Mitochondrial Respiration and Superoxide Production in Healthy and Failing Heart. In cardiac myocytes, mitochondrion plays multi-functional roles in oxidative metabolism, ion homeostasis, signal transduction, and cell fate regulation. Mitochondrial respiration through the electron transport chain (ETC) activity drives ATP synthesis and reactive oxygen species (ROS) generation. In the failing heart, mitochondrial respiration is often compromised, resulting in decreased ATP production and, paradoxically, increased oxidative stress. It is therefore of great interest to determine how mitochondrial respiration and ROS production are regulated in the healthy heart and how they contribute to oxidative stress in the failing heart. Recently, we discovered a transient superoxide production event, named superoxide flash, in individual mitochondria of cardiac myocytes and the myocardium. Preliminary data indicate that the superoxide flash requires intact ETC activity, and its frequency is altered by physiological or pathological treatments. We hypothesize that the superoxide flash is coupled to stochastic acceleration of ETC activity in single mitochondria and modulated by key regulators of mitochondrial bioenergetics, including Ca2+, permeability transition pore (PTP), and fission/fusion. If this hypothesis is true, superoxide flashes may serve as a composite index of single mitochondrion respiration and ROS production. Further, imaging superoxide flashes may help determine whether mitochondrial or cytosolic ROS is responsible for oxidative stress in the failing heart. We propose the following specific aims to determine the mechanistic coupling of mitochondrial respiration and superoxide flash production and their role in oxidative stress in heart failure:
Aim 1 : To test the hypothesis that superoxide flash arises from transient acceleration of mitochondrial respiration and is modulated by mitochondrial Ca2+, PTP and fission/fusion dynamics.
Aim 2 : To test the hypothesis that pathological stress inhibits superoxide flash activity at an early stage of heart failure and prior to detection of overt signs f mitochondrial dysfunction.
Aim 3 : To determine whether increased mitochondrial or cytosolic ROS contributes to oxidative stress during mitochondrial respiratory dysfunction.

Public Health Relevance

This project investigates the mechanistic coupling of mitochondrial respiration and bursting superoxide production. Our goal is to establish that decreased superoxide flash activity is a novel and early biomarker for mitochondrial dysfunction, which leads to oxidative stress in heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL114760-03
Application #
8656807
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2012-08-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Zhang, Huiliang; Wang, Pei; Bisetto, Sara et al. (2017) A novel fission-independent role of dynamin-related protein 1 in cardiac mitochondrial respiration. Cardiovasc Res 113:160-170
Wang, Wang; Fernandez-Sanz, Celia; Sheu, Shey-Shing (2017) Regulation of mitochondrial bioenergetics by the non-canonical roles of mitochondrial dynamics proteins in the heart. Biochim Biophys Acta :
Prins, Kurt W; Asp, Michelle L; Zhang, Huiliang et al. (2016) Microtubule-Mediated Misregulation of Junctophilin-2 Underlies T-Tubule Disruptions and Calcium Mishandling in mdx Mice. JACC Basic Transl Sci 1:122-130
Wang, Wang; Zhang, Huiliang; Cheng, Heping (2016) Mitochondrial flashes: From indicator characterization to in vivo imaging. Methods 109:12-20
Wang, Wang; Karamanlidis, Georgios; Tian, Rong (2016) Novel targets for mitochondrial medicine. Sci Transl Med 8:326rv3
Xu, Shangcheng; Wang, Pei; Zhang, Huiliang et al. (2016) CaMKII induces permeability transition through Drp1 phosphorylation during chronic ?-AR stimulation. Nat Commun 7:13189
Liu, Xiaoyun; Xu, Shangcheng; Wang, Pei et al. (2015) Transient mitochondrial permeability transition mediates excitotoxicity in glutamate-sensitive NSC34D motor neuron-like cells. Exp Neurol 271:122-30
Gong, Guohua; Liu, Xiaoyun; Zhang, Huiliang et al. (2015) Mitochondrial flash as a novel biomarker of mitochondrial respiration in the heart. Am J Physiol Heart Circ Physiol 309:H1166-77
O-Uchi, Jin; Jhun, Bong Sook; Xu, Shangcheng et al. (2014) Adrenergic signaling regulates mitochondrial Ca2+ uptake through Pyk2-dependent tyrosine phosphorylation of the mitochondrial Ca2+ uniporter. Antioxid Redox Signal 21:863-79

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