The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import

Abstract

Mitochondria play a key role in cellular energy metabolism. Transitions between glycolytic and respiratory conditions induce considerable adaptations of the cellular proteome. These metabolism-dependent changes are particularly pronounced for the protein composition of mitochondria. Here, we show that the yeast cytosolic ubiquitin conjugase Ubc8 plays a crucial role in the remodeling process when cells transition from respiratory to fermentative conditions. Ubc8 is a conserved and well-studied component of the catabolite control system that is known to regulate the stability of gluconeogenic enzymes. Unexpectedly, we found that Ubc8 also promotes the assembly of the translocase of the outer membrane of mitochondria (TOM) and increases the levels of its cytosol-exposed receptor subunit Tom22. Ubc8 deficiency results in compromised protein import into mitochondria and reduced steady-state levels of mitochondrial proteins. Our observations show that Ubc8, which is controlled by the prevailing metabolic conditions, promotes the switch from glucose synthesis to glucose usage in the cytosol and induces the biogenesis of the mitochondrial TOM machinery to improve mitochondrial protein import during phases of metabolic transition.

MitoStores: chaperone‐controlled protein granules store mitochondrial precursors in the cytosol

“…The balance of both processes is not clear, but the immediate Rpn4‐mediated induction of the proteasome system (Boos et al , 2019 ) indicates that cytosolic precursors are under tight proteolytic control. The proteasome plays a direct and crucial role in the removal of stalled import intermediates from the mitochondrial outer membrane translocase or from other cellular nonproductive binding sites (Itakura et al , 2016 ; Weidberg & Amon, 2018 ; Mårtensson et al , 2019 ; Mohanraj et al , 2019 ; Basch et al , 2020 ; Murschall et al , 2020 ; Shakya et al , 2021 ; Rodl et al , 2023 ). Hence, proteasomal upregulation appears to be the primary and immediate cellular response to mitoprotein‐induced stress conditions.…”

The role of the proteasome in mitochondrial protein quality control

“…Glucose‐induced shutdown (catabolic degradation) of gluconeogenic enzymes prevents excessive energy consumption by futile cycles 65 . In addition to their role in the degradation of gluconeogenic enzymes, Ubc8 and the GID complex are important for efficient protein import into mitochondria 66 (Figure 5b). Loss of Ubc8 or the substrate binding proteins of the GID complex (Gid4 and Gid10, respectively) results in decreased protein levels of a crucial TOM subunit, Tom22, and in incomplete assembly of the TOM complex.…”