Complex I Deficiency Triggered Acceleration of Heart Failure Mitochondrial dysfunction has been repeatedly observed in heart failure but its role in the development and progression of heart failure remains elusive. We hypothesize that mitochondrial function is a critical modifier of the signaling pathways that cause pathological cardiac hypertrophy and the transition to heart failure. To test this hypothesis, we generated a mouse model with cardiac-specific deficiency of Complex I function by deleting the Ndufs4 subunit (Ndusf4H-/-). Our preliminary data show that the lack of Ndusf4 impairs Complex I assembly and function resulting marked decrease (by ~70%) of Complex I activity and Complex I dependent respiration. Interestingly, the impairment does not affect cardiac energetics and function in up to one year in the Ndusf4H-/- mice under unstressed conditions. However, when stressed with pressure overload the Ndusf4H-/- mice develop severe cardiac hypertrophy and accelerated heart failure. Thus, this model provides a unique tool to dissect the mechanistic role of mitochondrial dysfunction in modifying the course of cardiac hypertrophy and failure. We propose the following specific aims to determine the molecular mechanisms linking mitochondrial dysfunction to the development of pathological hypertrophy and heart failure.
Aim 1 : To determine the interaction of energy metabolism and the accelerated course of heart failure by Complex I deficiency. Hypothesis 1a: Defective Complex I function is compensated under resting conditions but limits ATP synthesis during chronic increases in workload. Hypothesis 1b: The shift of substrate utilization from fatty acids to glucose in cardiac hypertrophy exacerbates the impaired energetics due to Complex I deficiency.
Aim 2 : To test the hypothesis that Ndusf4H-/- mitochondria produce a greater amount of ROS in response to chronic increases in energy demand and excessive mitochondrial ROS exacerbates the pathological hypertrophy and heart failure.
Aim 3 : To identify novel molecular mediators linking mitochondrial dysfunction and heart failure by analyzing a gene co-expression network.

Public Health Relevance

This project investigates the mechanistic role of mitochondrial dysfunction in the development of heart failure. Our goal is to identify novel signals and target molecules that link mitochondrial dysfunction to the worsening of heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Wong, Renee P
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University of Washington
Schools of Medicine
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Walker, Matthew A; Tian, Rong (2018) Raising NAD in Heart Failure: Time to Translate? Circulation 137:2274-2277
Chavez, Juan D; Lee, Chi Fung; Caudal, Arianne et al. (2018) Chemical Crosslinking Mass Spectrometry Analysis of Protein Conformations and Supercomplexes in Heart Tissue. Cell Syst 6:136-141.e5
Zhang, Huiliang; Gong, Guohua; Wang, Pei et al. (2018) Heart specific knockout of Ndufs4 ameliorates ischemia reperfusion injury. J Mol Cell Cardiol 123:38-45
Lee, Chi Fung; Cao, Yang; Tian, Rong (2018) Failed Power Plant Turns Into Mass Murder: New Insight on Mitochondrial Cardiomyopathy. Circ Res 122:11-13
Nguyen, Son; Shao, Dan; Tomasi, Loreta C et al. (2017) The effects of fatty acid composition on cardiac hypertrophy and function in mouse models of diet-induced obesity. J Nutr Biochem 46:137-142
Li, Tao; Zhang, Zhen; Kolwicz Jr, Stephen C et al. (2017) Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury. Cell Metab 25:374-385
Xu, Shangcheng; Wang, Pei; Zhang, Huiliang et al. (2016) CaMKII induces permeability transition through Drp1 phosphorylation during chronic ?-AR stimulation. Nat Commun 7:13189
Kolwicz Jr, Stephen C; Airhart, Sophia; Tian, Rong (2016) Ketones Step to the Plate: A Game Changer for Metabolic Remodeling in Heart Failure? Circulation 133:689-91
Wang, Wang; Karamanlidis, Georgios; Tian, Rong (2016) Novel targets for mitochondrial medicine. Sci Transl Med 8:326rv3
Roe, Nathan D; Standage, Stephen W; Tian, Rong (2016) The Relationship Between KLF5 and PPAR? in the Heart: It's Complicated. Circ Res 118:193-5

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