Molecular Cell
Volume 77, Issue 1, 2 January 2020, Pages 189-202.e6
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Article
The NADH Dehydrogenase Nde1 Executes Cell Death after Integrating Signals from Metabolism and Proteostasis on the Mitochondrial Surface

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Highlights

  • A fraction of the mitochondrial NADH dehydrogenase Nde1 is exposed to the cytosol

  • Nde1 is degraded by the proteasome but accumulates in respiration-deficient cells

  • Cytosol-exposed Nde1 generates a toxic fragment that triggers apoptosis

  • Nde1-mediated cell death prevents the propagation of respiratory compromised cells

Summary

The proteolytic turnover of mitochondrial proteins is poorly understood. Here, we used a combination of dynamic isotope labeling and mass spectrometry to gain a global overview of mitochondrial protein turnover in yeast cells. Intriguingly, we found an exceptionally high turnover of 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 while the other spans the outer membrane and is exposed to the cytosol. The surface-exposed topomer triggers cell death in response to pro-apoptotic stimuli. The surface-exposed topomer is degraded by the cytosolic proteasome/Cdc48 system and the mitochondrial protease Yme1; 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 cells from growing populations.

Keywords

apoptosis
apoptosis-inducing factor
mitochondria
NADH:ubiquinone dehydrogenase
protein import
respiration

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These authors contributed equally

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