Disease-associated mutations in Drp1 have fundamentally different effects on the mitochondrial fission machinery

Author:

Bauer Brianna L1,Rochon Kristy1,Liu Jasmine C1,Ramachandran Rajesh23,Mears Jason A134ORCID

Affiliation:

1. Case Western Reserve University School of Medicine Department of Pharmacology, , Cleveland, OH 44106 , USA

2. Case Western Reserve University School of Medicine Department of Physiology and Biophysics, , Cleveland, OH 44106 , USA

3. Case Western Reserve University School of Medicine Cleveland Center for Membrane and Structural Biology, , Cleveland, OH 44106 , USA

4. Case Western Reserve University School of Medicine Center for Mitochondrial Diseases, , Cleveland, OH 44016 , USA

Abstract

Abstract Patient mutations have been identified throughout dynamin-related protein 1 (Drp1), the key protein mediator of mitochondrial fission. These changes generally impact young children and often result in severe neurological defects and, in some instances, death. Until now, the underlying functional defect leading to patient phenotypes has been largely speculative. We therefore analyzed six disease-associated mutations throughout the GTPase and middle domains (MD) of Drp1. The MD plays a role in Drp1 oligomerization, and three mutations in this region were predictably impaired in self-assembly. However, another mutant in this region (F370C) retained oligomerization capability on pre-curved membranes despite being assembly-limited in solution. Instead, this mutation impaired membrane remodeling of liposomes, which highlights the importance of Drp1 in generating local membrane curvature before fission. Two GTPase domain mutations were also observed in different patients. The G32A mutation was impaired in GTP hydrolysis both in solution and in the presence of lipid but remains capable of self-assembly on these lipid templates. The G223V mutation also exhibited decreased GTPase activity and was able to assemble on pre-curved lipid templates; however, this change impaired membrane remodeling of unilamellar liposomes similar to F370C. This demonstrates that the Drp1 GTPase domain also contributes to self-assembly interactions that drive membrane curvature. Overall, the functional defects caused by mutations in Drp1 are highly variable even for mutations that reside within the same functional domain. This study provides a framework for characterizing additional Drp1 mutations to provide a comprehensive understanding of functional sites within this essential protein.

Funder

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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