Abstract 1269: Depressed Mitochondrial Fusion in Heart Failure
Mitochondrial fission and fusion are essential ongoing processes for the maintenance of normal mitochondrial function. Fission and fusion are thought to be important mechanisms for protecting the mitochondrial genome, which is vulnerable to damage from reactive oxygen species (ROS). These critical, complementary processes have been studied primarily in yeast. We hypothesized that mitochondrial fission and fusion would be abnormal in heart failure. Two models were use for these studies: explanted failing human hearts and rat heart 9 wks after high LAD ligation. Western blotting compared expression of the 3 fusion proteins, Opa1, Mfn1 and Mfn2. Opa1 expression decreased in both rat and human failing hearts compared with sham control rat hearts (0.34 ± 0.05 vs. 0.61 ± 0.05, n = 3, P < 0.05) and normal human hearts (0.16 ± 0.12 vs. 0.66 ± 0.15, n = 5, P < 0.05), respectively. Mfn1/Mfn2 were increased in human failing hearts (0.60 ± 0.03 vs. 1.00 ± 0.08, n = 5, P < 0.05) but were not changed in rat failing hearts (; 0.88 ± 0.05 vs. 0.78 ± 0.04, n = 3, P ns). In contrast, for the fission proteins, Drp1 and Fis1, western blotting demonstrated that Drp1 increased in human ( 0 ± 0 vs. 0.27 ± 0.09, n = 5, P < 0.001), but not in rat failing heart (0.67 ± 0.09 vs. 0.76 ± 0.06, n = 3, P ns); while Fis1 was unchanged in both rat (0.52 ± 0.07 vs. 0.57 ± 0.04, n = 3, P ns) and human hearts (0.79 ± 0.06 vs. 0.71 ± 0.05, n = 5, P ns). Electron microscopy of the failing rat hears demonstrated the development of small, fragmented mitochondria by 9 wks post ligation.
Conclusions: This demonstrates for the first time that Opa1, a critical protein for mitochondrial fusion, is significantly decreased in heart failure. The decrease in Opa1 is accompanied by the development of small, abnormal mitochondria. Depression of Opa1 expression may play a pivotal role in the progression of heart failure.