bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2026–02–08
two papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial complex I subunit NDUFS4 overexpression drives glioma progression by regulating mitochondrial function and COX5B.
  2. LRRK2 controls COX assembly through regulation of redox status of mitochondrial copper chaperones.
  1. NPJ Precis Oncol. 2026 Jan 30.
    Mitochondrial complex I subunit NDUFS4 overexpression drives glioma progression by regulating mitochondrial function and COX5B.
    Jiang Wu, Juan Li, Li Xu, Yuanyuan Liu, Li Jiang.
      The current study explores the expression, functional significance, and underlying mechanisms of the mitochondrial protein NDUFS4 (NADH:ubiquinone oxidoreductase subunit S4) in glioma cells. TCGA shows that elevated NDUFS4 expression is consistently observed in glioma tissues, correlating with advanced tumor grade and diminished patient survival. Single-cell RNA sequencing further localizes this elevated expression primarily to glioma cells, where NDUFS4 co-expressed genes are integral to cellular respiration and mitochondrial ATP synthesis. These findings were corroborated in patient tissues and various primary and established glioma cell types, confirming consistent NDUFS4 overexpression. Genetic silencing (via shRNA) or CRISPR/Cas9-mediated knockout of NDUFS4 impaired mitochondrial function, evidenced by reduced oxygen consumption rate, inhibited mitochondrial complex I activity and ATP production and increased oxidative stress. NDUFS4 depletion also suppressed glioma cell proliferation, migration, and invasion, while promoting apoptosis. This inhibitory effect is specific to malignant cells, sparing non-cancerous astrocytes. Conversely, NDUFS4 overexpression enhanced mitochondrial activity and promoted aggressive malignant phenotypes in primary and immortalized glioma cells. Further multi-omics integration and experimental investigation established COX5B (cytochrome c oxidase subunit 5B) as an important downstream effector of NDUFS4. shRNA-induced silencing of COX5B replicated the outcomes of NDUFS4 depletion in primary glioma cells, and crucially, restoring COX5B in NDUFS4-silenced glioma cells abrogated the anti-glioma effects. In vivo studies demonstrated that NDUFS4 silencing effectively impeded intracranial growth of patient-derived glioma xenografts by compromising mitochondrial function, downregulating COX5B, inhibiting proliferation and inducing apoptosis. Collectively, these comprehensive data underscore NDUFS4's essential role in glioma progression and position it as a promising therapeutic target for this aggressive malignancy.
    DOI:  https://doi.org/10.1038/s41698-026-01281-9
  2. Redox Biol. 2026 Jan 28. pii: S2213-2317(26)00059-5. [Epub ahead of print]90 104061
    LRRK2 controls COX assembly through regulation of redox status of mitochondrial copper chaperones.
    Tae Young Kim, Eun-Hae Jang, Yun-Hee Bae, Eun-Mi Hur, Byoung Dae Lee.
      Mitochondrial dysfunction is a common pathological hallmark of neurodegenerative diseases. In Parkinson's disease (PD), the most popular age-related movement disorder, the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is closely associated with mitochondrial energetic deficits, reflecting their exceptionally high metabolic demand. The electron transport chain (ETC), essential for ATP production, comprises multiple protein complexes that require coordinated assembly and redox-sensitive regulation. In this study, we identified LRRK2-the most common genetic contributor to both familial and sporadic PD-as a regulator of cytochrome c oxidase (COX), the terminal enzyme of the ETC, through its control of the redox status of mitochondrial copper chaperones. Expression of pathogenic LRRK2 G2019S mutant increased the proportion of reduced (Cu-deficient) forms of COX11 and SCO1, two chaperones essential for COX metalation, thereby impairing COX assembly and promoting ETC dysfunction. Within this regulatory hierarchy, COX19 functions as a downstream effector of LRRK2 and an upstream modulator of COX11 and SCO1 redox status. Moreover, LRRK2 and COX19 reciprocally regulate each other's expression and cooperatively disrupted COX biogenesis. In vivo, exogenous expression of COX19 via AAV gene delivery induced dopaminergic neurodegeneration and motor deficits, which were effectively rescued by pharmacological inhibition of LRRK2 kinase activity. Together, these findings define a positive feedback LRRK2-COX19 signaling axis that governs mitochondrial redox homeostasis and COX assembly, highlighting a promising therapeutic target for PD and related mitochondrial disorders.
    Keywords:  COX; COX19; Copper chaperone; LRRK2; Neurodegeneration; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.redox.2026.104061
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