Mitochondrial dysfunction in cardiac myocytes occurs early in the pathogenesis of heart failure. In the heart, the primary function of mitochondria is to meet the high energy demand of the beating heart by providing ATP through oxidative phosphorylation. However, mitochondria are also important regulators of cell death and they monitor changes in the intracellular environment such as presence of reactive oxygen species and DNA damage. When mitochondria become damaged or dysfunctional, can serve as a source of reactive oxygen species which can cause further damage to nearby mitochondria. Therefore, they are rapidly removed by autophagy, an evolutionarily conserved process involved in the degradation of long-lived proteins and organelles. Autophagy is used in the heart to clear dysfunctional mitochondria and studies have shown that its deregulation has severe consequences to the myocytes. The molecular mechanism and regulation of mitochondrial removal via autophagy are not well characterized. However, the ubiquitin ligase Parkin was recently reported to be selectively recruited to dysfunctional mitochondria which subsequently promoted their autophagy. Loss-of-function mutations in Park2, the gene encoding Parkin, play a significant role in autosomal recessive Parkinson's disease. Interestingly, Parkin is also highly expressed in the heart, but its functiona role in the myocardium is currently unknown. Our preliminary studies have uncovered evidence that Parkin plays an important role in the adaptation to stress such as a myocardial infarction. Therefore, in this proposal, we will explore the hypothesis that Parkin is essential in clearing damaged mitochondria via autophagy during stress and that a defect in this process contributes to rapid development of heart failure. This hypothesis will be tested with three aims.
Aim 1 will examine the role of Parkin in mitochondrial autophagy and cardioprotection.
In aim 2, we will define the molecular mechanism by which Parkin recognizes dysfunctional mitochondria. Finally, in aim 3, we will identify novel Parkin substrates and characterize their roles in mitochondrial autophagy and cell survival. These studies will provide important new information into the functional role of Parkin and how dysfunctional and potentially dangerous mitochondria are cleared in the heart. These studies will also provide insights into new potential therapeutic targets in this pathway.

Public Health Relevance

Mitochondria are important in providing energy for the contracting myocyte, but mitochondrial dysfunction occurs early in the pathogenesis of heart failure. This project will provide important new insights into mitochondrial autophagy in cardiac myocytes and how defects in this process contribute to development of cardiovascular disease. It will also provide new knowledge into the biological function of Parkin in the heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL087023-09S1
Application #
9102527
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2006-12-01
Project End
2017-05-31
Budget Start
2015-08-10
Budget End
2016-05-31
Support Year
9
Fiscal Year
2015
Total Cost
$70,973
Indirect Cost
$25,184
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Shires, Sarah E; Gustafsson, Åsa B (2018) Regulating Renewable Energy: Connecting AMPK?2 to PINK1/Parkin-Mediated Mitophagy in the Heart. Circ Res 122:649-651
Woodall, Benjamin P; Gustafsson, Åsa B (2018) Mesenchymal Stem Cell-Mediated Autophagy Inhibition. Circ Res 123:518-520
Lampert, Mark A; Gustafsson, Åsa B (2018) Balancing Autophagy for a Healthy Heart. Curr Opin Physiol 1:21-26
Shires, Sarah E; Kitsis, Richard N; Gustafsson, Åsa B (2017) Beyond Mitophagy: The Diversity and Complexity of Parkin Function. Circ Res 120:1234-1236
Hammerling, Babette C; Najor, Rita H; Cortez, Melissa Q et al. (2017) A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance. Nat Commun 8:14050
Zhong, Zhenyu; Umemura, Atsushi; Sanchez-Lopez, Elsa et al. (2016) NF-?B Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell 164:896-910
Leon, Leonardo J; Gustafsson, Åsa B (2016) Staying young at heart: autophagy and adaptation to cardiac aging. J Mol Cell Cardiol 95:78-85
Shirakabe, Akihiro; Fritzky, Luke; Saito, Toshiro et al. (2016) Evaluating mitochondrial autophagy in the mouse heart. J Mol Cell Cardiol 92:134-9
Kubli, Dieter A; Gustafsson, Åsa B (2015) Unbreak my heart: targeting mitochondrial autophagy in diabetic cardiomyopathy. Antioxid Redox Signal 22:1527-44
Lee, Youngil; Kubli, Dieter A; Hanna, Rita A et al. (2015) Cellular redox status determines sensitivity to BNIP3-mediated cell death in cardiac myocytes. Am J Physiol Cell Physiol 308:C983-92

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