Cordero-Reyes 2014 J Mol Cell Cardiol
|Cordero-Reyes AM, Gupte AA, Youker KA, Loebe M, Hsueh WA, Torre-Amione G, Taegtmeyer H, Hamilton DJ (2014) Freshly isolated mitochondria from failing human hearts exhibit preserved respiratory function. J Mol Cell Cardiol 68:98-105.|
Abstract: In heart failure mitochondrial dysfunction is thought to be responsible for energy depletion and contractile dysfunction. The difficulties in procuring fresh left ventricular (LV) myocardium from humans for assessment of mitochondrial function have resulted in the reliance on surrogate markers of mitochondrial function and limited our understanding of cardiac energetics. We isolated mitochondria from fresh LV wall tissue of patients with heart failure and reduced systolic function undergoing heart transplant or left ventricular assist device placement, and compared their function to mitochondria isolated from the non-failing LV (NFLV) wall tissue with normal systolic function from patients with pulmonary hypertension undergoing heart-lung transplant. We performed detailed mitochondrial functional analyses using 4 substrates: glutamate-malate (GM), pyruvate-malate (PM) palmitoyl carnitine-malate (PC) and succinate. NFLV mitochondria showed preserved respiratory control ratios and electron chain integrity with only few differences for the 4 substrates. In contrast, HF mitochondria had greater respiration with GM, PM and PC substrates and higher electron chain capacity for PM than for PC. Surprisingly, HF mitochondria had greater respiratory control ratios and lower ADP-independent state 4 rates than NFLV mitochondria for GM, PM and PC substrates demonstrating that HF mitochondria are capable of coupled respiration ex vivo. Gene expression studies revealed decreased expression of key genes in pathways for oxidation of both fatty acids and glucose. Our results suggest that mitochondria from the failing LV myocardium are capable of tightly coupled respiration when isolated and supplied with ample substrates. Thus energy starvation in the failing heart may be the result of dysregulation of metabolic pathways, impaired substrate supply or reduced mitochondrial number but not the result of reduced mitochondrial electron transport capacity.
• Keywords: 3-hydroxyacyl-coenzyme A dehydrogenase, 5′ AMP-activated protein kinase, ACADl, ACADm, ACADvl, AMPK, CD36, CPT2, ETC, Electron transport chain, FAD+, FCCP, GLUT1, GLUT4, GM, HADHA, HF, HFrEF, Human heart failure, ICM, IFM, L/E ratio, LV, LV internal diameter at diastole, LVIDd, ME3, Mitochondrial function, NAD(+), NFLV, NICM, Oxidative phosphorylation, P/E ratio, PC, PDHB, PDK4, PGC1α, PHTN, PM, PPARα, PPIA, RCR, RT-PCR, SSM, Succ, acyl-CoA dehydrogenase, long chain, acyl-CoA dehydrogenase, medium chain, acyl-CoA dehydrogenase, very long chain, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, carnitine palmitoyltransferase II, cluster of differentiation 36, electron transport chain, flavin adenine dinucleotide, glucose transporter 1, glucose transporter 4, glutamate–malate, heart failure, heart failure with reduced ejection fraction, interfibrillar mitochondria, ischemic cardiomyopathy, left ventricle, malic enzyme 3, nicotinamide adenine dinucleotide, non-failing left ventricle, non-ischemic cardiomyopathy, palmitoylcarnitine–malate, peptidylprolyl isomerase A (cyclophilin A), peroxisome proliferator-activated receptor (PPAR)-γ coactivator 1α, peroxisome proliferator-activated receptor α, pulmonary hypertension, pyruvate carboxylase, pyruvate dehydrogenase kinase 4, pyruvate dehydrogenase subunit B, pyruvate–malate, respiratory control ratio, reverse transcriptase-polymerized chain reaction, state 3 respiration to the uncoupled rate, state 4 respiration to uncoupled rate, subsarcolemmal mitochondria, succinate
Labels: MiParea: Respiration, mt-Medicine Pathology: Cardiovascular
Organism: Human Tissue;cell: Heart Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, ROX HRR: Oxygraph-2k