Abstract
Coronary artery disease (CAD) is a leading cause of death worldwide and frequently associated with mitochondrial dysfunction. Detailed understanding of abnormalities in mitochondrial function that occur in patients with CAD is lacking. We evaluated mitochondrial damage, energy production, and mitochondrial complex activity in human non-CAD and CAD hearts. Fresh and frozen human heart tissue was used. Cell lysate or mitochondria were isolated using standard techniques. Mitochondrial DNA (mtDNA), NAD + and ATP levels, and mitochondrial oxidative phosphorylation capacity were evaluated. Proteins critical to the regulation of mitochondrial metabolism and function were also evaluated in tissue lysates. PCR analysis revealed an increase in mtDNA lesions and the frequency of mitochondrial common deletion, both established markers for impaired mitochondrial integrity in CAD compared to non-CAD patient samples. NAD+ and ATP levels were significantly decreased in CAD subjects compared to Non-CAD (NAD+ fold change: non-CAD 1.00 ± 0.17 vs. CAD 0.32 ± 0.12* and ATP fold change: non-CAD 1.00 ± 0.294 vs. CAD 0.01 ± 0.001*; N = 15, P < 0.005). We observed decreased respiration control index in CAD tissue and decreased activity of complexes I, II, and III. Expression of ETC complex subunits and respirasome formation were increased; however, elevations in the de-active form of complex I were observed in CAD. We observed a corresponding increase in glycolytic flux, indicated by a rise in pyruvate kinase and lactate dehydrogenase activity, indicating a compensatory increase in glycolysis for cellular energetics. Together, these results indicate a shift in mitochondrial metabolism from oxidative phosphorylation to glycolysis in human hearts subjects with CAD.
Highlights
The mammalian Mitochondrial DNA (mtDNA) is a small genome of 16,000 base pairs that encodes for proteins of the ETC (13 subunits of complexes I, III,IV, and the ATP synthase) that are essential for oxidative phosphorylation (OXPHOS), and various non-coding RNA and signaling peptides critical for normal mitochondrial function[8]
As viability of mitochondria is mandatory for the mitochondrial respiration studies, most samples used for direct measurement of mitochondrial oxygen consumption were collected from otherwise atrial discarded appendages within 1–2 hours after removal of the tissue during cardiopulmonary bypass surgery
Our main findings describe an overall decline in mitochondrial function and energy production in patients with Coronary artery disease (CAD)
Summary
The mammalian mtDNA is a small genome of 16,000 base pairs that encodes for proteins of the ETC (13 subunits of complexes I, III,IV, and the ATP synthase (complex V)) that are essential for oxidative phosphorylation (OXPHOS), and various non-coding RNA and signaling peptides critical for normal mitochondrial function[8]. A detailed characterization of the cellular changes occurring in the cardiac tissue of human CAD patients is lacking. Previous studies from our group have shown an increased level of mtROS in CAD patients as determined by the increase release of mitochondrial H2O2, a very important pro-inflammatory signaling factor[15,16]. We hypothesized that as a consequence of this rise of mtROS in human tissue from patients with CAD, we would observe increased mtDNA damage, reduced OXPHOS, decreased mitochondrial respiration, and a corresponding rise in glycolytic flux. The goal of this study was to determine the bioenergetic profile of cardiac mitochondria in tissue from subjects suffering from CAD compared to non-CAD controls
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