Mitochondrial Energetics and Ca2+-Activated ATPase in Obstructive Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium associated to mutations in sarcomeric genes, but the link between genotype and phenotype remains poorly understood. Magnetic resonance spectroscopy studies have demonstrated impaired cardiac energetics in patients with HCM, and altered mitochondria were described in biopsies, but little is known about possible perturbations of mitochondrial function and adenosine triphosphate (ATP) production/consumption. The aim of this study was to investigate possible abnormalities in mitochondrial enzymes generating/scavenging reactive oxygen species, and changes in the Ca2+-activated ATPases in myocardial tissue from patients with obstructive HCM undergoing surgical myectomy compared to unused donor hearts (CTRL). Methods and Results: Both the amount and activity of mitochondrial Complex I (nicotinamide adenine dinucleotide -reduced form, NADH, dehydrogenase) were upregulated in HCM vs. CTRL, whilst the activity of Complex V (ATP synthase) was not reduced and ATP levels were significantly higher in HCM vs. CTRL. Antioxidant Mn-activated superoxide dismutase (SOD2) and (m)-aconitase activities were increased in HCM vs. CTRL. The Cu/Zn-activated superoxide dismutase (SOD1) amount and mtDNA copy number were unaltered in HCM. Total Ca2+-activated ATPase activity and absolute amount were not different HCM vs. CTRL, but the ratio between ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting type 2 (ATP2A2) and type 1 (ATP2A1), ATP2A2/ATP2A1, was increased in HCM in favor of the slow isoform (ATP2A2). Conclusion: HCM is characterized by mitochondrial Complex I hyperactivity and preserved Ca2+-activated ATPase activity with a partial switch towards slow ATP2A2. This data may give insight into the abnormal cellular energetics observed in HCM cardiomyopathy but other studies would need to be performed to confirm the observations described here.

Oxidative stress in cardiac hypertrophy: From molecular mechanisms to novel therapeutic targets

“…Unsurprisingly, disturbances in mitochondrial or antioxidant proteins have been associated with cardiac hypertrophy. In patients with HCM, mitochondrial complex I has been found to be upregulated with elevated ATP levels and increased antioxidant enzymes [46], suggesting hyperactivity of complex I which was proposed to contribute to elevated ROS levels. ROS can also effect ATP levels as evidenced by a study which compared differential status of energy metabolism between myocardial infarction and pathological hypertrophy, where ATP levels were found to be significantly impaired in the former, while being preserved in the latter [47].…”

Whole-Exome Sequencing Reveals Mutational Signature of Hypertrophic Cardiomyopathy

“… 25 A previous study reported that in obstructive HCM, ATP2A2/ZTP2A1 played a key role. 30 From completely asymptomatic to outflow tract obstruction, diastolic dysfunction, progressive heart failure, various tachyarrhythmias and sudden cardiac death, the abnormal individualization of clinical phenotype of HCM patients leads to difficulties in clinical decision-making and prognosis evaluation. In addition to significant genetic heterogeneity, the heterogeneity of clinical phenotype is also obvious among different HCMs, and the complex genotype-clinical phenotype relationship also brings challenges to the clinical diagnosis and genetic susceptibility assessment of HCM.…”

Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review

“…Elevated ROS levels can cause oxidative damage to mitochondria and DNA, harm proteins and lipids, activate the mitochondrial permeability transition pore, cause mitochondrial dysfunction, and lead to cellular death. Additionally, it can disrupt the ATP and ADP balance [13,29,70]. While the exact mechanisms of HCM are still not fully understood, previous noninvasive studies have shed light on certain aspects of the disease.…”