CLD1 Reverses the ubiquinone insufficiency of mutant cat5/coq7 in a Saccharomyces cerevisiae model system

Adwitiya Kar, Haley Beam, Megan B. Borror, Michael Luckow, Xiaoli Gao, Shane L. Rea

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Ubiquinone (Qn ) functions as a mobile electron carrier in mitochondria. In humans, Q biosynthetic pathway mutations lead to Q10 deficiency, a life threatening disorder. We have used a Saccharomyces cerevisiae model of Q6 deficiency to screen for new modulators of ubiquinone biosynthesis. We generated several hypomorphic alleles of coq7/cat5 (clk-1 in Caenorhabditis elegans) encoding the penultimate enzyme in Q biosynthesis which converts 5-demethoxy Q6 (DMQ6) to 5-demethyl Q6 , and screened for genes that, when overexpressed, suppressed their inability to grow on non-fermentable ethanol-implying recovery of lost mitochondrial function. Through this approach we identified Cardiolipin-specific Deacylase 1 (CLD1), a gene encoding a phospholipase A2 required for cardiolipin acyl remodeling. Interestingly, not all coq7 mutants were suppressed by Cld1p overexpression, and molecular modeling of the mutant Coq7p proteins that were suppressed showed they all contained disruptions in a hydrophobic α-helix that is predicted to mediate membrane-binding. CLD1 overexpression in the suppressible coq7 mutants restored the ratio of DMQ6 to Q6 toward wild type levels, suggesting recovery of lost Coq7p function. Identification of a spontaneous Cld1p loss-of-function mutation illustrated that Cld1p activity was required for coq7 suppression. This observation was further supported by HPLC-ESI-MS/MS profiling of monolysocardiolipin, the product of Cld1p. In summary, our results present a novel example of a lipid remodeling enzyme reversing a mitochondrial ubiquinone insufficiency by facilitating recovery of hypomorphic enzymatic function.

Original languageEnglish (US)
Article numbere0162165
JournalPloS one
Volume11
Issue number9
DOIs
StatePublished - Sep 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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