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Mechanisms of Drp1 Recruitment to Mitochondria

Citation

Liu, Raymond (2017) Mechanisms of Drp1 Recruitment to Mitochondria. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z99Z92ZF. http://resolver.caltech.edu/CaltechTHESIS:05312017-190514797

Abstract

Dynamin-related protein 1 (Drp1) is a GTPase of the dynamin superfamily that catalyzes mitochondrial fission in the cell. Cytosolic Drp1 is recruited to mitochondria by receptors anchored to the outer mitochondrial membrane. Once there, Drp1 assembles into a complex around the mitochondrial circumference to drive division via a GTP-dependent constriction process. The four known receptors of Drp1 are Fis1, Mff, MiD51, and MiD49, but stable interactions between Drp1 and these proteins have not been established. In addition, though mounting evidence suggests these receptors have non-redundant roles in their interaction with Drp1, mechanistic details explaining these distinctions are lacking. Here we address these questions, and show that the Insert B domain of Drp1 inhibits its interaction with Mff. Removal of this domain stabilizes a complex of Drp1 and Mff in vitro. In addition, we show that Drp1 oligomerization is a requirement for Mff recruitment, but not for MiD51 or MiD49-mediated recruitment. Together the results suggest a model in which Drp1 recruitment to mitochondria is regulated by the oligomeric state of Drp1, such that Mff, MiD51, and MiD49 recruit different subpopulations of Drp1 from the cytosol.

With this model as a framework, we analyze the effect that a Drp1 R403C mutant, identified in several human patients presenting with encephalopathy and refractory epilepsy, has on mitochondrial morphology in cultured cells. We find that the loss of Drp1 oligomerization in these mutants impedes its ability to be recruited by Mff, leading to abnormal elongation of the mitochondrial population.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Mitochondria; Drp1; Mff; MiD51; Dynamin; Fission; Dynamics
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:
  • Campbell, Judith L. (chair)
  • Deshaies, Raymond Joseph
  • Dunphy, William G.
  • Chan, David C.
Defense Date:24 April 2017
Funders:
Funding AgencyGrant Number
NSF Graduate Research FellowshipDGE-1144469
Record Number:CaltechTHESIS:05312017-190514797
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:05312017-190514797
DOI:10.7907/Z99Z92ZF
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1091/mbc.E15-08-0591DOIArticle adapted for Ch. 2.
http://dx.doi.org/10.1002/ajmg.a.37721DOIArticle adapted for Ch. 3.
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:10239
Collection:CaltechTHESIS
Deposited By: Raymond Liu
Deposited On:05 Jun 2017 21:50
Last Modified:12 Jun 2017 20:55

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