Linking Fatty Acid Stress to β-Cell Mitochondrial Dynamics

Mitochondria form a highly dynamic filamentous network. The elongated shape of the individual mitochondrion, visualized by fluorescence microscopy, contrasts with the classic text book representation that shows the mitochondrion as an elliptical short rod-like structure. The networks are in constant motion and undergo continuous remodeling through the fusion of mitochondria with each other and the fission of filamentous mitochondria into shorter fragments (1–3). Both processes are mediated by a few core fusion/fission proteins. Tethering and fusion of the outer mitochondrial membrane is mediated by the related GTPases Mitofusin1 and 2, whereas OPA1 catalyzes the fusion of the inner mitochondrial membrane. Fis1 catalyzes the assembly of the dynamin-related protein Drp1 into oligomeric complexes on the outer mitochondrial membrane to drive mitochondrial scission. Mutations in OPA1 and Mfn2 cause, respectively, autosomal dominant optic atrophy and peripheral neuropathy (Charcot-Marie-Tooth disease) associated with insulin resistance in type 2 diabetes (1,2,4,5). The ability of mitochondria to undergo fusion/fission dynamics is intimately linked with mitochondrial function. Mitochondria may use this mechanism for even distribution of metabolites, lipids, and proteins. Fission is also used to mediate the removal of nonfunctional or aged mitochondria to be targeted for autophagy as also shown for β-cells (6). Fusion/fission proteins have attracted attention for their close link with mitochondrial respiration/energy metabolism, impact on cristae structure, and mitochondria-linked cell …