@article{550a3978c45040f3b851df4f68e3884e,
title = "Distinct Roles of Mitochondrial HIGD1A and HIGD2A in Respiratory Complex and Supercomplex Biogenesis",
abstract = "The mitochondrial respiratory chain enzymes are organized as individual complexes and supercomplexes, whose biogenesis remains to be fully understood. To disclose the role of the human Hypoxia Inducible Gene Domain family proteins HIGD1A and HIGD2A in these processes, we generate and characterize HIGD-knockout (KO) cell lines. We show that HIGD2A controls and coordinates the modular assembly of isolated and supercomplexed complex IV (CIV) by acting on the COX3 assembly module. In contrast, HIGD1A regulates CIII and CIII-containing supercomplex biogenesis by supporting the incorporation of UQCRFS1. HIGD1A also clusters with COX4-1 and COX5A CIV subunits and, when overexpressed, suppresses the CIV biogenesis defect of HIGD2A-KO cells. We conclude that HIGD1A and HIGD2A have both independent and overlapping functions in the biogenesis of respiratory complexes and supercomplexes. Our data illuminate the existence of multiple pathways to assemble these structures by dynamic HIGD-mediated CIV biogenesis, potentially to adapt to changing environmental and nutritional conditions.",
keywords = "COX7A2L, HIGD1A, HIGD2A, OXPHOS, mitochondrial respiratory chain, respirasomes, supercomplexes",
author = "Alba Tim{\'o}n-G{\'o}mez and Joshua Garlich and Stuart, {Rosemary A.} and Cristina Ugalde and Antoni Barrientos",
note = "Funding Information: This research was supported by the National Institutes of Health (NIH)-R35 grant GM118141 (to A.B.), Muscular Dystrophy Association (MDA) Research Grant MDA-381828 (to A.B.), NIH-R15GM101594 and NIH-R15GM117551 (to R.A.S.), Instituto de Salud Carlos III-MINECO/European FEDER Funds grants PI14-00209 and PI17-00048 (to C.U.), Comunidad Aut{\'o}noma de Madrid/ERDF-ESF grant P2018/BAA-4403 (to C.U.), and NIH-RO1 grant GM105781 (to A.B. and C.U.). Funding Information: We thank Drs. F. Fontanesi and E. Fern?ndez-Vizarra for critical reading of the manuscript. We thank Drs. G. Manfredi, J.A. Enriquez, V. Tiranti, and C.T. Moraes for providing cybrid cell lines and Dr. E. Fern?ndez-Vizarra for human fibroblasts lines. This research was supported by the National Institutes of Health (NIH)-R35 grant GM118141 (to A.B.), Muscular Dystrophy Association (MDA) Research Grant MDA-381828 (to A.B.), NIH-R15GM101594 and NIH-R15GM117551 (to R.A.S.), Instituto de Salud Carlos III-MINECO/European FEDER Funds grants PI14-00209 and PI17-00048 (to C.U.), Comunidad Aut?noma de Madrid/ERDF-ESF grant P2018/BAA-4403 (to C.U.), and NIH-RO1 grant GM105781 (to A.B. and C.U.). A.T.-G. and A.B. designed the study. A.T.-G. created and characterized the HEK293T HIGD-KO lines and performed the vast majority of the experiments. A.B. contributed with OXPHOS measurements. J.G. and R.A.S. designed and performed the experiments in yeast. C.U. developed the idea of CIV assembly in SCs and provided technical and intellectual guidance. A.T.-G. and A.B. wrote the paper. All authors read, edited, and approved the manuscript. The authors declare no competing interests.",
year = "2020",
month = may,
day = "5",
doi = "10.1016/j.celrep.2020.107607",
language = "English (US)",
volume = "31",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}