TY - JOUR
T1 - Freshly isolated mitochondria from failing human hearts exhibit preserved respiratory function
AU - Cordero-Reyes, Andrea M.
AU - Gupte, Anisha A.
AU - Youker, Keith A.
AU - Loebe, Matthias
AU - Hsueh, Willa A.
AU - Torre-Amione, Guillermo
AU - Taegtmeyer, Heinrich
AU - Hamilton, Dale J.
N1 - Funding Information:
Our study was supported by the NIH ( R21 CA133153 to DJH and R01HL061483 to HT); generous gifts from the MacDonald Foundation and Zucker Family to WAH; The Methodist DeBakey Heart & Vascular Center Texans Grant , TMH Foundation John Kotts Family , the Rodney Bradley Family and the Stedman-West Foundation to DJH; and American Heart Association fellowship to AAG.
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
KW - Electron transport chain
KW - Human heart failure
KW - Mitochondrial function
KW - Oxidative phosphorylation
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U2 - 10.1016/j.yjmcc.2013.12.029
DO - 10.1016/j.yjmcc.2013.12.029
M3 - Article
C2 - 24412531
AN - SCOPUS:84894312074
SN - 0022-2828
VL - 68
SP - 98
EP - 105
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -