TNF-induced mitochondrial damage: a link between mitochondrial complex I activity and left ventricular dysfunction.
Mitochondrial damage is implicated in the progression of cardiac disease. Considerable evidence suggests that proinflammatory cytokines induce oxidative stress and contribute to cardiac dysfunction. This study was conducted to determine whether a TNF-induced increase in superoxide (O(2)(*)(-)) contributes to mitochondrial damage in the left ventricle (LV) by impairing respiratory complex I activity. We employed an electron paramagnetic resonance (EPR) method to measure O(2)(*)(-) and oxygen consumption in mitochondrial respiratory complexes, using an oxygen label. Adult male Sprague-Dawley rats were divided into four groups: control, TNF treatment (ip), TNF+ apocynin (APO; 200 micromol/kg bw, orally), and TNF+ Tempol (Temp; 300 micromol/kg bw, orally). TNF was injected daily for 5 days. Rats were sacrificed, LV tissue was collected, and mitochondria were isolated for EPR studies. Total LV ROS production was significantly higher in TNF animals than in controls; APO or Temp treatment ameliorated TNF-induced LV ROS production. Total mitochondrial ROS production was significantly higher in the TNF and TNF+ APO groups than in the control and TNF+ Temp groups. These findings suggest that TNF alters the cellular redox state, reduces the expression of four complex I subunits by increasing mitochondrial O(2)(*)(-) production and depleting ATP synthesis, and decreases oxygen consumption, thereby resulting in mitochondrial damage and leading to LV dysfunction.
Mariappan
Nithya
N
Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA.
Elks
Carrie M
CM
Fink
Bruno
B
Francis
Joseph
J
D000098:Acetophenones / Q000008:administration & dosage; D000818:Animals; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D003497:Cyclic N-Oxides / Q000008:administration & dosage; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000502:physiology*; D004452:Echocardiography; D004578:Electron Spin Resonance Spectroscopy; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000008:administration & dosage; D008297:Male; D008929:Mitochondria, Heart / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology / Q000276:immunology / Q000648:ultrastructure; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000276:immunology / Q000473:pathology
D000098:Acetophenones; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D013113:Spin Labels; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C056165:acetovanillone; D019255:NADPH Oxidases; D042967:Electron Transport Complex I; C001803:tempol