All ETDs from UAB

Advisory Committee Chair

Kasturi Mitra

Advisory Committee Members

Anita Hjelmeland

Deeann Wallis

Keshav Singh

Ralph Sanderson

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Mitochondrial dynamics primarily refers to the opposing fission or fusion events between individual mitochondria, which maintains steady-state mitochondrial morphology in cells. Fission and fusion activities maintain the energetics of normal and neoplastic stem cells. We developed the novel approach mito-SinCe2 to study the bidirectional relationship between mitochondrial dynamics and energetics. Application of this method led to the hypothesis that mitochondria-dependent ovarian tumor initiating cells interconvert between 3 states with distinct mitochondrial energetics/dynamics relationships. Cells in one state, characterized by high mitochondrial ROS and low fission activity, appear to be primed for self-renewal by mitochondria. We call these cells mitochondria-primed stem cells (mpSCs). Fission and fusion activities are also crucial in stem cell cell cycle maintenance. Drp1 repression causes upregulation of the cell cycle regulator and oncogene Cyclin E, which is highly expressed in pluripotent stem cells. We developed an in vitro model to study mpSCs by using oxidative carcinogenic transformation of immortalized keratinocytes. Using this as a model, we identified a mechanism for regulation of the Cyclin E driven cell cycle in which both mitochondrial fission activity and ROS are implicated. Based on these results, we hypothesize the existence of a Drp1-CyclinE-Sox2 axis in the neoplastic mpSCs. Future work should aim for a mechanistic understanding of coregulation of energetics and cell cycle by mitochondria.

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