SOD2 Deficiency in Cardiomyocytes Defines Defective Mitochondrial Bioenergetics as a Cause of Lethal Dilated Cardiomyopathy

Authors

Sudha Sharma, Louisiana State University
Susmita Bhattarai, Louisiana State University
Hosne Ara, Louisiana State University
Grace Sun, Louisiana State University
Daret K. St. Clair, University of KentuckyFollow
Md Shenuarin Bhuiyan, Louisiana State University
Christopher Kevil, Louisiana State University
Megan N. Watts, Louisiana State University
Paari Dominic, Louisiana State University
Takahiko Shimizu, National Center for Geriatrics and Gerontology, Japan
Kevin J. McCarthy, Louisiana State University
Hong Sun, Louisiana State University
Manikandan Panchatcharam, Louisiana State University
Sumitra Miriyala, Louisiana State University

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 (O2^•-) 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 O₂ consumption, particularly during basal conditions and after the addition of FCCP (H⁺ ionophore/uncoupler), compared to that in SOD2fl 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 SOD2fl 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.

Document Type

Article

Publication Date

10-2020

Notes/Citation Information

Published in Redox Biology, v. 37, 101740.

© 2020 The Authors

This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.redox.2020.101740

Funding Information

This work was supported by Louisiana State University Health Sciences-Shreveport Intramural Grant 110101074A to SM; National Institutes of Health grants HL141998 and HL141998-01S1 to SM, AA025744, AA026708, and AA025744-02S1 to MP, AA023610 to HS, HL122354 and HL145753 to MSB, and P20GM121307 to CGK. Funding to pay the publication charges for this article was provided by Dr. Miriyala.

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Repository Citation

Sharma, Sudha; Bhattarai, Susmita; Ara, Hosne; Sun, Grace; St. Clair, Daret K.; Bhuiyan, Md Shenuarin; Kevil, Christopher; Watts, Megan N.; Dominic, Paari; Shimizu, Takahiko; McCarthy, Kevin J.; Sun, Hong; Panchatcharam, Manikandan; and Miriyala, Sumitra, "SOD2 Deficiency in Cardiomyocytes Defines Defective Mitochondrial Bioenergetics as a Cause of Lethal Dilated Cardiomyopathy" (2020). Toxicology and Cancer Biology Faculty Publications. 96.
https://uknowledge.uky.edu/toxicology_facpub/96