Congratulations to David Gius, MD, PhD and his lab on their publication in Free Radical Biology and Medicine!
Congratulations to the lab of Dr. David Gius. His lab’s recent publication outlines how the regulation of mitochondrial antioxidant MnSOD drives mitochondrial physiology and heart dysfunction. Dr. Gius is a Professor of Radiation Oncology, the Assistant Dean for Research with the Joe R. & Teresa Lozano Long School of Medicine, and the Associate Cancer Center Director with the Mays Cancer Center at UT Health San Antonio MD Anderson.
MnSOD non-acetylation mimic knock-in mice exhibit dilated cardiomyopathy
Joseph R Schell, Sung-Jen Wei, Jun Zhang, Rolando Trevino Jr, Wan Hsi Chen, Leonardo Aguilar, Wei Qian, Cole W Corbett, Haiyan Jiang, Felix F Dong, E Sandra Chocron, Alia Nazarullah, Jenny Chang, Margaret E Flanagan, Vaida Glatt, Sergey Dikalov, Erin Munkácsy, Nobuo Horikoshi, David Gius
Free Radic Biol Med. 2025 Mar 1:229:58-67. doi: 10.1016/j.freeradbiomed.2025.01.028. Epub 2025 Jan 15.
Abstract:
Manganese superoxide dismutase (MnSOD/SOD2) is an essential mitochondrial enzyme that detoxifies superoxide radicals generated during oxidative respiration. MnSOD/SOD2 lysine 68 acetylation (K68-Ac) is an important post-translational modification (PTM) that regulates enzymatic activity, responding to nutrient status or oxidative stress, and elevated levels have been associated with human illness. To determine the in vivo role of MnSOD-K68 in the heart, we used a whole-body non-acetylation mimic mutant (MnSODK68R) knock-in mouse. These mice exhibited several cardiovascular phenotypes, including lower blood pressure, decreased ejection fraction, and importantly, dilated cardiomyopathy, as evidenced by echocardiography at four months of age. In addition, both mouse embryo fibroblasts (MEFs) and cardiovascular tissue from MnSODK68R/K68R mice exhibited an increase in cellular senescence. Finally, MnSODK68R/K68R mouse hearts also showed an increase in lipid peroxidation. We conclude that constitutively active MnSOD detoxification activity, lacking the normal switch between non-acetylated and acetylated forms, dysregulates mitochondrial physiology during development, leading to dilated cardiomyopathy.
Keywords: Acetylation; Cardiomyopathy; Cell senescence; Echocardiography; Manganese superoxide dismutase; Mitochondria; MnSOD; SIRT3; SOD2; Sirtuin.