Genes and lipids that impact uptake and assimilation of exogenous coenzyme Q in Saccharomyces cerevisiae

Free Radic Biol Med. 2020 Jul;154:105-118. doi: 10.1016/j.freeradbiomed.2020.04.029. Epub 2020 May 6.

Abstract

Coenzyme Q (CoQ) is an essential player in the respiratory electron transport chain and is the only lipid-soluble antioxidant synthesized endogenously in mammalian and yeast cells. In humans, genetic mutations, pathologies, certain medical treatments, and aging, result in CoQ deficiencies, which are linked to mitochondrial, cardiovascular, and neurodegenerative diseases. The only strategy available for these patients is CoQ supplementation. CoQ supplements benefit a small subset of patients, but the poor solubility of CoQ greatly limits treatment efficacy. Consequently, the efficient delivery of CoQ to the mitochondria and restoration of respiratory function remains a major challenge. A better understanding of CoQ uptake and mitochondrial delivery is crucial to make this molecule a more efficient and effective therapeutic tool. In this study, we investigated the mechanism of CoQ uptake and distribution using the yeast Saccharomyces cerevisiae as a model organism. The addition of exogenous CoQ was tested for the ability to restore growth on non-fermentable medium in several strains that lack CoQ synthesis (coq mutants). Surprisingly, we discovered that the presence of CoQ biosynthetic intermediates impairs assimilation of CoQ into a functional respiratory chain in yeast cells. Moreover, a screen of 40 gene deletions considered to be candidates to prevent exogenous CoQ from rescuing growth of the CoQ-less coq2Δ mutant, identified six novel genes (CDC10, RTS1, RVS161, RVS167, VPS1, and NAT3) as necessary for efficient trafficking of CoQ to mitochondria. The proteins encoded by these genes represent essential steps in the pathways responsible for transport of exogenously supplied CoQ to its functional sites in the cell, and definitively associate CoQ distribution with endocytosis and intracellular vesicular trafficking pathways conserved from yeast to human cells.

Keywords: CoQ(6) rescue; Coenzyme Q; Endocytosis; Saccharomyces cerevisiae; Transport; Ubiquinone; Uptake.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • GTP-Binding Proteins
  • Humans
  • Lipids
  • Microfilament Proteins
  • Mitochondrial Diseases*
  • N-Terminal Acetyltransferase B
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins* / genetics
  • Saccharomyces cerevisiae Proteins* / metabolism
  • Ubiquinone / metabolism
  • Vesicular Transport Proteins

Substances

  • Lipids
  • Microfilament Proteins
  • Nat3 protein, S cerevisiae
  • RVS167 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Vesicular Transport Proteins
  • Ubiquinone
  • N-Terminal Acetyltransferase B
  • GTP-Binding Proteins
  • VPS1 protein, S cerevisiae