Paulina Cortés-Hernández, M.D., Ph.D.

Research

Mitochondria continually divide and fuse. These balanced events are critical for mitochondrial-DNA inheritance and for the organelle’s function and distribution. The molecular mechanisms underlying mitochondrial dynamics as well as the proteins responsible for these events are conserved from yeast to mammals. Among these proteins are three highly conserved dynamin related proteins (DRPs), which function via self-assembly to regulate membrane dynamics in a variety of cellular events. DRPs are relatively large proteins that contain a canonical GTPase domain and several regions that facilitate self-assembly via both intra- and intermolecular interactions. Self-assembly of DRPs greatly stimulates the hydrolysis of GTP and both features are critical for the cellular functions of these proteins. Two distinct DRPs are required for mitochondrial fusion, the transmembrane proteins Fzo1 (in yeast)/Mfn1 and 2 (in mammals) and Mgm1 (in yeast)/Opa1 (in mammals), which drive outer and inner mitochondrial membrane fusion respectively. Current models suggest that self-assembly of mitochondrial fusion DRPs tethers membranes together by intermolecular trans interactions. In contrast a single DRP, Dnm1 (in yeast)/Drp1 (in mammals), is required for mitochondrial division. Biochemical and structural analyses indicate that the self-assembly of this DRP into helical structures around mitochondria directly drives membrane constriction and fission during organelle division when the concerted GTPase activity of the monomers tightens the helix Even though mitochondrial DRPs are conserved, their regulation has diverged to coordinate with cellular signaling and apoptosis in vertebrates and their characterization is therefore crucial to understand the role of mitochondrial dynamics in human health and disease. We have developed transgenic zebrafish to study mitochondrial dynamics and characterize DRPs in a complete vertebrate organism, throughout development, in different organs and under specific circumstances like tissue injury and regeneration. The genetic manipulability and optical translucency of this model makes it ideal for live analyses of subcellular structures in specific organs of an intact fish, while in the context of a high level of tissue organization and subject to the regulation characteristic of vertebrate organisms.