Mitochondrial Networking Protects β-Cells From Nutrient-Induced Apoptosis

Mitochondrial Networking Protects β-Cells From Nutrient-Induced Apoptosis Anthony J.A. Molina 1 , Jakob D. Wikstrom 1 , 2 , Linsey Stiles 1 , 3 , Guy Las 1 , Hibo Mohamed 3 , Alvaro Elorza 1 , Gil Walzer 3 , Gilad Twig 1 , Steve Katz 3 , Barbara E. Corkey 1 and Orian S. Shirihai 1 1 Department of Molecular Medicine, Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts; 2 The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Stockholm, Sweden; 3 Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts. Corresponding author: Orian S. Shirihai, orian.shirihai{at}tufts.edu . 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 article, we investigate β-cell mitochondrial fusion and fission in detail and report alterations in response to various combinations of nutrients. RESEARCH DESIGN AND METHODS Using matrix-targeted photoactivatable green fluorescent protein, 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 combined effects of free fatty acid 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 underlies the overall morphology of the organelle. We find that networking activity among mitochondria is capable of distributing a localized green fluorescent protein signal throughout an isolated β-cell, a β-cell within an islet, and an 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