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M sp1/ ATAD 1 maintains mitochondrial function by facilitating the degradation of mislocalized tail‐anchored proteins

2014; Springer Nature; Volume: 33; Issue: 14 Linguagem: Inglês

10.15252/embj.201487943

1460-2075

Yuchan Chen, George K. E. Umanah, Noah Dephoure, Shaida A. Andrabi, Steven P. Gygi, Ted M. Dawson, Valina L. Dawson, Jared Rutter,

Endoplasmic Reticulum Stress and Disease

Abstract The majority of ER ‐targeted tail‐anchored ( TA ) proteins are inserted into membranes by the Guided Entry of Tail‐anchored protein ( GET ) system. Disruption of this system causes a subset of TA proteins to mislocalize to mitochondria. We show that the AAA + ATP ase Msp1 limits the accumulation of mislocalized TA proteins on mitochondria. Deletion of MSP 1 causes the Pex15 and Gos1 TA proteins to accumulate on mitochondria when the GET system is impaired. Likely as a result of failing to extract mislocalized TA proteins, yeast with combined mutation of the MSP 1 gene and the GET system exhibit strong synergistic growth defects and severe mitochondrial damage, including loss of mitochondrial DNA and protein and aberrant mitochondrial morphology. Like yeast Msp1, human ATAD 1 limits the mitochondrial mislocalization of PEX 26 and GOS 28, orthologs of Pex15 and Gos1, respectively. GOS 28 protein level is also increased in ATAD 1 −/− mouse tissues. Therefore, we propose that yeast Msp1 and mammalian ATAD 1 are conserved members of the mitochondrial protein quality control system that might promote the extraction and degradation of mislocalized TA proteins to maintain mitochondrial integrity.