Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis

• DOI: 10.1016/j.celrep.2022.111204
• Publication Date: 2022-08-16T14:46:19Z
• Authors: Chao Liang; Shan Zhang; David Robinson; Matthew Vander Ploeg; Rebecca Wilson; Jiemin Nah; Dale Taylor; Sheryl Beh; Radiance Lim; Lei Sun; Deborah M. Muoio; David A. Stroud; Lena Ho
• Keywords: Electron Transport; Mammals; Mitochondrial Proteins; 0301 basic medicine; 570; 03 medical and health sciences; Mitochondrial Membranes; Animals; Cues; Mitochondria; Molecular Chaperones

Electron transport chain (ETC) biogenesis is tightly coupled to energy levels and availability of ETC subunits. Complex III (CIII), controlling ubiquinol:ubiquinone ratio in ETC, is an attractive node for modulating ETC levels during metabolic stress. Here, we report the discovery of mammalian Co-ordinator of mitochondrial CYTB (COM) complexes that regulate the stepwise CIII biogenesis in response to nutrient and nuclear-encoded ETC subunit availability. The COMA complex, consisting of UQCC1/2 and membrane anchor C16ORF91, facilitates translation of CIII enzymatic core subunit CYTB. Subsequently, microproteins SMIM4 and BRAWNIN together with COMA subunits form the COMB complex to stabilize nascent CYTB. Finally, UQCC3-containing COMC facilitates CYTB hemylation and association with downstream CIII subunits. Furthermore, when nuclear CIII subunits are limiting, COMB is required to chaperone nascent CYTB to prevent OXPHOS collapse. Our studies highlight CYTB synthesis as a key regulatory node of ETC biogenesis and uncover the roles of microproteins in maintaining mitochondrial homeostasis.