Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal.
During the progression of certain degenerative conditions, including myocardial ischemia-reperfusion injury, mitochondria are a source of increased free-radical generation and exhibit declines in respiratory function(s). It has therefore been suggested that oxidative damage to mitochondrial components plays a critical role in the pathology of these processes. Polyunsaturated fatty acids of membrane lipids are prime molecular targets of free-radical damage. A major product of lipid peroxidation, 4-hydroxy-2-nonenal (HNE), is highly cytotoxic and can readily react with and damage protein. In this study, the effects of HNE on intact cardiac mitochondria were investigated to gain insight into potential mechanisms by which free radicals mediate mitochondrial dysfunction. Exposure of mitochondria to micromolar concentrations of HNE caused rapid declines in NADH-linked but not succinate-linked state 3 and uncoupled respiration. The activity of complex I was unaffected by HNE under the conditions of our experiments. Loss of respiratory activity reflected the inability of HNE-treated mitochondria to meet NADH demand during maximum rates of O2 consumption. HNE exerted its effects on intact mitochondria by inactivating alpha-ketoglutarate dehydrogenase. These results therefore identify a potentially important mechanism by which free radicals bring about declines in mitochondrial respiration.
Humphries
K M
KM
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4970, USA.
Yoo
Y
Y
Szweda
L I
LI
D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D005969:Glutamate Dehydrogenase / Q000187:drug effects; D007655:Ketoglutarate Dehydrogenase Complex / Q000187:drug effects; D015227:Lipid Peroxidation; D008929:Mitochondria, Heart / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma; D014475:Uncoupling Agents / Q000494:pharmacology
D000447:Aldehydes; D014475:Uncoupling Agents; D009243:NAD; D007655:Ketoglutarate Dehydrogenase Complex; D005969:Glutamate Dehydrogenase; D016660:NAD(P)H Dehydrogenase (Quinone); C027576:4-hydroxy-2-nonenal