Abstract
Dysfunction of the mitochondrial electron transport chain (mETC) is a major cause of human mitochondrial diseases. To identify determinants of mETC function, we screened a genome-wide human CRISPRi library under oxidative metabolic conditions with selective inhibition of mitochondrial Complex III and identified ovarian carcinoma immunoreactive antigen (OCIA) domain-containing protein 1 (OCIAD1) as a Complex III assembly factor. We find that OCIAD1 is an inner mitochondrial membrane protein that forms a complex with supramolecular prohibitin assemblies. Our data indicate that OCIAD1 is required for maintenance of normal steady-state levels of Complex III and the proteolytic processing of the catalytic subunit cytochrome c1 (CYC1). In OCIAD1 depleted mitochondria, unprocessed CYC1 is hemylated and incorporated into Complex III. We propose that OCIAD1 acts as an adaptor within prohibitin assemblies to stabilize and/or chaperone CYC1 and to facilitate its proteolytic processing by the IMMP2L protease.
Highlights
Mitochondria are double membrane-bound organelles of endosymbiotic origin that produce most of the ATP in eukaryotic cells through oxidative phosphorylation (OXPHOS) (Mitchell, 2011)
Our data indicate that ovarian carcinoma immunoreactive antigen domain-containing protein 1 (OCIAD1) is a conserved regulatory determinant of CIII2 assembly that controls the proteolytic processing of holo-cytochrome c1 (CYC1)
In all CIII2 atomic models, mature holo-CYC1 possesses one C-terminal transmembrane helix and an N-terminal domain composed of six a-helices and two-strand b-sheet extending in the intermembrane space (IMS) (Maldonado et al, 2021; Xia et al, 1997)
Summary
Mitochondria are double membrane-bound organelles of endosymbiotic origin that produce most of the ATP in eukaryotic cells through oxidative phosphorylation (OXPHOS) (Mitchell, 2011). Prohibitins are thought to promote mETC assembly and quality control by assembling into inner membrane ring-like scaffold structures that specify local protein and lipid composition (Nijtmans et al, 2000; Singh et al, 2020). Prohibitins associate with a variety of inner membrane proteins, including mitochondrial translocases, subunits of mETC, the DnaJ-like chaperone DNACJ19, and matrix-AAA (m-AAA) proteases (Nijtmans et al, 2000; Richter-Dennerlein et al, 2014; Steglich et al, 1999; Yoshinaka et al, 2019). The interaction of prohibitin with these key assembly and quality control proteins either directly modulates their activities and/or influences their client interactions to regulate and potentially coordinate a plethora of mitochondrial functions. We postulate that within prohibitin assemblies, OCIAD1 facilitates CYC1 proteolytic processing by the IMMP2L
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