Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


BLB Thesis_Final ETD.pdf (4.32 MB)

ETD Abstract Container

Abstract Header

Investigating the Effect of Clinically Relevant Mutations on the Functionality of Dynamic-Related Protein 1

Bauer, Brianna L
http://orcid.org/0000-0002-9894-6886
http://rave.ohiolink.edu/etdc/view?acc_num=case1702295295349835

Abstract Details

2023, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Mitochondria form dynamic networks and need to maintain a delicate balance between fission and fusion to satisfy the cell’s energetic and metabolic requirements. Fission is necessary to ensure mitochondria are properly distributed throughout the cell and to remove damaged mitochondrial components. The dysregulation of mitochondrial dynamics resulting in either an abnormally fragmented or interconnected mitochondrial network is associated with a variety of pathologies. Mutations in dynamin-related protein 1 (Drp1), the master regulator of mitochondrial fission, have been identified in patients presenting with severe neurological defects. Patient-derived fibroblasts exhibit hyperfused mitochondria, indicating mitochondrial dysregulation. Thus, these clinically relevant mutations impair Drp1 function, but the mechanism by which these mutations disrupt mitochondrial fission was undetermined. To address this lack of knowledge, the overarching objective of this research was to elucidate the specific Drp1 functional defects that are caused by these disease-associated mutations to better understand the relationship between impaired Drp1 function and disease. Drp1 self-assembles around the outer mitochondrial membrane (OMM) and, subsequently, hydrolyzes GTP which provides the mechanical force required to cleave apart the mitochondrion. The recruitment of Drp1 to the OMM is mediated in part by lipid interactions. A mitochondria-specific lipid, cardiolipin, promotes Drp1 self-assembly, enhances its GTPase activity, and is believed to facilitate membrane constriction. Disease-associated mutations in Drp1 are predominantly located within the GTPase and middle domains, which mediate its capabilities for hydrolysis and self-assembly, respectively. We have employed an ensemble of biochemical and EM-based techniques to investigate the impact of these mutations on the self-assembly, lipid recognition, and enzymatic capabilities of Drp1. Ultimately, we have shown that even mutations located in the same domain may confer unique functional defects. For example, we describe a mutation in the middle domain that retains the ability to self-assemble on a lipid template despite also possessing a limited propensity for oligomerization. Additionally, we demonstrate that a mutation located at a unique position in the GTPase domain forms distinctly structured assemblies due to altered interactions between adjacent GTPase domains. Taken together, these studies provide a foundation for the characterization of clinically relevant mutations in Drp1 and clarify the structure-function relationship of Drp1.
Jason Mears (Advisor)
Marvin Nieman (Committee Chair)
Phoebe Stewart (Committee Member)
Danny Manor (Committee Member)
Edward Yu (Committee Member)
189 p.
Biochemistry; Biomedical Research; Biophysics; Molecular Biology
Drp1; Mitochondria; GTPase; Mitochondrial Dynamics; Biochemistry; Molecular Biology; Dynamin; Mitochondrial Fission; Structural Biology

Recommended Citations

Citations

  • Bauer, B. L. (2023). Investigating the Effect of Clinically Relevant Mutations on the Functionality of Dynamic-Related Protein 1 [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1702295295349835

    APA Style (7th edition)

  • Bauer, Brianna. Investigating the Effect of Clinically Relevant Mutations on the Functionality of Dynamic-Related Protein 1. 2023. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1702295295349835.

    MLA Style (8th edition)

  • Bauer, Brianna. "Investigating the Effect of Clinically Relevant Mutations on the Functionality of Dynamic-Related Protein 1." Doctoral dissertation, Case Western Reserve University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=case1702295295349835

    Chicago Manual of Style (17th edition)

case1702295295349835
78
© 2023, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.