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Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins
Yu-Chan Chen1, George K E Umanah2, Noah Dephoure3
1Department of Biochemistry, University of Utah School of Medicine, Salt Lake City UT, USA.
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+ ATPase Msp1 limits the accumulation of mislocalized TA proteins on mitochondria. Deletion of MSP1 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 MSP1 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 ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28, orthologs of Pex15 and Gos1, respectively. GOS28 protein level is also increased in ATAD1(-/-) mouse tissues. Therefore, we propose that yeast Msp1 and mammalian ATAD1 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.
Insights
Mitochondria accumulate mislocalized tail-anchored proteins when the Guided Entry (GET) system is impaired. The AAA+ ATPase Msp1/ATAD1 prevents this, maintaining mitochondrial integrity by extracting aberrant proteins.
Area of Science:
- Cell Biology
- Molecular Biology
- Mitochondrial Biology
Background:
- Tail-anchored (TA) proteins are typically inserted into membranes via the Guided Entry (GET) system.
- Disruption of the GET system leads to TA protein mislocalization to mitochondria.
Purpose of the Study:
- To investigate the role of AAA+ ATPase Msp1 in preventing TA protein accumulation on mitochondria.
- To determine if Msp1 and its mammalian ortholog ATAD1 are conserved in mitochondrial protein quality control.
Main Methods:
- Yeast genetics and microscopy to study TA protein localization.
- Analysis of mitochondrial morphology and DNA/protein content in mutant strains.
- Comparison of yeast Msp1 function with human ATAD1 in mammalian tissues.
Main Results:
- Deletion of MSP1 exacerbates TA protein mislocalization to mitochondria when the GET system is impaired.
- Combined mutations in MSP1 and GET cause severe synergistic growth defects and mitochondrial damage.
- Yeast Msp1 and human ATAD1 limit the mitochondrial mislocalization of specific TA proteins (Pex15, Gos1, PEX26, GOS28).
Conclusions:
- Yeast Msp1 and mammalian ATAD1 are conserved in a mitochondrial protein quality control system.
- These proteins likely extract and degrade mislocalized TA proteins, preserving mitochondrial integrity.
- Msp1/ATAD1 function is crucial for preventing mitochondrial dysfunction caused by GET pathway defects.