Increased levels of reduced cytochrome b and mitophagy components are required to trigger nonspecific autophagy following induced mitochondrial dysfunction

Abstract

SummaryMitochondria are essential organelles producing most of the energy required for the cell. A selective autophagic process called mitophagy removes damaged mitochondria, which is critical for proper cellular homeostasis; dysfunctional mitochondria can generate excess reactive oxygen species that can further damage the organelle as well as other cellular components. Although proper cell physiology requires the maintenance of a healthy pool of mitochondria, little is known about the mechanism underlying the recognition and selection of damaged organelles. In this study, we investigated the cellular fate of mitochondria damaged by the action of respiratory inhibitors (antimycin A, myxothiazol, KCN) that act on mitochondrial respiratory complexes III and IV, but have different effects with regard to the production of reactive oxygen species and increased levels of reduced cytochromes. Antimycin A and potassium cyanide effectively induced nonspecific autophagy, but not mitophagy, in a wild-type strain of Saccharomyces cerevisiae; however, low or no autophagic activity was measured in strains deficient for genes that encode proteins involved in mitophagy, including ATG32, ATG11 and BCK1. These results provide evidence for a major role of specific mitophagy factors in the control of a general autophagic cellular response induced by mitochondrial alteration. Moreover, increased levels of reduced cytochrome b, one of the components of the respiratory chain, could be the first signal of this induction pathway.

Mitochondrial depolarization in yeast zygotes inhibits clonal expansion of selfish mtDNA

“…In that work, Deffieu and co-authors found that prolonged incubation of yeast cells in the presence of the uncoupler CCCP also induced GFP-Atg8 proteolysis (Deffieu et al, 2013), although the effect was much less pronounced than in the case of treatment with myxothiazole. Uncouplers dissipate energy in mitochondria and, therefore, theoretically, can induce an unspecific starvation response, which is known to induce macroautophagy (Tal et al, 2007).…”

“…Inhibitors of the respiratory chain have been shown to induce bulk autophagy in yeast cells, but required the selective autophagy receptor Atg32 (Deffieu et al, 2013). In that work, Deffieu and co-authors found that prolonged incubation of yeast cells in the presence of the uncoupler CCCP also induced GFP-Atg8 proteolysis (Deffieu et al, 2013), although the effect was much less pronounced than in the case of treatment with myxothiazole.…”

Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma

“…These observations support YME1LI as a NUMT suppressor gene in humans whose inactivation leads to increased numtogenesis. Yme1 removes the damaged or dysfunctional mitochondria by mitophagy and maintains a healthy pool of mitochondria in the cell [81]. These observations implicate mitophagy in mediating accumulation and transfer of mtDNA into the nuclear genome.…”

Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome

“…In addition, we have identified that inactivation of YME1L1 in colorectal tumors induces migration of mtDNA to the nuclear genome [173]. In yeast, Yme1 (yeast homolog of human YME1L1) aids in the removal of damaged mitochondria by mitophagy, a stringent mechanism that controls the quality of mitochondria and maintains a healthy pool of this organelle within the cells [174]. These observations lead us to suggest that compromised mitophagy is involved in the accumulation of mtDNA in the nucleus [174].…”

“…In yeast, Yme1 (yeast homolog of human YME1L1) aids in the removal of damaged mitochondria by mitophagy, a stringent mechanism that controls the quality of mitochondria and maintains a healthy pool of this organelle within the cells [174]. These observations lead us to suggest that compromised mitophagy is involved in the accumulation of mtDNA in the nucleus [174]. Indeed, compromised mitophagy due to loss of Yme1 [175] or acid endonuclease DNase IIα [176] can lead to the cytoplasmic accumulation of incompletely digested mtDNA, which ultimately ends up in the nucleus.…”