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COA5 has an essential role in the early stage of mitochondrial complex IV assembly

Lookup NU author(s): Lucie Taylor, Dr Langping He, Sila Hopton, Dr Angela Pyle, Professor Robert Taylor

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2025 Tang et al. Pathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in whom we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with a similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role of COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role in the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.

Publication metadata

Author(s): Tang JX, Cabrera-Orefice A, Meisterknecht J, Taylor LS, Monteuuis G, Stensland ME, Szczepanek A, Stals K, Davison J, He L, Hopton S, Nyman TA, Jackson CB, Pyle A, Winter M, Wittig I, Taylor RW

Publication type: Article

Publication status: Published

Journal: Life Science Alliance

Year: 2025

Volume: 8

Issue: 3

Online publication date: 08/01/2025

Acceptance date: 19/12/2024

Date deposited: 27/01/2025

ISSN (electronic): 2575-1077

Publisher: Life Science Alliance LLC

URL: https://doi.org/10.26508/lsa.202403013

DOI: 10.26508/lsa.202403013

Data Access Statement: The mass spectrometry proteomics data for label-free whole-cell proteomics and complexome profiling produced in this study have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository (Perez-Riverol et al, 2022) and assigned the dataset identifier PXD050891 and PXD053461, respectively.

PubMed id: 39779219

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