Abstract
Fission and fusion of mitochondrial tubules are the major processes regulating mitochondrial morphology. However, the physiological significance of mitochondrial shape change is poorly understood. Glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells requires mitochondrial ATP production which evokes Ca2+ influx through plasma membrane depolarization, triggering insulin vesicle exocytosis. Therefore, GSIS reflects mitochondrial function and can be used for evaluating functional changes associated with morphological alterations of mitochondria. Using the insulin-secreting cell line INS-1E, we found that glucose stimulation induced rapid mitochondrial shortening and recovery. Inhibition of mitochondrial fission through expression of the dominant-negative mutant DLP1-K38A eliminated this dynamic mitochondrial shape change and, importantly, blocked GSIS. We found that abolishing mitochondrial morphology change in glucose stimulation increased the mitochondrial inner membrane proton leak, and thus significantly diminished the mitochondrial ATP producing capacity in response to glucose stimulation. These results demonstrate that dynamic change of mitochondrial morphology is a previously unrecognized component for metabolism-secretion coupling of pancreatic β-cells by participating in efficient ATP production in response to elevated glucose levels.
Highlights
Mitochondria are dynamic organelles, constantly changing their shape and size through fission and fusion
While mitochondrial hyperfusion upon fission inhibition was less appreciable in resting conditions due to highly interconnected networks of INS-1E mitochondria [16,18,19], we found that the long tubular mitochondrial morphology persisted in glucose stimulation (Fig. 3A and B, Videos S3 and S4)
The results described in this study indicate that dynamic change of mitochondrial morphology in glucose stimulation is necessary for insulin secretion activity of INS-1E cells by controlling mitochondrial ATP production
Summary
Mitochondria are dynamic organelles, constantly changing their shape and size through fission and fusion. Dynamin-related large GTPases are the main components mediating mitochondrial fission and fusion. Mitochondrial fission and fusion have been implicated in preserving proper mitochondrial function. Mutations in fission/fusion proteins resulting in hereditary diseases or lethal effect in humans indicate that disrupted mitochondrial morphology is causal for the harmful consequence presumably through mitochondrial dysfunction [6,7,8,9]. Mitochondrial poisons causing mitochondrial dysfunction induce disrupted mitochondrial morphology [10,11,12,13]. These observations suggest that mitochondrial morphology and function are closely linked and influence each other. Mechanistic link of the mitochondrial form-function relationship and the physiological significance of mitochondrial shape change are poorly understood
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