytox1 2026-03-08 papers

Seizure. 2026 Feb 18. pii: S1059-1311(26)00050-6. [Epub ahead of print]

Mitochondrial complex assembly in epilepsy of primary mitochondrial disease origin.

Primary mitochondrial diseases are caused by mutations in genes required for expression, function or assembly of the mitochondrial oxidative phosphorylation system. The pathology of primary mitochondrial diseases is varied and a subset of these are associated with epilepsy and seizures. Mutations are found in each of the 5 complexes of the oxidative phosphorylation system in both structural subunits and assembly factors along with mitochondrially encoded components of the protein synthesis machinery. This review will highlight the mutations identified in clinical case studies that are associated with epilepsy and seizures and include the studies using cell systems and other model organisms where molecular characterisation of oxidative phosphorylation is more extensive. The molecular causes of epilepsy have not been well characterised in the relevant cells. This review identifies gaps in knowledge and suggestions for future studies to advance the understanding of the molecular pathogenesis of epilepsy that is associated with primary mitochondrial disease.

Keywords: Biogenesis; Electron transport chain; Epilepsy; Mitochondria; Oxidative phosphorylation; Seizures

DOI: https://doi.org/10.1016/j.seizure.2026.02.016

Life Sci. 2026 Feb 26. pii: S0024-3205(26)00104-9. [Epub ahead of print] 124295

Deciphering the role of mitochondrial cytochrome C oxidase subunit 4 in cardiac health and disease.

Pranjali Anil Indian, Mansi Vinodkumar Trivedi, Anil Bhanudas Gaikwad.

Cardiovascular diseases (CVDs) are the primary cause of mortality across the globe, making maintaining cardiac health and homeostasis imperative. The cardiac muscle cells have a 30% stake of the area occupied by mitochondria. The efficient generation of ATP, despite metabolic and other cellular shifts, is crucial for maintaining sufficient blood flow throughout the system. Therefore, maintaining mitochondrial health by balancing the levels of intracellular reactive oxygen species (ROS) and quality control systems is vital for cardiac cell survival. This review highlights the role of cytochrome c oxidase subunit 4 (COX4), which is primarily located in the mitochondrial electron transport chain, in the context of the heart. There are two isoforms, i.e., COX4-1 and COX4-2. The intricate balance between the two isoforms combats cellular stress while maintaining efficient ATP generation through oxidative phosphorylation. However, persistent stress impairs the ability of COX4 to dynamically shift between isoforms, resulting in massive ROS production and less efficient mitochondrial respiration, which ultimately hampers cardiac function. The subsequent review highlights the role of COX4, its dynamic isoform shifts, and the contribution of COX-4 to cardiac physiology, as well as its contribution to date in aggravating CVDs. Additionally, compounds capable of modulating COX4 in cardiac disease conditions both preclinically as well as clinically are being explored.

Keywords: Cardiovascular diseases; Cytochrome C oxidase subunit 4; Heart failure; Mitochondrial dysfunction; Oxidative phosphorylation

DOI: https://doi.org/10.1016/j.lfs.2026.124295

Cell Death Discov. 2026 Mar 06.

Lysophosphatidylcholine acyltransferase 1 promotes head and neck squamous cell carcinoma progression by enhancing COX17-dependent oxidative phosphorylation.

Yuanyang Zhao, Yun Li, Yanshi Li, Zhihai Wang, Chuan Liu, Lin Chen, Min Wang, Mengna Wang, Zhaobo Cheng, Guohua Hu, Min Pan.

Metabolic dysregulation is increasingly recognized as a driver of tumor progression, yet its specific role in head and neck squamous cell carcinoma (HNSCC) remains poorly characterized. This study integrated untargeted metabolomics of HNSCC patient tissues with multi-omics validation to identify key metabolic alterations. We discovered a significant accumulation of sn-2 saturated fatty acyl-phosphatidylcholines, implicating disrupted phospholipid remodeling in HNSCC pathogenesis. Analysis of The Cancer Genome Atlas and Human Protein Atlas databases revealed consistent upregulation of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in HNSCC. This finding was further validated at mRNA, protein, and tissue levels by quantitative PCR, western blotting, and immunohistochemistry, respectively. Functional assays demonstrated that LPCAT1 knockdown suppressed tumor cell proliferation, migration, and invasion while increasing cell death in vitro, and inhibited tumor growth in nude mouse xenograft models. Mechanistically, LPCAT1 depletion impaired mitochondrial oxidative phosphorylation by reducing Cytochrome c oxidase activity, thereby decreasing ATP production. Our data further demonstrate that LPCAT1 regulates the expression of COX17, suggesting that the promotion of Cytochrome c oxidase activity and tumor bioenergetics by LPCAT1 is mediated through COX17. Thus, LPCAT1 drives HNSCC progression via a COX17-dependent metabolic reprogramming pathway. Targeting LPCAT1 represents a promising therapeutic strategy, while tissue-saturated fatty acyl-phosphatidylcholines may serve as early diagnostic biomarkers for HNSCC.

DOI: https://doi.org/10.1038/s41420-026-02994-3

Mol Neurobiol. 2026 Mar 04. pii: 485. [Epub ahead of print]63(1):

A Heteroplasmic MT-CO2 m.8024G > A Variant Is Associated with Mitochondrial Bioenergetic Deficiency and Optic Atrophy.

Jing Wu, Cunhui Pan, Ruowei Zhu, Xi Huang, Xiaoting Lou, Li Yang.

Leber's hereditary optic neuropathy (LHON) is a hereditary neurodegenerative disorder caused by pathogenic mitochondrial DNA (mtDNA) variants. While MT-CO2 defects are implicated in neurodegeneration, their direct association with optic atrophy has not been reported. We identify a heteroplasmic MT-CO2 variant, m.8024G > A (p.Glu147Lys), in a patient with progressive optic atrophy and explore its potential association with mitochondrial dysfunction. A 13-year-old male with progressive unilateral-then-bilateral vision loss underwent comprehensive ophthalmic/neurological evaluation, trio whole-exome sequencing, and mtDNA sequencing. The pathogenicity of the identified variant was assessed in patient-derived fibroblasts using mitochondrial stress tests, ATP/ROS assays, enzymatic profiling, BN-PAGE, mitochondrial membrane potential, mtDNA copy number, ultrastructural microscopy, and immunoblotting. Functional analyses revealed that this variant, which reduces the expression of mtDNA-encoded electron transport chain (ETC) subunits and induces severe Complex IV deficiency, reduced cellular oxygen consumption rate (OCR), impaired ATP synthesis, decreased mtDNA copy number, and elevated reactive oxygen species (ROS) production. Concurrently, mutant cells exhibited enhanced mitophagy with preserved flux, a compensatory response to persistent mitochondrial damage. Unlike canonical optic neuropathy associated with homoplasmic mtDNA mutations, this heteroplasmic variant is linked to mitochondrial dysfunction potentially related to tissue-specific heteroplasmy and altered mitophagic responses. We report a heteroplasmic m.8024G > A mutation in MT-CO2 associated with childhood-onset isolated optic atrophy. Functional analyses in patient fibroblasts show that this variant is associated with MT-CO2 structural perturbation, Complex IV dysfunction, altered mitophagy, and mitochondrial energy failure-supporting its potential pathogenic relevance. This study expands the genotypic and phenotypic spectrum of mitochondrial optic neuropathies and provides mechanistic insights into the pathogenesis of heteroplasmic mtDNA variant-related disease.

Keywords: MT-CO2; Mitochondrial complex IV; Optic atrophy; Optic neuropathy

DOI: https://doi.org/10.1007/s12035-026-05774-3