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A Core Mitophagic Machinery Promotes Selective Degradation of Paternal Mitochondria in Mouse Embryos and MEF Cells

Citation

Rojansky, Rebecca Bloom (2016) A Core Mitophagic Machinery Promotes Selective Degradation of Paternal Mitochondria in Mouse Embryos and MEF Cells. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z96Q1V75. http://resolver.caltech.edu/CaltechTHESIS:04292016-193643737

Abstract

The maternal mode of mitochondrial inheritance is conserved across mammalian species; however, little is known about how mitochondria from the sperm are eliminated from early mammalian embryos. Mitophagy, the regulated degradation of mitochondria in the lysosome, has been proposed as a possible mechanism. Mitophagy is an important means by which the cell responds to changes in mitochondrial fitness, and has been observed under a number of physiological and non-physiological circumstances, including, but not limited to, hypoxia, mitochondrial depolarization, mitochondrial fission, and erythrocyte differentiation.

Here we examine the core component of mitophagy proteins involved in three physiological states: respiration-induced mitophagy in cultured mouse fibroblasts, mitophagy of dysfunctional mitochondria in the absence of mitochondrial fusion, and degradation of paternal mitochondria in pre-implantation mouse embryos. We find that a common pathway is used for elimination of mitochondria, involving mitochondrial depolarization, and the E3 ubiquitin ligases PARKIN and MUL1. We find that PARKIN and MUL1 play partially redundant roles in elimination of paternal mitochondria that is also dependent on PINK1 kinase, the fission factor, FIS1, and the autophagy receptor, p62. We find that p62 is specifically recruited to defective mitochondria in fusion deficient cells by a mechanism independent of ubiquitin binding. Our results elucidate the molecular mechanism of strict maternal transmission of mitochondria and uncover a collaboration between MUL1 and PARKIN in mitophagy.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:mitochondria, parkin, pink, mitophagy, p62, sqstm1
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Biology
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Chan, David C.
Thesis Committee:
  • Newman, Dianne K. (chair)
  • Stathopoulos, Angelike
  • Shan, Shu-ou
  • Chan, David C.
Defense Date:18 April 2016
Funders:
Funding AgencyGrant Number
NIH NIGMSGM08042
Record Number:CaltechTHESIS:04292016-193643737
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:04292016-193643737
DOI:10.7907/Z96Q1V75
ORCID:
AuthorORCID
Rojansky, Rebecca Bloom0000-0002-3735-8159
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:9692
Collection:CaltechTHESIS
Deposited By: Rebecca Rojansky
Deposited On:09 Mar 2017 18:09
Last Modified:26 Sep 2017 20:11

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