No abstract

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.

The mitochondrial respiratory chain (RC) enables many metabolic processes by regenerating both mitochondrial and cytosolic NAD+ and ATP. In contrast to ADP, NADH metabolically produced in the cytosol is not transported across the inner mitochondrial membrane and must be indirectly transferred inside mitochondria through the malate-aspartate shuttle (MAS) to fuel RC with electrons. MAS is the major pathway maintaining cytosolic NADH/NAD+ redox balance in mammalian tissues such as liver and heart and its activity is crucial for cell metabolism, division and survival. However, the specific metabolic regulations allowing mitochondrial respiration to prioritize NADH oxidation in response to high NADH/NAD+ redox stress have not been elucidated. The recent discovery that complex I (NADH dehydrogenase), and not complex II (Succinate dehydrogenase), can assemble with other RC complexes to form functional entities called respirasomes, led to the assumption that this supramolecular organisation would favour NADH oxidation. Surprisingly, our bioenergetic characterization of liver and heart mitochondria demonstrates that the RC systematically favours electrons provided by complex II. However, mitochondrial malate dehydrogenase (MDH2) mediated metabolic regulation can rewire respiratory chain electrons flow from succinate toward NADH oxidation in response to increase MAS activity. Interestingly, this new regulatory mechanism synergistically increases the NADH oxidative capacity of the RC and rewires MDH2 driven anaplerosis of the TCA, preventing malate production from succinate to favor oxidation of cytosolic malate. This discovery demonstrates that MAS does not only passively balance cytosolic and mitochondrial NADH but instead, in response to cytosolic redox stress, MAS actively rewires fuelling of the RC, inhibiting complex II to prioritize cytosolic NADH oxidation and increase complex I oxidative capacity.