Mitochondrial tolerance to stress impaired in failing heart.
Mitochondrial integrity is critical in the maintenance of bioenergetic homeostasis of the myocardium, with oxidative or metabolic challenge to mitochondria precipitating cell injury. In heart failure, where cardiac cells are exposed to elevated stress, mitochondrial vulnerability could contribute to the disease state. However, the mitochondrial response to stress is yet to be established in heart failure. Here, mitochondrial function and structure was evaluated prior and following stress using a transgenic (TG) model of heart failure, generated by cardiac overexpression of the cytokine TNFalpha. Compared to the wild type, mitochondria from TG failing hearts demonstrated impaired oxidative phosphorylation, mitochondrial DNA damage, reduced mitochondrial creatine kinase activity, abnormal calcium handling, and altered ultrastructure. Under anoxia/reoxygenation or calcium stress, mitochondria from failing hearts suffered exacerbated energetic failure with pronounced cytochrome c release. Thus, mitochondria from TNFalpha-TG failing hearts demonstrate structural and functional abnormalities, with reduced tolerance to stress manifested by impaired bioenergetics and increased susceptibility to injury. This abnormal vulnerability to stress underscores the impact of mitochondrial dysfunction in the pathobiology of heart failure.
Ozcan
Cevher
C
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic and Foundation, Guggenheim-7F, Rochester, MN 55905, USA.
Bienengraeber
Martin
M
Hodgson
Denice M
DM
Mann
Douglas L
DL
Terzic
Andre
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015687:Cell Hypoxia; D003402:Creatine Kinase / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000648:ultrastructure; D010085:Oxidative Phosphorylation; D013312:Stress, Physiological; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D003402:Creatine Kinase; D002118:Calcium