Balanced CoQ6 biosynthesis is required for lifespan and mitophagy in yeast

Abstract

Coenzyme Q is an essential lipid with redox capacity that is present in all organisms. In yeast its biosynthesis depends on a multiprotein complex in which Coq7 protein has both catalytic and regulatory functions. Coq7 modulates CoQ6 levels through a phosphorylation cycle, where dephosphorylation of three amino acids (Ser/Thr) by the mitochondrial phosphatase Ptc7 increases the levels of CoQ6. Here we analyzed the role of Ptc7 and the phosphorylation state of Coq7 in yeast mitochondrial function. The conversion of the three Ser/Thr to alanine led to a permanently active form of Coq7 that caused a 2.5-fold increase of CoQ6 levels, albeit decreased mitochondrial respiratory chain activity and oxidative stress resistance capacity. This resulted in an increase in endogenous ROS production and shortened the chronological life span (CLS) compared to wild type. The null PTC7 mutant (ptc7∆) strain showed a lower biosynthesis rate of CoQ6 and a significant shortening of the CLS. The reduced CLS observed in ptc7Δ was restored by the overexpression of PTC7 but not by the addition of exogenous CoQ6. Overexpression of PTC7 increased mitophagy in a wild type strain. This finding suggests an additional Ptc7 function beyond the regulation of CoQ biosynthesis. Genetic disruption of PTC7 prevented mitophagy activation in conditions of nitrogen deprivation. In brief, we show that, in yeast, Ptc7 modulates the adaptation to respiratory metabolism by dephosphorylating Coq7 to supply newly synthesized CoQ6, and by activating mitophagy to remove defective mitochondria at stationary phase, guaranteeing a proper CLS in yeast.

Chromatin-remodeling SWI/SNF complex regulates coenzyme Q6 synthesis and a metabolic shift to respiration in yeast

“…To determine the effect of each Ptc7 isoform on CoQ 6 synthesis, we assayed CoQ 6 levels in cells expressing both forms of Ptc7, Ptc7 s only, Ptc7 ns only, or neither (ptc7⌬). As reported previously, there is no significant change in CoQ 6 synthesis levels in the ptc7⌬ mutant (12,30). However, exclusive expression of Ptc7 s leads to an increase in CoQ 6 synthesis, whereas exclusive expression of Ptc7 ns leads to a decrease in CoQ 6 synthesis (Fig.…”

A dedicated flavin-dependent monooxygenase catalyzes the hydroxylation of demethoxyubiquinone into ubiquinone (coenzyme Q) in Arabidopsis

“…Our data also indicate that overexpression of demethoxyubiquinone hydroxylase alone is not sufficient to boost ubiquinone content in Arabidopsis . This finding is in marked contrast with the situation observed in yeast, in which deregulation of Coq7 activity has been shown to result in a 250% increase in ubiquinone level ( 18 , 48 ). Last, our functional complementation assays demonstrating that At1g24340 encodes for a strictly monofunctional monooxygenase imply that plants must possess a separate enzyme for the C-1 hydroxylation step of their ubiquinone biosynthetic pathway.…”

Ser/Thr protein phosphatases in fungi: structure, regulation and function

“…This would explain the observed increase in both the rate of synthesis and steady-state levels of CoQ in Snf2-deficient cells and might contribute to justify the contradictory results on CoQ production described above. Lack of Ptc7 has been also related to the shortening of the chronological life span (CLS) and prevention of mitophagy, whereas overexpression of the protein had the opposite effects [352]. Since CLS shortening could not be rescue by exogenous yeast CoQ supplementation, this was additional evidence pointing out that Ptc7 could function beyond the regulation of CoQ biosynthesis.…”