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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Gong, Guohua; Liu, Xiaoyun; Wang, Wang (2014) Regulation of metabolism in individual mitochondria during excitation-contraction coupling. J Mol Cell Cardiol 76:235-46
Ma, Xiaoke; Gao, Long; Tan, Kai (2014) Modeling disease progression using dynamics of pathway connectivity. Bioinformatics 30:2343-50
Yu, Qiujun; Lee, Chi Fung; Wang, Wang et al. (2014) Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury. J Am Heart Assoc 3:e000555
Matsushima, Shouji; Kuroda, Junya; Ago, Tetsuro et al. (2013) Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1? and upregulation of peroxisome proliferator-activated receptor-?. Circ Res 112:1135-49
Kolwicz Jr, Stephen C; Purohit, Suneet; Tian, Rong (2013) Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ Res 113:603-16
Garcia-Menendez, Lorena; Karamanlidis, Georgios; Kolwicz, Stephen et al. (2013) Substrain specific response to cardiac pressure overload in C57BL/6 mice. Am J Physiol Heart Circ Physiol 305:H397-402
Nowakowski, Sarah G; Kolwicz, Stephen C; Korte, Frederick Steven et al. (2013) Transgenic overexpression of ribonucleotide reductase improves cardiac performance. Proc Natl Acad Sci U S A 110:6187-92
Karamanlidis, Georgios; Lee, Chi Fung; Garcia-Menendez, Lorena et al. (2013) Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab 18:239-50
Karamanlidis, Georgios; Bautista-Hernandez, Victor; Fynn-Thompson, Francis et al. (2011) Impaired mitochondrial biogenesis precedes heart failure in right ventricular hypertrophy in congenital heart disease. Circ Heart Fail 4:707-13