The central goal of this project is to define the mechanism of myocardial bioenergetic failure in heart failure (HF) and design therapeutic strategies targeted to improve mitochondrial energy production. We recently found a dramatic decrease in oxidative phosphorylation (OXPHOS) of heart mitochondria in canine moderate severity micromebolism-induced HF. The mitochondrial defect does not lie in the total amount and activity of individual electron transport chain complexes but in their assembly in supercomplexes (respirasomes). Complex IV not incorporated in respirasomes contains an increased content of serine and threonine phosphorylation in mitochodria isolated from HF compared with the control. We hypothesize that HF-induced adrenergic stimulation increases C3^osolic cAMP which is transported into the mitochondrial intermembrane space through the mitochondrial outer membrane voltage-dependent anion channel (VDAC) and activates the mitochondrial cAMP dependent kinase (mtPKA). mt PKA-induced phosphorylation of matrix-exposed serine and threonine residues of cytochrome c oxidase (COX) subunits impairs the incorporation of COX into supercomplexes, reduces the amount of fijnctional respirasomes, and decreases OXPHOS of heart mitochondria. Complexes I and III not incorporated in respirasomes facilitate electron leakage and produce superoxide, which causes oxidative modifications of both mitochondrial matrix and myofibrillar proteins, with decreased contractile performance. Experiments will be performed in the well established canine coronary microembolization model ofHF, transgenic mice and cultured cells.
Specific aim 1 wil investigate mitochondrial respirasome organization, OXPHOS, ATP production, and ROS generation in moderate severity and severe canine HF.
Specific aim 2 will identify the role of the adrenergic stimulation in disruption of the assembly of mitochondrial respirasomes in HF.
Specific aim 3 will delineate the mechanistic pathway responsible for the translation of the adrenergic signal into mitochondrial alterations.
Specific aim 4 will identify the specific mitochondrial targets for the cAMP-induced phosphorylation and their functional consequences.
Specific aim 5 proposes a rational approach for therapeutic strategies that targets cAMP/mtPKA signaling with the attempt to prevent mitochondrial ROS generation,

Public Health Relevance

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
7P01HL074237-10
Application #
8532021
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$265,462
Indirect Cost
$28,833
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Flori, Alessandra; Liserani, Matteo; Frijia, Francesca et al. (2015) Real-time cardiac metabolism assessed with hyperpolarized [1-(13) C]acetate in a large-animal model. Contrast Media Mol Imaging 10:194-202
Vimercati, Claudio; Qanud, Khaled; Mitacchione, Gianfranco et al. (2014) Beneficial effects of acute inhibition of the oxidative pentose phosphate pathway in the failing heart. Am J Physiol Heart Circ Physiol 306:H709-17
Mitacchione, Gianfranco; Powers, Jeffrey C; Grifoni, Gino et al. (2014) The gut hormone ghrelin partially reverses energy substrate metabolic alterations in the failing heart. Circ Heart Fail 7:643-51
Velez, Mauricio; Kohli, Smita; Sabbah, Hani N (2014) Animal models of insulin resistance and heart failure. Heart Fail Rev 19:1-13
Prosdocimo, Domenick A; Anand, Priti; Liao, Xudong et al. (2014) Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism. J Biol Chem 289:5914-24
Shekar, Kadambari Chandra; Li, Ling; Dabkowski, Erinne R et al. (2014) Cardiac mitochondrial proteome dynamics with heavy water reveals stable rate of mitochondrial protein synthesis in heart failure despite decline in mitochondrial oxidative capacity. J Mol Cell Cardiol 75:88-97
Clericò, Vito; Masini, Luca; Boni, Adriano et al. (2014) Water-dispersible three-dimensional LC-nanoresonators. PLoS One 9:e105474
Rosca, Mariana G; Tandler, Bernard; Hoppel, Charles L (2013) Mitochondria in cardiac hypertrophy and heart failure. J Mol Cell Cardiol 55:31-41
Hecker, Peter A; Lionetti, Vincenzo; Ribeiro Jr, Rogerio F et al. (2013) Glucose 6-phosphate dehydrogenase deficiency increases redox stress and moderately accelerates the development of heart failure. Circ Heart Fail 6:118-26
Galvao, Tatiana F; Khairallah, Ramzi J; Dabkowski, Erinne R et al. (2013) Marine n3 polyunsaturated fatty acids enhance resistance to mitochondrial permeability transition in heart failure but do not improve survival. Am J Physiol Heart Circ Physiol 304:H12-21

Showing the most recent 10 out of 139 publications