PT  - JOURNAL ARTICLE
AU  - Tang, Jia Xin
AU  - Cabrera-Orefice, Alfredo
AU  - Meisterknecht, Jana
AU  - Taylor, Lucie S
AU  - Monteuuis, Geoffray
AU  - Stensland, Maria Ekman
AU  - Szczepanek, Adam
AU  - Stals, Karen
AU  - Davison, James
AU  - He, Langping
AU  - Hopton, Sila
AU  - Nyman, Tuula A
AU  - Jackson, Christopher B
AU  - Pyle, Angela
AU  - Winter, Monika
AU  - Wittig, Ilka
AU  - Taylor, Robert W
TI  - COA5 has an essential role in the early stage of mitochondrial complex IV assembly
AID  - 10.26508/lsa.202403013
DP  - 2025 Mar 01
TA  - Life Science Alliance
PG  - e202403013
VI  - 8
IP  - 3
4099  - http://www.life-science-alliance.org/content/8/3/e202403013.short
4100  - http://www.life-science-alliance.org/content/8/3/e202403013.full
SO  - Life Sci. Alliance2025 Mar 01; 8
AB  - 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.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.