Discipline: Biological Sciences
Subcategory: Cell and Molecular Biology
Brittany Gamble - Auburn University
Co-Author(s): Shravanthi Mouli, Abdullah AlAsmari, Haitham Eldoumani, Andreas Kavazis and Rajesh Amin, Cardiometabolic Research Lab, Department of Drug Discovery and Development, Harrison School of Pharmacy, Department of Kinesiology
Heart Failure is a leading cause of mortality and fatality world wide today. However understanding the underlying causes for the development this pathologic condition remains relatively unknown and is the central focus of our lab. The pathological condition of cardiac hypertrophy normal develops over time into heart failure, and is associated with several disease states such as Type 2 diabetes and cancer from the cardiotoxic effects of chemotherapy. Because type 2 diabetes is at epidemic proportions especially in the state of Alabama, understanding the underlying signaling mechanisms associated with the development of cardiac hypertrophy is highly relevant. Our lab has recently found that the underlying mechanism associated with the development of cardiac hypertrophy in various disease states is associated with myocardial energy dysregulation and attenuated anti-oxidative protection. These impairments lead to a series of events which eventually lead the heart to fail. Our lab is focused upon understanding how myocardial energy dysregulation associated with diabetes and the chemotherapeutic agent Doxorubicin leads to heart failure. Recently, we have discovered that the mitochondrial iron-sulfur cluster biogenesis protein, Frataxin (FXN) is severely compromised in expression in hearts from diabetic (db/db) and animals treated with Doxorubicin. This protein is centrally involved in regulating aconitase and is a key regulator of oxidative phosphorylation (OXPHOS). Our research focusses on investigating the mechanism of FXN attenuation in a hypertrophic setting and exploring the consequence of this upon mitochondrial bioenergetics and anti-oxidative mechanisms. To further understand the significance of FXN upon cellular energy regulation, cells from individuals with Friedreich’s ataxia (FRDA) show reduced activities of antioxidant enzymes as well as reduced aconitase and OXPHOS activity. This blunted antioxidant response and attenuated OXPHOS may play a central role in the pathogenesis of cardiac hypertrophy. In the current study we have observed that that Peroxisome Proliferator Activated Receptor Gamma (PPARγ) Coactivator 1-alpha (PGC-1α), a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in cardiomyocytes exposed to hypertrophic stress from doxorubicin (DOX). Most significantly cells from FRDA patients and animal models show significantly reduced levels of PGC-1α. Surprisingly we have observed an increase in mitochondrial biogenesis in FXN over expressing cardiomyocytes. PGC-1 is a key transcriptional regulator of mitochondrial metabolic pathways such as OXPHOS and lipid oxidation and thus plays a central role in mitochondrial biogenesis and aging. Further we also observed an increase in PGC-1a expression in these cells and were significantly reduced in FXN-knock down cells. Our current study focusses on stabilizing the FXN expression by improving the PGC1α expression in a hypertrophic setting. Improving FXN expression we predict will induce an increase in PGC1α expression resulting in the detoxification of reactive oxygen species and prevent oxidative. Further, findings from this study will significantly advance the knowledge base for understanding and exploring the FXN – PGC1α axial signaling as a potential therapeutic target to prevent heart failure.
Funder Acknowledgement(s): REU allowed me to conduct my research in Dr. Rajesh Amin's lab.
Faculty Advisor: Rajesh Amin, email@example.com
Role: I investigated if the overexpression of Frataxin induces an increase in PGC-1alpha thus promoting mitochondrial biogenesis. I was apart of discovering the downstream effectors of PGC-1a that are involved in mitochondrial biogenesis and how dox damages these effectors. Understanding these mediators will significantly advance the knowledgebase for understanding the molecular signaling pathways by which Doxorubicin damages the heart. Further it will offer potential therapeutic potential for adjuvant therapy for improving patient outcome.