SOD2 deficiency in cardiomyocytes defines defective mitochondrial bioenergetics as a cause of lethal dilated cardiomyopathy

Abstract

Electrophilic aldehyde (4-hydroxynonenal; 4-HNE), formed after lipid peroxidation, is a mediator of mitochondrial dysfunction and implicated in both the pathogenesis and the progression of cardiovascular disease. Manganese superoxide dismutase (MnSOD), a nuclear-encoded antioxidant enzyme, catalyzes the dismutation of superoxide radicals (O 2 •- ) in mitochondria. To study the role of MnSOD in the myocardium, we generated a cardiomyocyte-specific SOD2 ( SOD2Δ ) deficient mouse strain. Unlike global SOD2 knockout mice, SOD2Δ mice reached adolescence; however, they die at ~4 months of age due to heart failure. Ultrastructural analysis of SOD2Δ hearts revealed altered mitochondrial architecture, with prominent disruption of the cristae and vacuole formation. Noninvasive echocardiographic measurements in SOD2 Δ mice showed dilated cardiomyopathic features such as decreased ejection fraction and fractional shortening along with increased left ventricular internal diameter. An increased incidence of ventricular tachycardia was observed during electrophysiological studies of the heart in SOD2Δ mice. Oxidative phosphorylation (OXPHOS) measurement using a Seahorse XF analyzer in SOD2Δ neonatal cardiomyocytes and adult cardiac mitochondria displayed reduced O 2 consumption, particularly during basal conditions and after the addition of FCCP (H + ionophore/uncoupler), compared to that in SOD2f l hearts. Measurement of extracellular acidification (ECAR) to examine glycolysis in these cells showed a pattern precisely opposite that of the oxygen consumption rate (OCR) among SOD2Δ mice compared to their SOD2 fl littermates. Analysis of the activity of the electron transport chain complex identified a reduction in Complex I and Complex V activity in SOD2Δ compared to SOD2f l mice. We demonstrated that a deficiency of SOD2 increases reactive oxygen species (ROS), leading to subsequent overproduction of 4-HNE inside mitochondria. Mechanistically, proteins in the mitochondrial respiratory chain complex and TCA cycle (NDUFS2, SDHA, ATP5B, and DLD) were the target of 4-HNE adduction in SOD2Δ hearts. Our findings suggest that the SOD2 mediated 4-HNE signaling nexus may play an important role in cardiomyopathy.

Genetics of Myocardial Interstitial Fibrosis in the Human Heart and Association with Disease

“…This is congruent with findings from Sod2 knockout mice which exhibit increased levels of oxygen reactive species with associated myocardial fibrosis and development of dilated cardiomyopathy. 26 Furthermore, we found an association between rheumatoid arthritis as well as baseline C-reactive protein (a well-established clinical inflammatory marker) with increased native myocardial T1 time emphasizing the role of inflammation in the propagation of myocardial interstitial fibrosis.…”

“…SLC2A12 encodes solute facilitated glucose transporter member 12 (GLUT12), a basal and insulin-independent glucose transporter in the heart 22 with previously reported associations with heart failure, 23 diabetes, 24 and kidney disease. 25 Lead SNPs in SOD2 (rs6912979, P = 1.06×10 −10 ) and VEGFC (rs365843, P = 3.19×10 −9 ), two genes with established roles in cardiac hypertrophy and fibrosis in animal models, 26,27 were associated with decreased interventricular septum T1 times. Another lead SNP associated with interventricular septum T1 time is an intronic variant in ADAMTSL1 (rs1576900, P = 3.63×10 −11 ), a gene encoding an ADAMTS-like protein which is thought to modulate the function of ADAMTS metalloproteinases with integral roles in extracellular matrix turnover.…”

Extracellular Superoxide Dismutase (EC-SOD) Regulates Gene Methylation and Cardiac Fibrosis During Chronic Hypoxic Stress

“…SOD1 overexpression leads to ROS scavenging and blocking production and block collagen production, suggesting that SOD1 may be a promising therapeutic agent for treating ROS-mediated cardiac fibrosis ( 25 ). Mice deficient in SOD2 die of cardiomyopathy within 10 days of birth, whereas heterozygous SOD2(+/–) mice show ultrastructural damage of the myocardium and mitochondria, associated with an increased oxidative stress as well as an activation of apoptotic signaling pathways in the heart ( 26 , 27 ). MnSOD overexpression offers protection against oxidative stress, fibrosis, and apoptosis in the aging heart ( 28 ).…”

Exploration the Mechanism of Doxorubicin-Induced Heart Failure in Rats by Integration of Proteomics and Metabolomics Data

“…On the other hand, Sharma Sudha et al demonstrated that the absence of SOD2 leads to an increase in ROS ( Sharma et al, 2020 ). Nrf2 is widely recognized as a transcription factor activated by oxidative stress, and cells lacking Nrf2 can lead to mitochondrial dysfunction, resulting in increased ROS and impaired antioxidant capacity and further aggravated heart failure ( Tebay et al, 2015 ).…”