eLife (Mar 2021)

A nuclear-based quality control pathway for non-imported mitochondrial proteins

  • Viplendra PS Shakya,
  • William A Barbeau,
  • Tianyao Xiao,
  • Christina S Knutson,
  • Max H Schuler,
  • Adam L Hughes

DOI
https://doi.org/10.7554/eLife.61230
Journal volume & issue
Vol. 10

Abstract

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Mitochondrial import deficiency causes cellular toxicity due to the accumulation of non-imported mitochondrial precursor proteins, termed mitoprotein-induced stress. Despite the burden mis-localized mitochondrial precursors place on cells, our understanding of the systems that dispose of these proteins is incomplete. Here, we cataloged the location and steady-state abundance of mitochondrial precursor proteins during mitochondrial impairment in Saccharomyces cerevisiae. We found that a number of non-imported mitochondrial proteins localize to the nucleus, where they are subjected to proteasome-dependent degradation through a process we term nuclear-associated mitoprotein degradation (mitoNUC). Recognition and destruction of mitochondrial precursors by the mitoNUC pathway requires the presence of an N-terminal mitochondrial targeting sequence and is mediated by combined action of the E3 ubiquitin ligases San1, Ubr1, and Doa10. Impaired breakdown of precursors leads to alternative sequestration in nuclear-associated foci. These results identify the nucleus as an important destination for the disposal of non-imported mitochondrial precursors.

Keywords