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.
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.
Joshua S. Chappie, Jason A. Mears, Shunming Fang, Marilyn Leonard, Sandra L. Schmid, Ronald A. Milligan, Jenny E. Hinshaw and Fred Dyda. (2011) A pseudoatomic model of the dynamin polymer identifies a hydrolysis-dependent powerstroke. Cell. 2011 Sep 30;147(1):209-22. doi: 10.1016/j.cell.2011.09.003.
Jason A. Mears, Laura Lackner, Shunming Fang, Elena Ingerman, Jodi Nunnari and Jenny E. Hinshaw. (2011) Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nat. Struct. Mol. Biol., 18, 20-26.
Timothy A. Schulz, Mal-Gi Choi, Sumana Raychaudhuri, Jason A. Mears, Rodolfo Ghirlando, Jenny E. Hinshaw, and William A. Prinz (2009) Lipid-regulated sterol transfer between closely apposed membranes by oxysterol-binding protein homologs. J. Cell Biol., 187, 889-903.
Jason A. Mears and Jenny E. Hinshaw (2008) Visualization of dynamins. Methods in Cell Biol., 88, 237-256.
Jason A. Mears, Pampa Ray and Jenny E. Hinshaw (2007) A corkscrew model for dynamin constriction. Structure, 15, 1190-1202
Jason A. Mears*, Manjuli R. Sharma*, Robin R. Gutell, Amanda S. McCook, Paul E. Richardson, Thomas R. Caulfield, Rajendra K. Agrawal and Stephen C. Harvey (2006) A structural model of the large subunit of the mammalian mitochondrial ribosome. J. Mol. Biol., 358, 193-212.
Elena Ingerman, Edward M. Perkins, Michael Marino, Jason A. Mears, J. Michael McCaffery, Jenny E. Hinshaw and Jodi Nunnari (2005) Dnm1 forms spirals that are structurally tailored to fit mitochondria. J. Cell Biol., 170, 1021-1027.
Jason A. Mears, Scott M. Stagg, and Stephen C. Harvey (2005) "Modeling large RNA assemblies using a reduced representation." In Handbook of RNA Biochemistry. Eds. Hartmann, R.K., Bindereif, A., Schon, A. and Westof, E. Wiley-VCH, Weinheim, Germany, pp. 546-559.
Valery I. Ivanov and Jason A. Mears (2004) Using crosslinks to study ribosomal dynamics. J. Biomol. Struct. Dyn., 21, 691-698.
Scott M. Stagg*, Jason A. Mears*, and Stephen C. Harvey (2003) A Structural Model for the Assembly of the 30S Subunit of the Ribosome. J Mol Biol. 2003 Apr 18;328(1):49-61.
Jason A. Mears, Jamie J. Cannone, Scott M. Stagg, Robin R. Gutell, Rajendra K. Agrawal, and Stephen C. Harvey (2002) Modeling a minimal ribosome based on comparative sequence analysis. J. Mol. Biol., 321, 215-234.