The Dep1 protein: A new regulator of mitophagy in yeast.

Mitochondria play a crucial role in most eukaryotic cells. Mitophagy is a process that controls their quality and quantity within the cells. The outer mitochondrial membrane protein, Atg32, serves as the mitophagic receptor. It interacts with the Atg11 protein to initiate mitophagy and with the Atg8 protein to ensure the engulfment of mitochondria into the autophagosomes for elimination. The Atg32 protein is regulated at the transcriptional level but also by posttranslational modifications. In this study, we described a new regulator of mitophagy, the protein Dep1, identified as a part of the Rpd3L histone deacetylase complex. We showed that the Dep1 protein is localized in the nucleus and associated with mitochondria. This protein is needed for mitophagy and to regulate the transcription and expression of the Atg32 protein. The absence of this protein affects the mitophagy process induced by either starvation for nitrogen or the stationary phase of growth.

The yeast mitophagy receptor Atg32 is ubiquitinated and degraded by the proteasome.

Mitophagy, the process that degrades mitochondria selectively through autophagy, is involved in the quality control of mitochondria in cells grown under respiratory conditions. In yeast, the presence of the Atg32 protein on the outer mitochondrial membrane allows for the recognition and targeting of superfluous or damaged mitochondria for degradation. Post-translational modifications such as phosphorylation are crucial for the execution of mitophagy. In our study we monitor the stability of Atg32 protein in the yeast S. cerevisiae and show that Atg32 is degraded under normal growth conditions, upon starvation or rapamycin treatment. The Atg32 turnover can be prevented by inhibition of the proteasome activity, suggesting that Atg32 is also ubiquitinated. Mass spectrometry analysis of purified Atg32 protein revealed that at least lysine residue in position 282 is ubiquitinated. Interestingly, the replacement of lysine 282 with alanine impaired Atg32 degradation only partially in the course of cell growth, suggesting that additional lysine residues on Atg32 might also be ubiquitinated. Our results provide the foundation to further elucidate the physiological significance of Atg32 turnover and the interplay between mitophagy and the proteasome.

The mitochondrial phosphatidylserine decarboxylase Psd1 is involved in nitrogen starvation-induced mitophagy in yeast.

Mitophagy, the selective degradation of mitochondria by autophagy, is a central process that is essential for the maintenance of cell homeostasis. It is implicated in the clearance of superfluous or damaged mitochondria and requires specific proteins and regulators to perform. In yeast, Atg32, an outer mitochondrial membrane protein, interacts with the ubiquitin-like Atg8 protein, promoting the recruitment of mitochondria to the phagophore and their sequestration within autophagosomes. Atg8 is anchored to the phagophore and autophagosome membranes thanks to a phosphatidylethanolamine tail. In Saccharomyces cerevisiae, several phosphatidylethanolamine synthesis pathways have been characterized, but their contribution to autophagy and mitophagy are unknown. Through different approaches, we show that Psd1, the mitochondrial phosphatidylserine decarboxylase, is involved in mitophagy induction only after nitrogen starvation, whereas Psd2, which is located in vacuole, Golgi and endosome membranes, is required preferentially for mitophagy induction in the stationary phase of growth but also to a lesser extent for nitrogen starvation-induced mitophagy. Our results suggest that the mitophagy defect observed in Δpsd1 yeast cells after nitrogen starvation may be due to a failure of Atg8 recruitment to mitochondria.This article has an associated First Person interview with the first author of the paper.

Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance.

The maintenance of a healthy and functional mitochondrial network is critical during development as well as throughout life in the response to physiological adaptations and stress conditions. Owing to their role in energy production, mitochondria are exposed to high levels of reactive oxygen species, making them particularly vulnerable to mitochondrial DNA mutations and protein misfolding. Given that mitochondria are formed from proteins encoded by both nuclear and mitochondrial genomes, an additional layer of complexity is inherent in the coordination of protein synthesis and the mitochondrial import of nuclear-encoded proteins. For these reasons, mitochondria have evolved multiple systems of quality control to ensure that the requisite number of functional mitochondria are present to meet the demands of the cell. These pathways work to eliminate damaged mitochondrial proteins or parts of the mitochondrial network by mitophagy and renew components by adding protein and lipids through biogenesis, collectively resulting in mitochondrial turnover. Mitochondrial quality control mechanisms are multi-tiered, operating at the protein, organelle and cell levels. Herein, we discuss mitophagy in different physiological contexts and then relate it to other quality control pathways, including the unfolded protein response, shedding of vesicles, proteolysis, and degradation by the ubiquitin-proteasome system. Understanding how these pathways contribute to the maintenance of mitochondrial homeostasis could provide insights into the development of targeted treatments when these systems fail in disease.

[Role of mitophagy in the mitochondrial quality control]. / Mitophagie et contrôle qualité des mitochondries.

Mitochondria are highly dynamic organelles that provide essential metabolic functions and represent the major bioenergetic hub of eukaryotic cells. Mitochondrial dysfunctions are implicated in numerous diseases. Therefore, maintenance of a healthy pool of mitochondria is required for cellular function and survival. Mitochondrial quality control is achieved through several mechanisms that act at different levels: proteases and chaperones, the Ubiquitin-Proteasome-System (UPS) and mitophagy. Multiple mitophagy-involved programs operate independently or undergo crosstalk, and require modulated receptor activities at the outer membranes of mitochondria. In mammals, different mitophagy effectors have been characterized such as the receptors NIX, BNIP3, FUNDC1, BCL2L13, cardiolipin and the PINK1/Parkin pathway. Here we discuss the different molecular mechanisms of these mitophagy involved pathways.