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.

The ER protein Ema19 facilitates the degradation of nonimported mitochondrial precursor proteins

“…Consistent with previous reports, our data indicate that under normal conditions Oxa1 precursors associate with the ER surface only very transiently ( Hansen et al. , 2018 ; Shakya et al. , 2020 ; Xiao et al.…”

Increased levels of mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

“…Thereby, mitochondrial protein biogenesis directly depends on the cytosolic chaperone capacity. Presumably as a consequence of their strong tendency to sequester chaperones, the cytosolic accumulation of precursor proteins induces a sudden growth arrest and triggers the increased expression of components of the chaperone and proteasome system (Wang & Chen, 2015; Wrobel et al , 2015; Weidberg & Amon, 2018; Boos et al , 2019; Mårtensson, Priesnitz et al , 2019; Boos, Labbadia et al , 2020; Shakya et al , 2021). Obviously, the post‐translational import mode of mitochondrial proteins poses a threat for cellular proteostasis which is met by an adaptive network of cytosolic factors that can deal with unfolded precursors.…”

“…Owing to their post-translational mode of import, newly synthesized mitochondrial precursors initially explore the cytosol where they are maintained in a soluble and import-competent state by different chaperones that reside in the cytosol or are associated with the membranes of mitochondria and the ER (Deshaies, Koch et al, 1988;Becker, Walter et al, 1996;Terada, Kanazawa et al, 1997;F€ unfschilling & Rospert, 1999 Thereby, mitochondrial protein biogenesis directly depends on the cytosolic chaperone capacity. Presumably as a consequence of their strong tendency to sequester chaperones, the cytosolic accumulation of precursor proteins induces a sudden growth arrest and triggers the increased expression of components of the chaperone and proteasome system (Wang & Chen, 2015;Wrobel et al, 2015;Weidberg & Amon, 2018;Boos et al, 2019;M artensson, Priesnitz et al, 2019;Boos, Labbadia et al, 2020;Shakya et al, 2021). Obviously, the post-translational import mode of mitochondrial proteins poses a threat for cellular proteostasis which is met by an adaptive network of cytosolic factors that can deal with unfolded precursors.…”

ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

“…When mitochondrial import sites are limiting so that precursor proteins accumulate outside of mitochondria, a large number of precursors of mitochondrial membrane proteins were found to associate with the ER surface [56] and to induce the unfolded protein response pathway of the ER [57]. Since these precursor proteins, in particular those of the carriers, have a highly toxic potential [24,58,59], ER binding might serve as a safeguard mechanism [51].…”