DOI

10.17077/etd.2xf0-oabm

Document Type

Dissertation

Date of Degree

Summer 2019

Degree Name

PhD (Doctor of Philosophy)

Degree In

Genetics

First Advisor

Grueter, Chad E.

First Committee Member

Abel, Dale E.

Second Committee Member

Ahmad, Ferhaan

Third Committee Member

Fassler, Jan

Fourth Committee Member

Taylor, Eric

Fifth Committee Member

Tootle, Tina

Abstract

Although pathological alterations in gene expression and mitochondria function in response to cardiac ischemia are well recognized, the mechanisms driving these changes are incompletely understood. Nuclear to mitochondrial communication regulating gene expression and mitochondrial function is a critical process following cardiac ischemic injury. Here we determine that cyclin C, a component of the transcriptional regulator, Mediator complex, directly regulates cardiac and mitochondrial function by modifying mitochondrial fission. We tested the hypothesis that cyclin C has a binary function as a transcriptional cofactor in the nucleus and acute regulation of cardiac energetics in ischemia by enhancing mitochondrial fission in the cytoplasm.

In response to stress, cyclin C translocates to the cytoplasm enhancing mitochondria fission in part through interactions with Cdk1. Using cardiac specific cyclin C knockout and overexpression mouse models, we determined cyclin C regulates mitochondria morphology under basal and ischemic conditions in vivo. Furthermore, pretreatment with a Cdk1 inhibitor followed by ischemia in vivo results in reduced mitochondrial fission. Together, our study reveals that cyclin C regulates both hypertrophic gene expression and mitochondrial fission providing new insights into the regulation of cardiac energy metabolism following acute ischemic injury.

Keywords

Cardiovascular genetics, Metabolism, Mitochondrial dynamics, Transcriptional regulation

Pages

xii, 137 pages

Bibliography

Includes bibliographical references (pages 129-137).

Copyright

Copyright © 2019 Jessica Marie Ponce

Included in

Genetics Commons

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