ER targeting of non-imported mitochondrial carrier proteins is dependent on the GET pathway

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.

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

“…, 2020 ; Shakya et al. , 2021 ; Xiao et al. , 2020 ) and, maybe even more surprising, observed nonmitochondrial residents in mitochondria ( Ruan et al.…”

“…, 2018 ; Shakya et al. , 2020 ; Xiao et al. , 2020 ), and that Ema19 has a role in regulating the amount or extent of this interaction.…”

“…The association of mitochondrial precursors to the ER surface can retard their degradation and facilitate their productive targeting to the TOM complex by a process referred to as ER-SURF ( Hansen et al. , 2018 ; Xiao et al. , 2020 ).…”

The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering non-imported proteins

“…In addition, some organelle-specific factors of ER and mitochondria physically interact and functionally cooperate with each other 87 . (5) Protein transfer between mitochondrial and ER membranes is possible via dedicated machineries that can extract mislocalized proteins from the membrane and set them back en route to the respective other organelle 15,88-91 . (6) The close proximity of mitochondria and ER at membrane contact sites might facilitate the exchange of proteins between the two organelles.…”

“…In line with this idea, our analyses show that SRP recognizes and binds nascent chains of some mitochondrial proteins, suggesting that a portion of the mitochondrial proteome is synthesized at the ER surface. Also the GET pathway (guided entry of tail-anchored proteins) was recently identified to be involved in ER targeting of mitochondrial tail-anchored proteins and some carrier proteins 88,96 .…”