A Small Molecule Promotes Mitochondrial Fusion in Mammalian Cells

• DOI: 10.1002/anie.201204589
• Publication Date: 2012-08-21T07:58:50Z
• Authors: Danling Wang; Jianing Wang; Ghislain M. C. Bo...; Shelly Meeusen; Richard G. Brusch; Carolina Turk; Pengyu Yang; Peter G. Schultz
• Keywords: 0301 basic medicine; 0303 health sciences; Microscopy, Confocal; Cell Survival; Hydrazones; Fibroblasts; Mitochondrial Proton-Translocating ATPases; Mitochondrial Dynamics; Cell Line; GTP Phosphohydrolases; Mitochondria; Mice; 03 medical and health sciences; Oxidative Phosphorylation Coupling Factors; Hydrocarbons, Chlorinated; Animals; Humans

Mitochondria are highly dynamic cellular organelles that continuously undergo fission and fusion. This dynamic nature plays a key role in regulating mitochondrial function, and also gives mitochondria their heterogeneous morphology. Disruption of the balance between mitochondrial fusion and fission, especially a shift towards fission, contributes to a variety of human disorders, including neurodegenerative disease, metabolic disease, and ischemia. In addition, fragmented mitochondria are early signs of activation of apoptosis, and fusion of mitochondria by genetic or chemical manipulation has been shown to have an anti-apoptotic effect. Thus, the identification of small molecules that modulate mitochondrial dynamics can provide useful tools to study mitochondrial function and may ultimately lead to new therapeutics. Here, we report the identification and preliminary biological characterization of the small molecule, M1, which significantly restores the mitochondrial tubular network in response to genetically or chemically induced fragmentation. Mitochondrial fusion is a two-step process in which the outer and inner mitochondrial membranes (OMM and IMM, respectively) fuse separately, but in an ordered fashion. The core components of the mitochondrial fusion machinery are the OMM proteins, mitofusin 1 and 2 (Mfn1 and Mfn2), and the IMM protein, optic atrophy 1 (Opa1). Unlike wild-type mouse embryonic fibroblasts (WT MEFs), which mainly have interconnected tubular mitochondria, Mfn1 Knockout (KO) MEFs exhibit severely and uniformly frag-