Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast

Abstract

Autophagy, a highly regulated programme found in almost all eukaryotes, is mainly viewed as a catabolic process that degrades nonessential cellular components into molecular building blocks, subsequently available for biosynthesis at a lesser expense than de novo synthesis. Autophagy is largely known to be regulated by nutritional conditions. Here we show that, in yeast cells grown under nonstarving conditions, autophagy can be induced by mitochondrial dysfunction. Electron micrographs and biochemical studies show that an autophagic activity can result from impairing the mitochondrial electrochemical transmembrane potential. Furthermore, mitochondrial damage-induced autophagy results in the preferential degradation of impaired mitochondria (mitophagy), before leading to cell death. Mitophagy appears to rely on classical macroautophagy machinery while being independent of cellular ATP collapse. These results suggest that in this case, autophagy can be envisioned either as a process of mitochondrial quality control, or as an ultimate cellular response triggered when cells are overwhelmed with damaged mitochondria.

Macroautophagy versus mitochondrial autophagy: a question of fate?

“…Further evidence that the signal for mitophagy can originate from the mitochondria itself comes from the observation that yeast mutants unable to maintain an electrical potential across the inner mitochondrial membrane exhibit an increase in mitophagy compared to wildtype cells. 39 There is preferential degradation of the damaged mitochondria, which is inhibited by mutations in Atg5. 39 An independent study has confirmed that several genes involved in macroautophagy, including Atg1, play a role in the normal turnover of mitochondria, and that defects in autophagy lead to compromised mitochondrial function and accumulation of mutations in nuclear DNA (Shengkan Jin, personal communication).…”

“…39 There is preferential degradation of the damaged mitochondria, which is inhibited by mutations in Atg5. 39 An independent study has confirmed that several genes involved in macroautophagy, including Atg1, play a role in the normal turnover of mitochondria, and that defects in autophagy lead to compromised mitochondrial function and accumulation of mutations in nuclear DNA (Shengkan Jin, personal communication). Together, these data suggest that autophagy is involved in mitochondrial degradation during both vegetative (with degradation of individual damaged mitochondria) and starvation conditions (with bulk degradation of mitochondria).…”

“…38,39 In mammalian cells, although specific molecular targets have not been identified, confocal imaging studies have demonstrated that mitochondrial depolarization precedes mitochondrial autophagy in cultured hepatocytes (in response to serum starvation and glucagon treatment) and that inhibition of the mitochondrial permeability transition prevents mitochondrial autophagy. 41 These results suggest that factors increasing mitochondrial permeability may also promote mitophagy in mammalian cells.…”

Mdm38 protein depletion causes loss of mitochondrial K+/H+ exchange activity, osmotic swelling and mitophagy

“…The These vacuolar membrane formations have previously been described to occur in mitophagy. 11,15,16 In fact, at t 25 . Cells exhibiting these particular features of mitochondria and vacuoles were abundant at t 25 to t 29 of the Mdm38p depletion experiment.…”

“…Since we observed mitochondrial fragmentation upon Mdm38p shut-off, and the association of mitochondrial fragments with vacuoles, we asked whether breakdown of the mitochondrial reticulum due to osmotic swelling led to mitochondria-selective autophagy, which has been termed mitophagy. 11,12 Results Disturbance of mitochondrial translation and membrane insertion is not a primary effect of mdm38D. Yeast strains disrupted for the MDM38 gene (mdm38D) exhibit a growth defect on non-fermentable substrate (petite phenotype) and altered mitochondrial morphology, 5 reduced amounts of certain mitochondrially encoded proteins, reduced Dc 6,13 and a near total loss of mitochondrial K þ /H þ exchange activity associated with increased K þ content and osmotic swelling.…”