The Role of Mammalian Mitofusin-2 (Mfn-2) in Lipid Metabolism

Abstract

The architecture of mitochondria is closely associated with numerous functions for cell signaling, growth and senescence. The overall phenomenon of mitochondrial dynamics, which include fusion and fission events, characterizes the fundamental mechanism governing the cell’s bioenergetic needs. Mitofusins are fusogenic proteins that have emerged as key regulators of diverse functions such as respiration, mitochondrial biogenesis, and energy homeostasis. Thus, mitochondrial dynamics and bioenergetics together control the energy demand to supply ratio. Mitofusins (1 and 2) are both intricately associated with mitochondria and mitochondrial associated membranes (MAMs). These organellar communication sites drive and regulate mitochondrial metabolism and energy homeostasis. Although both mitofusin-1 (Mfn-1) and mitofusin 2 (Mfn-2) share some common roles, Mfn-1 is primarily involved in the fusion of the outer mitochondrial membrane, while Mfn-2 primarily affects mitochondrial metabolism by controlling the electron transport chain, fuel oxidation and mitochondrial membrane potential. The research presented in this thesis centers around the Mfn-2 fusion protein. Specifically, it focuses on the change in mitochondrial morphology and lipid content in the absence of Mfn-2. It was observed that the knockout of Mfn-2 in mouse embryonic stem fibroblasts (MEFs) drastically altered mitochondrial morphology and simultaneously increased lipid droplet size but not number. When cells were provided a further substrate for triglyceride synthesis i.e. oleic acid, the Mfn-2 KO MEFs showed an enhanced capacity to increase the number of lipid droplets compared to WT cells. In Mfn-2 knockout MEF cells, the ability to undergo adipogenesis is enhanced compared to WT MEF cells. Surprisingly we also observed that adipogenesis was induced with control, non-adipogenic media, supplemented with a high concentration (20%) of fetal bovine serum. In conclusion, the data suggest that Mfn-2 is a crucial protein controlling mitochondrial morphology, which has a major role in maintaining cellular homeostasis and lipid metabolism.