Publication Type |
dissertation |
School or College |
School of Medicine |
Department |
Biochemistry |
Author |
Chen, Yu-Chan |
Title |
Functionalizing the mitochondrial proteome-mitochondrial metabolism, protein quality control and beyond |
Date |
2015-08 |
Description |
This dissertation is to characterize two evolutionarily conserved but uncharacterized mitochondrial proteins using yeast and mammalian cells. The first protein, which we named respiratory supercomplex factor 1 (Rcf1), is required for the assembly of respiratory supercomplexes. Deletion of the RCF1 gene causes destabilization of respiratory supercomplexes, impaires respiration and elevates mitochondrial oxidative stress. We also show that HIG2A, a mammalian homolog of RCF1, performs the same function in mammalian cells. Therefore, we suggest that Rcf1 and HIG2A are members of a conserved protein family that acts to maintain the homeostasis of mitochondrial metabolism by promoting respiratory supercomplex assembly. The second protein on which my dissertation research was based, originally annotated as mitochondrial sorting of protein 1 (Msp1), performs multiple tasks. The first function is its role in facilitating the removal of tail-anchored (TA) proteins that are mislocalized to mitochondria. Disruption of the guided entry of tail-anchored protein (GET) system was shown to cause a subset of TA proteins to mislocalize to mitochondria. The AAA+ ATPase Msp1 can limit the accumulation of mislocalized TA proteins on mitochondria. The human homolog of Msp1, ATAD1, also limits the mitochondrial mislocalization of TA proteins in mammalian cells. Therefore, Msp1 and ATAD1 are conserved members of a mitochondrial protein quality control system that iv functions to promote the extraction and degradation of mislocalized TA proteins to maintain mitochondrial integrity. The second role of Msp1 and ATAD1 is in a novel vesicular trafficking system from mitochondria to peroxisomes in an ATPase activitydependent manner. Impaired peroxisome biogenesis and mislocalization of peroxins (peroxisomal biogenesis factors) to the mitochondria has been observed in cells from Zellweger patients. Overexpression of ATAD1 facilitates the removal of these peroxins from mitochondria and the accumulation in vesicle-like structures of unknown character and function. We speculate that these vesicles might sort the peroxins to peroxisomes for peroxisomal biogenesis. Therefore, we propose that Msp1 and ATAD1 participate in a novel vesicular trafficking pathway, which is likely associated with protein sorting from mitochondria to peroxisomes. In conclusion, our findings provide a better understanding of mitochondrial biology, which further sheds light on the etiology of human mitochondrial diseases. |
Type |
Text |
Publisher |
University of Utah |
Subject MESH |
DNA, Mitochondrial; Mitochondria; Mitochondrial Proteins; Proteome; Proteomics; Genome, Mitochondria; Quality Control; Oxidative Stress; Metabolic Diseases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphatases; Protein Binding; Protein Transport; Membrane Proteins; Electron Transport Chain Complex Proteins |
Dissertation Institution |
University of Utah |
Dissertation Name |
Doctor of Philosophy |
Language |
eng |
Relation is Version of |
Digital version of Functionalizing the Mitochondrial Proteome-Mitochondrial Metabolism, Protein Quality Control and Beyond |
Rights Management |
Copyright © Yu-Chan Chen 2015 |
Format Medium |
application/pdf |
Format Extent |
54,862,450 bytes |
Source |
Original in Marriott Library Special Collections |
ARK |
ark:/87278/s6zd2mph |
Setname |
ir_etd |
ID |
1432964 |
Reference URL |
https://collections.lib.utah.edu/ark:/87278/s6zd2mph |