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.
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.
|Lee, Chi Fung; Chavez, Juan D; Garcia-Menendez, Lorena et al. (2016) Normalization of NAD+ Redox Balance as a Therapy for Heart Failure. Circulation 134:883-94|
|Xu, Shangcheng; Wang, Pei; Zhang, Huiliang et al. (2016) CaMKII induces permeability transition through Drp1 phosphorylation during chronic Î²-AR stimulation. Nat Commun 7:13189|
|Roe, Nathan D; Standage, Stephen W; Tian, Rong (2016) The Relationship Between KLF5 and PPARÎ± in the Heart: It's Complicated. Circ Res 118:193-5|
|Nagana Gowda, G A; Abell, Lauren; Lee, Chi Fung et al. (2016) Simultaneous Analysis of Major Coenzymes of Cellular Redox Reactions and Energy Using ex Vivo (1)H NMR Spectroscopy. Anal Chem 88:4817-24|
|Wang, Wang; Karamanlidis, Georgios; Tian, Rong (2016) Novel targets for mitochondrial medicine. Sci Transl Med 8:326rv3|
|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|
|Choi, Yong Seon; de Mattos, Ana Barbosa Marcondes; Shao, Dan et al. (2016) Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin II infusion. J Mol Cell Cardiol 100:64-71|
|Shao, Dan; Tian, Rong (2015) Glucose Transporters in Cardiac Metabolism and Hypertrophy. Compr Physiol 6:331-51|
|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|
|Ma, Xiaoke; Gao, Long; Karamanlidis, Georgios et al. (2015) Revealing Pathway Dynamics in Heart Diseases by Analyzing Multiple Differential Networks. PLoS Comput Biol 11:e1004332|
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