Mitochondrial dysfunction accompanies diastolic dysfunction in diabetic rat heart

Abstract

The objective of this study was to determine whether a defect in mitochondrial respiratory function accompanies the development of diabetic cardiomyopathy. The hypothesis tested in this study is that a decrease in Ca2+ uptake into mitochondria may prevent the stimulation of Ca(2+)-sensitive matrix dehydrogenases and the rate of ATP synthesis. Streptozotocin (55 mg/kg)-induced diabetic rats were used as a model of insulin-dependent diabetes mellitus. Hearts from 4-wk diabetic rats had basal heart rates and rates of contraction and relaxation similar to control. Isoproterenol caused a similar increase in the rate of contraction in diabetic and control hearts, whereas the peak rate of relaxation was reduced in diabetic hearts. Mitochondrial Ca2+ uptake was reduced in mitochondria from diabetic hearts after 2 wk of diabetes. Na(+)-induced Ca2+ release was unchanged. State 3 respiration rate was depressed in mitochondria from diabetic rats only when the respiration was supported by the substrate of a Ca(2+)-regulated matrix enzyme. The pyruvate dehydrogenase activity was reduced in diabetic mitochondria compared with that of control. It was concluded that mitochondria from diabetic hearts had a decreased capacity to upregulate ATP synthesis via stimulation of Ca(2+)-sensitive matrix dehydrogenases. The impairment in the augmentation of ATP synthesis rate accompanies a decreased rate of relaxation during increased work load.

Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin‐induced diabetic rats

“…This compound, a known MPTP inhibitor [7], inhibited the v8 depolarization after calcium uptake and allowed mitochondria from STZ rats to accumulate calcium, identically to control mitochondria. The data suggest that the depressed calcium uptake was not due to dysfunctional calcium uptake machinery, nor to enhanced calcium release by MPT-independent processes, which is in agreement with previous reports [2]. Heart mitochondria from the STZ group also showed a lower state 3 respiration.…”

“…A relationship between dysfunctional cardiac work and defective mitochondrial function associated with diabetes has been previously reported [2]. This elegant study showed a reduced calcium uptake in heart mitochondria from STZ-injected rats, although the primary reason was not found.…”

“…In heart mitochondria, streptozotocin (STZ)-induced diabetes was shown to impair mitochondrial oxidative phosphorylation and calcium loading capacity, in close relation to observed diastolic dysfunction [2]. The results were con¢rmed by Tanaka et al [3] using permeabilized myocytes from STZ-injected animals.…”

“…Our starting hypothesis was that the reduced mitochondrial calcium uptake observed in STZ-induced diabetic rat hearts [2,3] was due to enhanced MPT induction, with all the consequences to cardiac cell associated with that condition.…”

Mitochondrial Morphology in Metabolic Diseases

“…In all models tested, except Akita mice where oxidative stress was not observed, cardiac and mitochondrial functions were decreased (9,10,16,18,19,41,53,73,80,96,122,123), and these decreases were associated with increases in oxidative stress (10,125,142,143). The OVE26 mouse model develops a type 1 diabetic phenotype through the overexpression of calmodulin, specifically in pancreatic b-cells, leading to damage and extremely low levels of insulin secretion (48).…”