Abstract

Objective: Previous studies have reported that β-cell mitochondria exist as discrete organelles that exhibit heterogeneous bioenergetic capacity. To date, networking activity, and its role in mediating β-cell mitochondrial morphology and function, remains unclear. In this manuscript, we investigate β-cell mitochondrial fusion and fission in detail and report alterations in response to different combinations of nutrients.

Research Design and Methods: Using matrix targeted photoactivatable GFP, mitochondria were tagged and tracked in β-cells within intact islets, as isolated cells, and as cell lines, revealing frequent fusion and fission events. Manipulations of key mitochondrial dynamics proteins, OPA1, DRP1, and Fis1 were tested for their role in β-cell mitochondrial morphology. The combinatory effect of FFA and glucose on β-cell survival, function, and mitochondrial morphology were explored with relation to alterations in fusion and fission capacity.

Results: β-cell mitochondria are constantly involved in fusion and fission activity that underlie that overall morphology of the organelle. We find that networking activity amongst mitochondria is capable of distributing a localized GFP signal throughout an isolated β-cell, β-cell within an islet, and INS1 cell. Under noxious conditions, we find that β-cell mitochondria become fragmented and lose their ability to undergo fusion. Interestingly, manipulations that shift the dynamic balance to favor fusion, are able to prevent mitochondrial fragmentation, maintain mitochondrial dynamics, and prevent apoptosis.

Conclusions: These data suggest that alterations in mitochondrial fusion and fission play a critical role in nutrient induced β-cell apoptosis and may be involved in the pathophysiology of type 2 diabetes.