All ETDs from UAB

Advisory Committee Chair

Keshav K Singh

Advisory Committee Members

John L Hartman

Trygve O Tollefsbol

Upender Manne

Lizhong Wang

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Mitochondrial dysfunction is considered a hallmark of cancer. Mitochondria are essential, cellular organelles that participate in processes including energy production, calcium homeostasis and steroid metabolism. Mitochondria have been more recently appreciated for their role in cellular signaling, bringing about a greater understanding of their role in many diseases including cancer. Retrograde signaling is a mechanism by which the nucleus responds to mitochondrial dysfunction by modulating its own transcriptional programs to maintain metabolic and cellular processes. Many genes have already been identified as participants in or mediators of this signaling mechanism; these include cell signaling, metabolic and structural genes as well as transcription factors. Importantly, there is a lack of knowledge surrounding the role of microRNAs and their downstream targets in retrograde signaling. In the work described here, we identify miR-663 as a retrograde-responsive microRNA involved in regulating the expression of oxidative phosphorylation (OXPHOS) subunits and assembly factors, the assembly of OXPHOS supercomplexes, and ultimately reducing breast tumor progression. We also give evidence that miR-663 regulates mitochondrial function by directly targeting the mitochondrial-localized transcription factor, MAFB. We demonstrate that MAFB itself regulates the OXPHOS subunit UQCRC2 and the assembly factors NDUFAF2, SDHAF2 and UQCC2. We show that this transcription factor localizes to mitochondria after post-translational modification. After localization, it forms a large complex with other mitochondrial proteins, potentially playing a transcription-independent role in regulating mitochondrial function. Moreover, our studies show that MAFB promotes breast tumorigenesis in a sumoylation-dependent manner. Collectively our data demonstrate that miR-663 is an important mediator of the retrograde response and tumorigenesis by regulating mitochondrial function.

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