COQ11 deletion mitigates respiratory deficiency caused by mutations in the gene encoding the coenzyme Q chaperone protein Coq10

Autor(es):Mostrar menos -

Bradley, Michelle C. ^[1] ; Yang, Krista ^[1] ; Fernandez-del-Rio, Lucia ^[1] ; Ngo, Jennifer ^{[1, 2]} ; Ayer, Anita ^{[3, 4]} ; Tsui, Hui S. ^[1] ; Novales, Noelle Alexa ^[1] ; Stocker, Roland ^{[3, 4]} ; Shirihai, Orian S. ^[2] ; Barros, Mario H. ^[5] ; Clarke, Catherine F. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Calif Los Angeles, Dept Chem & Biochem, Inst Mol Biol, Los Angeles, CA 90095 - USA

^[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol & Med, Los Angeles, CA 90095 - USA

^[3] Victor Chang Cardiac Res Inst, Vasc Biol Div, Sydney, NSW 2010 - Australia

^[4] Univ New South Wales Med, St Vincents Clin Sch, Sydney, NSW 2050 - Australia

^[5] Univ Sao Paulo, Dept Microbiol, BR-05508900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Biological Chemistry; v. 295, n. 18, p. 6023-6042, MAY 1 2020.
• Citações Web of Science: 1

Resumo

Coenzyme Q (Q(n)) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast Saccharomyces cerevisiae, coq1?coq9 deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q(6). The yeast coq10 deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q(6) at an impaired rate. Thus, Coq10 is required for the function of Q(6) in respiration and as an antioxidant and is believed to chaperone Q(6) from its site of synthesis to the respiratory complexes. In several fungi, Coq10 is encoded as a fusion polypeptide with Coq11, a recently identified protein of unknown function required for efficient Q(6) biosynthesis. Because ?fused? proteins are often involved in similar biochemical pathways, here we examined the putative functional relationship between Coq10 and Coq11 in yeast. We used plate growth and Seahorse assays and LC-MS/MS analysis to show that COQ11 deletion rescues respiratory deficiency, sensitivity to lipid peroxidation, and decreased Q(6) biosynthesis of the coq10? mutant. Additionally, immunoblotting indicated that yeast coq11? mutants accumulate increased amounts of certain Coq polypeptides and display a stabilized CoQ synthome. These effects suggest that Coq11 modulates Q(6) biosynthesis and that its absence increases mitochondrial Q(6) content in the coq10?coq11? double mutant. This augmented mitochondrial Q(6) content counteracts the respiratory deficiency and lipid peroxidation sensitivity phenotypes of the coq10? mutant. This study further clarifies the intricate connection between Q(6) biosynthesis, trafficking, and function in mitochondrial metabolism. (AU)

• Processo FAPESP: 13/09482-8 - Saccharomyces cerevisiae como modelo de estudo da tradução mitocondrial
• Beneficiário: Mario Henrique de Barros
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs