Mitochondrial networking protects beta-cells from nutrient-induced apoptosis.
OBJECTIVE
Previous studies have reported that beta-cell mitochondria exist as discrete organelles that exhibit heterogeneous bioenergetic capacity. To date, networking activity, and its role in mediating beta-cell mitochondrial morphology and function, remains unclear. In this article, we investigate beta-cell mitochondrial fusion and fission in detail and report alterations in response to various combinations of nutrients.


METHODS
Using matrix-targeted photoactivatable green fluorescent protein, mitochondria were tagged and tracked in beta-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 beta-cell mitochondrial morphology. The combined effects of free fatty acid and glucose on beta-cell survival, function, and mitochondrial morphology were explored with relation to alterations in fusion and fission capacity.


RESULTS
beta-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 beta-cell, a beta-cell within an islet, and an INS1 cell. Under noxious conditions, we find that beta-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 beta-cell apoptosis and may be involved in the pathophysiology of type 2 diabetes.
Molina
Anthony J A
AJ
Department of Molecular Medicine, Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts, USA.
Wikstrom
Jakob D
JD
Stiles
Linsey
L
Las
Guy
G
Mohamed
Hibo
H
Elorza
Alvaro
A
Walzer
Gil
G
Twig
Gilad
G
Katz
Steve
S
Corkey
Barbara E
BE
Shirihai
Orian S
OS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020558:GTP Phosphohydrolases / Q000235:genetics; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000502:physiology; D008561:Membrane Fusion / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000502:physiology
D049452:Green Fluorescent Proteins; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse