Decreased complex II respiration and HNE-modified SDH subunit in diabetic heart.
Several lines of research suggest that mitochondria play a role in the etiopathogenesis of diabetic cardiomyopathy, although the mechanisms involved are still debated. In the present study, we report that State 3 oxygen consumption decreases by approximately 35% with glutamate and by approximately 30% with succinate in mitochondria from diabetic rat hearts compared to controls. In these mitochondria the enzymatic activities of complex I and complex II are also decreased to a comparable extent. Western blot analysis of mitochondrial protein pattern using antibodies recognizing proteins modified by the lipid peroxidation product 4-hydroxynonenal indicates the FAD-containing subunit of succinate dehydrogenase as one of the targets of this highly reactive aldehyde. In rats diabetic for 6 or 12 weeks, insulin supplementation for 2 weeks decreases the level of protein modified by 4-hydroxynonenal and restores mitochondrial respiration and enzyme activity to control level. Taken together, these results: (1) indicate that 4-hydroxynonenal is endogenously produced within diabetic mitochondria and forms an adduct with selective mitochondrial proteins, (2) identify one of these proteins as a subunit of succinate dehydrogenase, and (3) provide strong evidence that insulin treatment can reverse and ameliorate free radical damage and mitochondrial function under diabetic conditions.
Lashin
Ossama M
OM
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106-4970, USA. amr5@po.cwru.edu
Szweda
Pamela A
PA
Szweda
Luke I
LI
Romani
Andrea M P
AM
D000447:Aldehydes / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D009202:Cardiomyopathies / Q000201:enzymology* / Q000209:etiology; D019069:Cell Respiration / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D042963:Electron Transport Complex II / Q000187:drug effects / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage; D015227:Lipid Peroxidation; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000378:metabolism; D010101:Oxygen Consumption; D051381:Rats; D017207:Rats, Sprague-Dawley; D013385:Succinate Dehydrogenase / Q000032:analysis* / Q000187:drug effects / Q000378:metabolism*
D000447:Aldehydes; D005609:Free Radicals; D007328:Insulin; D024101:Mitochondrial Proteins; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; C027576:4-hydroxy-2-nonenal