Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis

ABSTRACT: Electron transport chain (ETC) biogenesis is tightly coupled to energy levels and availability of ETC subunits. Coenzyme Q: cytochrome c oxidoreductase (complex III or CIII) occupies a central position in the ETC, receiving electrons from diverse fuel sources to control the ubiquinol:ubiquinone (CoQH2/CoQ) ratio. As such, CIII is an attractive node for controlling ETC biogenesis during metabolic stress. Here, we report the discovery of mammalian CoOrdinator of Mitochondrial CYTB or “COM” complexes that regulate CIII biogenesis in a step-wise fashion in response to nutrient and nuclear-encoded ETC subunit availability. The COMA complex, consisting of UQCC1/2 and the membrane anchor C16ORF91 (UQCC4), facilitates the translation of CIII enzymatic core subunit CYTB. Subsequently, microproteins SMIM4 and BRAWNIN, together with COMA subunits form the COMB complex that stabilizes nascent CYTB. Finally, UQCC3-containing COMC promotes CTYB maturation and association with downstream CIII subunits. This stepwise assembly enables cells to adapt to metabolic stress by increasing CIII biogenesis and inducing an integrated stress response when challenged. Furthermore, when nuclear CIII subunits are unavailable for assembly, 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 mito-SEPs in mitochondrial homeostasis during energy stress.

INSTRUMENT(S): Q Exactive Plus, Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: David Stroud  

LAB HEAD: David Stroud

PROVIDER: PXD030258 | Pride | 2022-09-25

REPOSITORIES: Pride