Mechanisms and Physiological Roles of Mitophagy in Yeast

Abstract

Mitochondria are responsible for supplying of most of the cell's energy via oxidative phosphorylation. However, mitochondria also can be deleterious for a cell because they are the primary source of reactive oxygen species, which are generated as a byproduct of respiration. Accumulation of mitochondrial and cellular oxidative damage leads to diverse pathologies. Thus, it is important to maintain a population of healthy and functional mitochondria for normal cellular metabolism. Eukaryotes have developed defense mechanisms to cope with aberrant mitochondria. Mitochondria autophagy (known as mitophagy) is thought to be one such process that selectively sequesters dysfunctional or excess mitochondria within double-membrane autophagosomes and carries them into lysosomes/vacuoles for degradation. The power of genetics and conservation of fundamental cellular processes among eukaryotes make yeast an excellent model for understanding the general mechanisms, regulation, and function of mitophagy. In budding yeast, a mitochondrial surface protein, Atg32, serves as a mitochondrial receptor for selective autophagy that interacts with Atg11, an adaptor protein for selective types of autophagy, and Atg8, a ubiquitin-like protein localized to the isolation membrane. Atg32 is regulated transcriptionally and post-translationally to control mitophagy. Moreover, because Atg32 is a mitophagy-specific protein, analysis of its deficient mutant enables investigation of the physiological roles of mitophagy. Here, we review recent progress in the understanding of the molecular mechanisms and functional importance of mitophagy in yeast at multiple levels.

Keywords: Atg32; autophagy; mitochondria; mitophagy; yeast.

Fig. 1. Mitophagy in yeast

(A) Schematic representation of autophagy. When autophagy is induced, isolation membranes nucleate at the preautophagosomal structure/phagophore assembly site (PAS). They grow and engulf cytoplasmic cargos to form a double-membrane vesicle called an autophagosome. Autophagosomes subsequently fuse with the lysosome/ vacuole and release the cargo for degradation. (B) Atg32-mediated mitophagy in yeast. Atg32 acts as a mitophagy receptor that interacts with the adaptor protein Atg11 and the ubiquitin-like protein Atg8 to recruit mitochondria to the PAS. The Atg32–Atg11 interaction depends on the phosphorylation of Atg32 at Ser¹¹⁴ by CK2. (C, D) Sequence alignments of the Atg8-interacting (C) and Atg11-interacting (D) regions in selective autophagy receptor proteins. Atg8-family-interacting motif and (I/V)LS motif, which are well conserved among receptor proteins, are underlined. Red letters indicate residues subjected to phosphorylation (Farre and Subramani, 2016). corroborating the role of Atg32 as a selective autophagy receptor.