The Yeast AIF Homolog Nde1 Integrates Signals from Metabolism and Proteostasis on the Mitochondrial Surface and Executes Cell Death

Abstract

Little is known about the proteolytic turnover of mitochondrial proteins under static growth conditions. Combining dynamic isotope labeling and mass spectrometry in yeast cells, we found an exceptionally high turnover for the NADH dehydrogenase Nde1. This homolog of the mammalian apoptosis inducing factor AIF forms two distinct topomers in mitochondria, one residing in the intermembrane space and one cytosol-exposed form that spans the outer membrane. The latter serves as trigger of cell death with the potential to kill yeast cells in response to pro-apoptotic stimuli. The surface-exposed topomer is degraded by the cytosolic proteasome/Cdc48 system and the mitochondrial protease Yme1 in wild type cells, however, it is strongly enriched in respiratory deficient cells. Our data suggest that in addition to their role in electron transfer, mitochondrial NADH dehydrogenases such as Nde1 or AIF integrate signals from energy metabolism and cytosolic proteostasis to eliminate compromised individuals from growing cell populations.