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.
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•HIGD1A promotes the incorporation of UQCRFS1 to mature CIII2•HIGD2A facilitates the assembly of the COX3 module to form holo-CIV•HIGD2A regulates modular assembly of isolated and supercomplexed CIV•HIGD1A and HIGD2A play overlapping functions in CIV assembly
Despite the importance of the mitochondrial respiratory chain enzymes in cellular metabolism, the elements and pathways involved in their biogenesis and organization remain incomplete. Timón-Gómez et al. describe the function of HIGD proteins in CIII, CIV, and supercomplex assembly and in alternative biogenetic pathways to adapt to changing environmental conditions.
