The functional analysis of mitochondrial fission adaptors in yeast and human

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Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Guo, Qian
Title The functional analysis of mitochondrial fission adaptors in yeast and human
Date 2012-12
Description The mitochondrion is an essential organelle in eukaryotic cells and organisms. This compartment is responsible for many important cellular activities. In many cell types, healthy mitochondria are branched and form tubular networks that spread evenly throughout the cytoplasm. The balance of mitochondrial fission, fusion and movement is required to maintain this morphology and proper mitochondrial functions. Recent studies suggest that disruption of mitochondria dynamics is associated with metabolic and neurodegenerative diseases. This dissertation interrogates the function of mitochondrial fission adaptors using Saccharomyces cerevisiae as a model system and research tool. Mitochondrial fission is mediated by protein complexes that encircle and divide mitochondrial tubules. In budding yeast, fission requires the membrane-anchored protein Fis1 and the dynamin-related GTPase Dnm1. Dnm1 is recruited to mitochondria via interactions with the adaptor proteins Caf4 and Mdv1, which bind directly to the mitochondrial outer membrane protein Fis1. Unlike Mdv1, a function for Caf4 in fission has not been established. In Chapter 2, I demonstrate that Caf4 is a bona fide adaptor that assembles at mitochondrial division sites. Fission complexes may contain Caf4 alone or both Caf4 and Mdv1 without compromising fission function. Furthermore, despite correspondence between Caf4 and Mdv1 expression levels, functional and phylogenetic analyses indicate that Caf4 mitochondrial fission activity has diverged from that of Mdv1. In mammals, mitochondrial fission is mediated by the dynamin-related GTPase Drp1, which is recruited to mitochondrial surface by additional membrane-associated adaptor proteins (hFis1, Mff and MiDs). In Chapter 3, a yeast strain lacking all fission proteins is used to identify whether these adaptors is able to participate in both membrane scission and GTPase recruitment. While hFis1 is dispensable for fission, membrane-anchored Mff or MiDs paired with Drp1 are sufficient to divide mitochondria. In addition, Drp1 coassembled with MiDs in vitro forms a heteropolymer that alters Drp1 homopolymer structure with a narrower diameter. It is the first demonstration that an adaptor protein alters the architecture of a mitochondrial dynamin GTPase polymer in a manner that could facilitate membrane constriction and severing activity. Altogether, these studies advance our understanding of the multiple adaptors that function in yeast and mammalian mitochondrial fission complexes.
Type Text
Publisher University of Utah
Subject Fission complex adaptor; Mammalian; Mitochondrial fission; Paralog; Yeast
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Rights Management Copyright © Qian Guo 2012
Format Medium application/pdf
Format Extent 4,497,481 bytes
Identifier etd3/id/3455
ARK ark:/87278/s6vt51d7
Setname ir_etd
Date Created 2015-04-27
Date Modified 2021-05-06
ID 197010
Reference URL
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