Mitochondrial Calpain-1 Disrupts ATP Synthase and Induces Superoxide Generation in Type 1 Diabetic Hearts: A Novel Mechanism Contributing to Diabetic Cardiomyopathy
Our recent study reported a critical role of calpain in cardiomyopathic changes in type-1 diabetes (T1D). This study investigated how calpain regulates mitochondrial reactive oxygen species (ROS) generation in the development of diabetic cardiomyopathy. T1D was induced in transgenic mice over-expressing calpastatin, in mice with cardiomyocyte-specific capn4 deletion or their wild-type littermates by injection of streptozotocin. Calpain-1 protein and activity in mitochondria were elevated in diabetic mouse hearts. The increased mitochondrial calpain-1 was associated with an increase in mitochondrial ROS generation and oxidative damage, and a reduction in ATP synthase-α (ATP5A1) protein and ATP synthase activity. Genetic inhibition of calpain or up-regulation of ATP5A1 increased ATP5A1 and ATP synthase activity, prevented mitochondrial ROS generation and oxidative damage, and reduced cardiomyopathic changes in diabetic mice. High glucose induced ATP synthase disruption, mitochondrial superoxide generation and cell death in cardiomyocytes, all of which were prevented by over-expression of mitochondria-targeted calpastatin or ATP5A1. Moreover, up-regulation of calpain-1 specifically in mitochondria induced the cleavage of ATP5A1, superoxide generation and apoptosis in cardiomyocytes. In summary, calpain-1 accumulation in mitochondria disrupts ATP synthase and induces ROS generation, which promotes diabetic cardiomyopathy. These findings suggest a novel mechanism and may have significant implications in diabetic cardiac complications.
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 23 December 2015.
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#13,901,936
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#7,050
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#134,199
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Outputs of similar age from Diabetes
#72
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