title: Freshly isolated mitochondria from failing human hearts exhibit preserved respiratory function.
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.
authors.affiliation: Methodist DeBakey Heart and Vascular Institute, Weill Cornell Medical College, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cordero-Reyes
authors.affiliation: Bioenergetics Program, Houston Methodist Research Institute, Weill Cornell Medical College, USA.
authors.forename: Anisha A
authors.initials: AA
authors.lastname: Gupte
authors.affiliation: Methodist DeBakey Heart and Vascular Institute, Weill Cornell Medical College, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Youker
authors.affiliation: Methodist DeBakey Heart and Vascular Institute, Weill Cornell Medical College, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Loebe
authors.affiliation: Methodist Diabetes and Metabolism Institute, Houston Methodist Research Institute, Weill Cornell Medical College, USA; Houston Methodist Hospital Department of Medicine, Weill Cornell Medical College, USA.
authors.forename: Willa A
authors.initials: WA
authors.lastname: Hsueh
authors.affiliation: Methodist DeBakey Heart and Vascular Institute, Weill Cornell Medical College, USA; Catedra de Cardiologia y Medicina Vascular, Tecnologico de Monterrey, Nuevo Leon, Mexico.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Torre-Amione
authors.affiliation: The University of Texas Medical School at Houston, Department of Internal Medicine, USA.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.affiliation: Bioenergetics Program, Houston Methodist Research Institute, Weill Cornell Medical College, USA; Houston Methodist Hospital Department of Medicine, Weill Cornell Medical College, USA. Electronic address: DJHamilton@houstonmethodist.org.
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Hamilton
mesh_terms: D000328:Adult; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D019069:Cell Respiration; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D059467:Transcriptome; D055815:Young Adult
chemical_list: D018955:CD36 Antigens; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I; D010100:Oxygen
keywords: Electron transport chain; Human heart failure; Mitochondrial function; Oxidative phosphorylation