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Regulation of mitochondrial division by the Drp1 receptors

Citation

Loson, Oliver Calvin (2014) Regulation of mitochondrial division by the Drp1 receptors. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:05072014-160207088

Abstract

Mitochondria can remodel their membranes by fusing or dividing. These processes are required for the proper development and viability of multicellular organisms. At the cellular level, fusion is important for mitochondrial Ca2+ homeostasis, mitochondrial DNA maintenance, mitochondrial membrane potential, and respiration. Mitochondrial division, which is better known as fission, is important for apoptosis, mitophagy, and for the proper allocation of mitochondria to daughter cells during cellular division.

The functions of proteins involved in fission have been best characterized in the yeast model organism Sarccharomyces cerevisiae. Mitochondrial fission in mammals has some similarities. In both systems, a cytosolic dynamin-like protein, called Dnm1 in yeast and Drp1 in mammals, must be recruited to the mitochondrial surface and polymerized to promote membrane division. Recruitment of yeast Dnm1 requires only one mitochondrial outer membrane protein, named Fis1. Fis1 is conserved in mammals, but its importance for Drp1 recruitment is minor. In mammals, three other receptor proteins—Mff, MiD49, and MiD51—play a major role in recruiting Drp1 to mitochondria. Why mammals require three additional receptors, and whether they function together or separately, are fundamental questions for understanding the mechanism of mitochondrial fission in mammals.

We have determined that Mff, MiD49, or MiD51 can function independently of one another to recruit Drp1 to mitochondria. Fis1 plays a minor role in Drp1 recruitment, suggesting that the emergence of these additional receptors has replaced the system used by yeast. Additionally, we found that Fis1/Mff and the MiDs regulate Drp1 activity differentially. Fis1 and Mff promote constitutive mitochondrial fission, whereas the MiDs activate recruited Drp1 only during loss of respiration.

To better understand the function of the MiDs, we have determined the atomic structure of the cytoplasmic domain of MiD51, and performed a structure-function analysis of MiD49 based on its homology to MiD51. MiD51 adopts a nucleotidyl transferase fold, and binds ADP as a co-factor that is essential for its function. Both MiDs contain a loop segment that is not present in other nucleotidyl transferase proteins, and this loop is used to interact with Drp1 and to recruit it to mitochondria.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:mitochondria, dynamics, fission, fusion, Drp1, MiD49, MiD51, Fis1, Mff
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Biochemistry
Biology
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Chan, David C.
Thesis Committee:
  • Lester, Henry A. (chair)
  • Rees, Douglas C.
  • Shan, Shu-ou
  • Elowitz, Michael B.
  • Chan, David C.
Defense Date:2 May 2014
Funders:
Funding AgencyGrant Number
National Institutes of Health fellowshipUNSPECIFIED
American Physiological Society fellowshipUNSPECIFIED
Record Number:CaltechTHESIS:05072014-160207088
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:05072014-160207088
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1091/mbc.E12-10-0721 DOIArticle adapted for ch. 2
http://dx.doi.org/10.1016/j.str.2014.01.001DOIArticle adapted for ch. 3
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8225
Collection:CaltechTHESIS
Deposited By: Oliver Loson
Deposited On:16 May 2014 22:46
Last Modified:09 May 2016 17:53

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