bims-cytox1 2026-07-26 papers

J Peripher Nerv Syst. 2026 Sep;31(3): e70150

Biallelic SCO2 Variants Presenting as Motor-Predominant Axonal Neuropathy With Complex IV Deficiency.

Adriana P Rebelo, Katie Lutz, Tiffany Grider, Craig M Zaidman, Michael E Shy, Stephan Zuchner.

BACKGROUND AND AIMS: SCO2 encodes a mitochondrial copper chaperone required for cytochrome c oxidase (COX) assembly and is classically associated with severe multisystem mitochondrial disease. We characterize a motor-predominant axonal neuropathy presentation associated with biallelic SCO2 variants.
METHODS: Clinical, genetic, and functional studies were performed in a 15-year-old female presenting with axonal neuropathy. Functional studies were conducted in patient-derived fibroblasts, including Western blot analysis and spectrophotometric cytochrome c oxidation assay. Structural modeling was performed using ChimeraX.
RESULTS: The patient presented with a motor-predominant axonal neuropathy consistent with Charcot-Marie-Tooth (CMT) disease. Clinical genetic testing identified compound heterozygous SCO2 variants of uncertain significance: a missense variant (p.Arg120Trp) and a frameshift variant (p.Asp252ValfsTer24). Structural modeling predicted disruption of protein stability for both variants. Functional studies in patient-derived fibroblasts demonstrated complete absence of SCO2 protein and reduced mitochondrial complex IV activity, supporting a loss-of-function mechanism.
INTERPRETATION: These findings demonstrate that SCO2-related disease can present as an isolated axonal neuropathy, a phenotype that remains rarely reported. Our study also highlights the value of integrating in silico prediction tools with functional assays to establish pathogenicity in rare sporadic cases of inherited neuropathy.

DOI: https://doi.org/10.1111/jns.70150

iScience. 2026 Jul 17. 29(7): 116442

Cox10-mediated mitochondrial respiration in brown adipocytes regulates adaptive thermogenesis and systemic metabolism.

Esther Paulo, Yuanyuan Wu, Biao Wang.

Mitochondrial respiration is essential for Ucp1-mediated thermogenesis in brown adipocytes, where heat production depends on oxygen-driven mitochondrial activity. To define the role of complex IV, we generated brown-adipocyte-specific Cox10-knockout mice (Cox10BKO), as Cox10 is required for cytochrome c oxidase assembly. Cox10-deficient brown adipocytes exhibited markedly reduced complex IV activity and impaired Ucp1-dependent thermogenesis. Although ATF4 signaling was strongly induced, the alternative ATF4-dependent thermogenic pathway failed due to suppression of global protein synthesis, consistent with severe mitochondrial stress and reduced ribosomal gene expression. Unexpectedly, Cox10BKO mice housed at room temperature or thermoneutrality were protected against high-fat-diet-induced obesity and insulin resistance. These findings demonstrate that brown adipocytes regulate systemic metabolic homeostasis independently of canonical thermogenic function and suggest that respiration-deficient brown fat may promote metabolic fitness through endocrine or metabolic signaling mechanisms.

Keywords: human metabolism; metabolic flux analysis; molecular biology

DOI: https://doi.org/10.1016/j.isci.2026.116442

Biochim Biophys Acta Mol Cell Res. 2026 Jul 20. pii: S0167-4889(26)00093-5. [Epub ahead of print]1873(7): 120194

Orchestration of OXPHOS biogenesis through regulation of mitochondrial translation.

Andreas Carlström, Carmela Vazquez-Calvo, Martin Ott.

Mitochondrial gene expression is a remnant of the endosymbiotic origin of the organelle, which contains a complete gene expression system that contributes only a handful of subunits to the complexes driving oxidative phosphorylation (OXPHOS). During evolution, many processes of gene expression in mitochondria have diverged from the bacterial ancestor. A central problem to assemble oxidative phosphorylation complexes is that they contain subunits from two genetic sources. Hence, mechanisms have evolved to synchronize expression of nuclear and mitochondrial genes to avoid problems with stoichiometry, which could hamper their assembly. Here, we will summarize recent insights into how gene expression operates with a focus on the mechanisms related to the control of mitochondrial translation in yeast and human cells.

Keywords: Evolution; Gene expression; Mitochondria; Mitoribosomes; Translation initiation; Translational activators; Translational regulation

DOI: https://doi.org/10.1016/j.bbamcr.2026.120194