The central goal of research in the Mears Lab is to investigate proteins that regulate mitochondrial dynamics. Mitochondrial dynamics has recently come to the forefront as a therapeutic target in several diseases, including neurodegeneration, cancer, and aging. But the lack of insight into the regulation of the mitochondrial fission complex is a major limitation. To address this shortcoming, my lab has been at the leading edge of research that has characterized the functional roles of proteins in the mitochondrial fission complex. We have also provided novel mechanistic insight for this process by showing that this protein machinery actively constricts membranes to drive ensuing fission. From these studies, we have developed novel in vitro assays that we will use to identify the functional consequences of specific cellular perturbations that modify the fission machinery in human disease.
Dr. Mears has a diverse scientific background that combines structural, biochemical and cellular methods to characterize functional relationships in macromolecular complexes. His studies as a post-doctoral fellow in the lab of Dr. Jenny Hinshaw at the NIH advanced our understanding of the basic mechanistic properties of dynamin mediated membrane remodeling. In his own lab, he has focused on the main regulator of mammalian mitochondrial fission, dynamin-related protein 1 (Drp1). While key attributes of the dynamin family are preserved in Drp1, several unique features have been identified. These differences highlight functional relationships within the larger protein family. In particular, the Mears lab has identified novel protein interactions that regulate Drp1 self-assembly and functional interactions with distinct partner proteins. The current research environment is optimally suited to address these fundamental questions about the mitochondrial fission complex using a variety of techniques, and regular interactions with mitochondrial, structural and cancer biologists continue to support our research interests. The over-arching goal is to resolve long-standing questions about key factors that alter mitochondrial dynamics, leading to organelle dysfunction in human pathologies.
My research focuses on structural and functional studies to reveal the impact of mitochondrial dynamics on cell health and proliferation in human diseases, including cancer, neurodegeneration and cardiomyopathy. My areas include cryo-electron microscopy, biochemistry, computational biology, and cancer stem cell models.
In multicellular organisms, mitochondria are involved in a range of cellular processes, including ATP production, Ca2+ homeostasis and regulation of programmed cell death (apoptosis). Control of these diverse processes is directly related to the dynamic nature of mitochondria, which continually divide and fuse. Inhibition of the fission machinery leads to an elongated mitochondrial network within the cell. Conversely, inhibition of fusion results in small, fragmented organelles. Therefore, a delicate balance of fission and fusion is needed to prevent morphological changes that impair mitochondrial redistribution and function.
Dr. Mears’s previous research has focused on Dnm1, the yeast DRP involved in mitochondrial fission. Using cryo-EM and image reconstruction techniques, he has examined the structure of Dnm1-lipid tubes and the molecular mechanism though which mitochondrial division occurs. Moving forward, his lab will pursue a detailed understanding of the molecular machinery associated with mitochondrial division in yeast and mammalian cells using cryo-EM along with biochemical and computational techniques, Dr. Mears’s group will investigate the structure of the DRPs and factors that regulate its activity. Mitochondrial dynamics play a critical role in maintaining the health of eukaryotic cells, and defects in mitochondrial morphology are associated with an increasing number of human diseases, including cancer, neurodegeneration and aging. Future research in the Mears laboratory will pursue a detailed understanding of the relationship between mitochondrial dynamics and disease.
Rochon K, Bauer BL, Roethler N, Buckley Y, Su C-C, Huang W, Ramachandran R, Stoll MS, Yu EW, Taylor DT, and Mears JA. (2023) Structural Basis for Regulated Assembly of the Mitochondrial Fission GTPase Drp1. bioRxiv 2023.06.22.546081
Bauer BL, Rochon K, Liu J, Ramachandran R, Mears JA. (2023) Disease-associated mutations in Drp1 have fundamentally different effects on the mitochondrial fission machinery. Hum. Mol. Genet. 32, 1975-87. PMCID: PMC10244223
Akinbiyi EO, Abramowitz LK, Bauer BL, Stoll M, Hoppel CL, Hsiao CP, Hanover JA, and Mears JA. (2021) Blocked O-GlcNAc cycling alters mitochondrial morphology, function, and mass. Sci. Rep. 11: 22106. PMCID: PMC8586252
Francy CA, Clinton RW, Fröhlich C, Murphy C, and Mears JA. (2017) Cryo-EM Studies of Drp1 Reveal Cardiolipin Interactions that Activate the Helical Oligomer. Sci. Rep., 7: 10744. PMCID: PMC5587723
Clinton RW, Francy CA, Ramachandran R, Qi X, Mears JA. (2016) Dynamin-related Protein 1 Oligomerization in Solution Impairs Functional Interactions with Membrane-anchored Mitochondrial Fission Factor. J. Biol. Chem., 291: 478-92. PMCID: PMC4697186.