TNF-alpha-induced mitochondrial oxidative stress and cardiac dysfunction: restoration by superoxide dismutase mimetic Tempol.
Mitochondria are indispensable for bioenergetics and for the regulation of physiological/signaling events in cellular life. Although TNF-alpha-induced oxidative stress and mitochondrial dysfunction are evident in several pathophysiological states, the molecular mechanisms coupled with impaired cardiac function and its potential reversal by drugs such as Tempol or apocyanin have not yet been explored. Here, we hypothesize that TNF-alpha-induced oxidative stress compromises cardiac function by altering the mitochondrial redox state and the membrane permeability transition pore (MPTP) opening, thereby causing mitochondrial dysfunction. We measured the redox states in the cytosol and mitochondria of the heart to understand the mechanisms related to the MPTP and the antioxidant defense system. Our studies demonstrate that TNF-alpha-induced oxidative stress alters redox homeostasis by impairing the MPTP proteins adenine nucleotide translocator and voltage-dependent anion channel, thereby resulting in the pore opening, causing uncontrolled transport of substances to alter mitochondrial pH, and subsequently leading to dysfunction of mitochondria and attenuated cardiac function. Interestingly, we show that the supplementation of Tempol along with TNF-alpha restores mitochondrial and cardiac function.
Department of Comparative Biomedical Sciences, Louisiana State University, School of Veterinary Medicine, Baton Rouge, LA 70803, USA.
Nithya
N
Mariappan
Rajasekaran Namakkal
RN
Soorappan
Masudul
M
Haque
Srinivas
S
Sriramula
Joseph
J
Francis
D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*
D003497:Cyclic N-Oxides; D013113:Spin Labels; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase; C001803:tempol