A nuclear-based quality control pathway for non-imported mitochondrial proteins
Abstract
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 S. 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 (MTS) 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.
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All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
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Funding
National Institute on Aging (AG043095)
- Adam L Hughes
National Institute of General Medical Sciences (GM119694)
- Adam L Hughes
American Federation for Aging Research
- Adam L Hughes
United Mitochondrial Disease Foundation
- Adam L Hughes
Kinship Foundation
- Adam L Hughes
Glenn Foundation for Medical Research
- Adam L Hughes
American Heart Association
- Max H Schuler
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Maya Schuldiner, Weizmann Institute, Israel
Publication history
- Received: July 19, 2020
- Accepted: March 17, 2021
- Accepted Manuscript published: March 18, 2021 (version 1)
- Version of Record published: March 25, 2021 (version 2)
Copyright
© 2021, Shakya et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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