Antagonistic effects of mitochondrial matrix and intermembrane space proteases on yeast aging

Abstract

Background: In many organisms, aging is characterized by a loss of mitochondrial homeostasis. Multiple factors such as respiratory metabolism, mitochondrial fusion/fission, or mitophagy have been linked to cell longevity, but the exact impact of each one on the aging process is still unclear. Results: Using the deletion mutant collection of the fission yeast Schizosaccharomyces pombe, we have developed a genome-wide screening for mutants with altered chronological lifespan. We have identified four mutants associated with proteolysis at the mitochondria that exhibit opposite effects on longevity. The analysis of the respiratory activity of these mutants revealed a positive correlation between increased respiration rate and prolonged lifespan. We also found that the phenotype of the long-lived protease mutants could not be explained by impaired mitochondrial fusion/fission activities, but it was dependent on mitophagy induction. The anti-aging role of mitophagy was supported by the effect of a mutant defective in degradation of mitochondria, which shortened lifespan of the long-lived mutants. Conclusions: Our characterization of the mitochondrial protease mutants demonstrates that mitophagy sustains the lifespan extension of long-lived mutants displaying a higher respiration potential.

This work is part of the projects PGC2018-093920-B-I00 to E.H and BFU2016-75116-P to M.C. funded by MCIN/AEI/10.13039/501100011033 and FEDER/UE “Una Manera de hacer Europa”. The Oxidative Stress and Cell Cycle group is also supported by Generalitat de Catalunya (Spain) (2017-SGR-539) and by Unidad de Excelencia María de Maeztu from MINECO (Spain) (MDM-2014–0370). M.C. is funded by the Ramon y Cajal program (MINECO-RYC2013-12858). E.H. is recipient of an ICREA Academia Award (Generalitat de Catalunya, Spain). Work in Huang’s lab was supported by the National Natural Science Foundation of China (Grant 31770810 to Y.H.).