Abstract
Deficiencies in mitochondrial import cause the toxic accumulation of non-imported mitochondrial precursor proteins. Numerous fates for non-imported mitochondrial precursors have been identified in budding yeast, including proteasomal destruction, deposition into protein aggregates, and mistargeting to other organelles. Amongst organelles, the ER has emerged as a key destination for a subset of non-imported mitochondrial proteins. However, how ER targeting of various types of mitochondrial proteins is achieved remains incompletely understood. Here, we show that the ER delivery of endogenous mitochondrial transmembrane proteins, especially those belonging to the SLC25A mitochondrial carrier family, is dependent on the guided entry of tail-anchored proteins (GET) complex. Without a functional GET pathway, non-imported mitochondrial proteins destined for the ER are alternatively sequestered into Hsp42-dependent protein foci. Loss of the GET pathway is detrimental to yeast cells experiencing mitochondrial import failure and prevents re-import of mitochondrial proteins from the ER via the ER-SURF pathway. Overall, this study outlines an important role for the GET complex in ER targeting of non-imported mitochondrial carrier proteins.
Highlights
Mitochondria play crucial roles in ATP production, metabolite synthesis, cell immunity, and apoptosis (Friedman & Nunnari, 2014)
Our current work shows that the guided entry of tail-anchored proteins (GET) complex is required for ER targeting of a specific group of proteins, the mitochondrial carrier proteins
Similar to these previously described OMM proteins, multi-pass mitochondrial carrier proteins that require the GET pathway for ER delivery, including Oac1, Mir1, and Dic1, all contain transmembrane domains that are very close to their C-termini (Kunji, 2004)
Summary
Mitochondria play crucial roles in ATP production, metabolite synthesis, cell immunity, and apoptosis (Friedman & Nunnari, 2014). A major consequence of mitochondrial dysfunction is the impairment of mitochondrial protein import. The vast majority of the mitochondrial proteome, which contains more than 1,000 proteins, is encoded in the nucleus and synthesized in the cytoplasm (Pagliarini etal, 2008). Mitochondrial precursor proteins are imported into mitochondria by translocase complexes located in the outer and inner mitochondrial membranes (OMM and IMM) (Wiedemann & Pfanner, 2017). The translocation of mitochondrial proteins containing mitochondrial targeting sequences is dependent on IMM potential (Wiedemann & Pfanner, 2017). In response to mitochondrial dysfunction, mitochondrial protein import is impaired and non-imported proteins accumulate outside of mitochondria (Hughes & Gottschling, 2012; Wang & Chen, 2015; Wrobel et al, 2015; Boos et al, 2020)
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