Involvement of mitochondrial dynamics in the segregation of mitochondrial matrix proteins during stationary phase mitophagy

Abstract

Mitophagy, the autophagic degradation of mitochondria, is an important housekeeping function in eukaryotic cells and defects in mitophagy correlate with ageing phenomena and with several neurodegenerative disorders. A central mechanistic question regarding mitophagy is whether mitochondria are consumed en masse, or whether an active process segregates defective molecules from functional ones within the mitochondrial network, thus allowing a more efficient culling mechanism. Here, we combine a proteomic study with a molecular genetic and cell biology approach to determine whether such a segregation process occurs in yeast mitochondria. We find that different mitochondrial matrix proteins undergo mitophagic degradation at distinctly different rates, supporting the active segregation hypothesis. These differential degradation rates depend on mitochondrial dynamics, suggesting a mechanism coupling weak physical segregation with mitochondrial dynamics to achieve a distillation-like effect. In agreement, the rates of mitophagic degradation strongly correlate with the degree of physical segregation of specific matrix proteins.

Roles of mitophagy in cellular physiology and development

“…The observation that asymmetric fission results in one hyperpolarized and one depolarized mitochondrion (Twig et al 2008), together with the fact that mitochondrial dynamics and content mixing and not mitochondrial size, determine the rate of mitophagy suggest a distillation-type mechanism for separating intra-mitochondrial components (Abeliovich 2011;Abeliovich et al 2013). Interestingly, a direct interaction between Atg11, an autophagy factor functioning in cargo selectivity and Dnm1, a dynamin like ATPase required for mitochondrial fission has been reported (Mao et al 2013).…”

“…Mitochondrial matrix proteins have been identified with widely diverging rates of mitophagy (Abeliovich et al 2013). Strikingly, mitochondrial matrix proteins that are inefficiently degraded by mitophagy clearly segregate within the matrix from those undergoing efficient mitophagy, whereas inefficiently degraded proteins appear to concentrate in specific foci inside the mitochondrial matrix, those proteins undergoing efficient mitophagy appear to be evenly distributed (Abeliovich et al 2013).…”

Mitochatting – If only we could be a fly on the cell wall

“…In mammalian cells, inhibition of mitochondrial fission resulted in impaired mitophagy and accumulation of dysfunctional mitochondria [93]. Several studies in yeast showed that the fission factor Dnm1is required for efficient mitophagy [84,89,94,95]. Dnm1 was further shown to directly interact with Atg11 [95].…”

Mitophagy as a stress response in mammalian cells and in respiring S. cerevisiae

“…The observation that mitochondrial fission results in one hyperpolarized and one depolarized daughter [13], together with the observation that mitochondrial content mixing, not mitochondrial size, is the determinant for the rate of mitophagy, both suggest a distillation-type mechanism for separating intra-mitochondrial components [43]. Indeed, a SILAC (stable isotope labelling by amino acids in cell culture)-based proteomic screen identified mitochondrial matrix proteins with widely diverging rates of mitophagy [44]. Strikingly, mitochondrial matrix proteins which are inefficiently degraded by mitophagy are clearly segregated from those undergoing efficient mitophagy, within the matrix: inefficiently degraded proteins seem to be concentrated in specific intra-mitochondrial foci, whereas those undergoing efficient mitophagy are evenly dispersed in the mitochondrial matrix [44].…”

“…Indeed, a SILAC (stable isotope labelling by amino acids in cell culture)-based proteomic screen identified mitochondrial matrix proteins with widely diverging rates of mitophagy [44]. Strikingly, mitochondrial matrix proteins which are inefficiently degraded by mitophagy are clearly segregated from those undergoing efficient mitophagy, within the matrix: inefficiently degraded proteins seem to be concentrated in specific intra-mitochondrial foci, whereas those undergoing efficient mitophagy are evenly dispersed in the mitochondrial matrix [44]. One possibility is that this reflects a distillation process that is coupled to mitochondrial dynamics on the one hand, and mitophagic engulfment on the other [45].…”