Abstract
Proteostasis is a challenge for cellular organisms, as all known protein synthesis machineries are error-prone. Here we show by cell fractionation and microscopy studies that misfolded proteins formed in the endoplasmic reticulum can become associated with and partly transported into mitochondria, resulting in impaired mitochondrial function. Blocking the endoplasmic reticulum-mitochondria encounter structure (ERMES), but not the mitochondrial sorting and assembly machinery (SAM) or the mitochondrial surveillance pathway components Msp1 and Vms1, abrogated mitochondrial sequestration of ER-misfolded proteins. We term this mitochondria-associated proteostatic mechanism for ER-misfolded proteins ERAMS (ER-associated mitochondrial sequestration). We testify to the relevance of this pathway by using mutant α-1-antitrypsin as an example of a human disease-related misfolded ER protein, and we hypothesize that ERAMS plays a role in pathological features such as mitochondrial dysfunction.
Highlights
Proteostasis is a challenge for cellular organisms, as all known protein synthesis machineries are error-prone
We used a similar construct without the PLN ERtargeting and the KDEL endoplasmic reticulum (ER)-retention signals, so that firefly luciferase reporter (Fluc) remains in the cytoplasm
Subsequent high-resolution SDS-gel analysis confirmed the identity of the higher molecular weight form as N-glycosylated Fluc and the lower molecular weight form as unglycosylated Fluc, both with cleavage of the signal peptide, demonstrating that ER-Fluc had passed into the ER (Fig. 1b)
Summary
Proteostasis is a challenge for cellular organisms, as all known protein synthesis machineries are error-prone. Blocking the endoplasmic reticulum-mitochondria encounter structure (ERMES), but not the mitochondrial sorting and assembly machinery (SAM) or the mitochondrial surveillance pathway components Msp[1] and Vms[1], abrogated mitochondrial sequestration of ER-misfolded proteins. We term this mitochondria-associated proteostatic mechanism for ER-misfolded proteins ERAMS (ER-associated mitochondrial sequestration). 1234567890():,; Protein homeostasis depends on a delicate balance between maintaining protein conformation, refolding misfolded proteins and degrading damaged proteins This process is most finely controlled in the endoplasmic reticulum (ER). We addressed the question of whether further to these functions, mitochondria play a role in ER proteostasis
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