2. Academic Validation
  3. Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis

Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis

  • Cell Rep. 2022 Aug 16;40(7):111204. doi: 10.1016/j.celrep.2022.111204.
Chao Liang 1,  Shan Zhang 2,  David Robinson 3,  Matthew Vander Ploeg 4,  Rebecca Wilson 4,  Jiemin Nah 1,  Dale Taylor 3,  Sheryl Beh 1,  Radiance Lim 1,  Lei Sun 1,  Deborah M Muoio 4,  David A Stroud 5,  Lena Ho 6
Affiliations

Affiliations

  • 1 Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, 169857 Singapore, Singapore.
  • 2 Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, 169857 Singapore, Singapore; Department of Biochemistry, Department of Cardiology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Department of Biochemistry and Pharmacology, the Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC 3052, Australia.
  • 4 Departments of Medicine and Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
  • 5 Department of Biochemistry and Pharmacology, the Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC 3052, Australia; Murdoch Children's Research Institute, the Royal Children's Hospital, 50 Flemington Road, Parkville, VIC 3052, Australia.
  • 6 Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, 169857 Singapore, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Dr, 138673 Singapore, Singapore. Electronic address: lena@ho-lab.org.
PMID: 35977508 DOI: 10.1016/j.celrep.2022.111204
Abstract

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.

Keywords

CP: Metabolism; CYTB; SEPs; SMIM4; UQCC1; UQCC2; complex III; electron transport chain; microproteins; nuclear-mitochondrial coordination; smORFs.

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