Regulation of mitofusin-2 expression in skeletal muscle

Fusion and fission of mitochondria regulate their morphology and distribution. Mitofusin-2 (Mfn2) is a mitochondrial protein involved in such fusion. Recent observations indicate that Mfn2 is a multifunctional protein that participates in cell proliferation and metabolism and that it is required for normal endoplasmic reticulum morphology. In relation to the metabolic role of Mfn2, alterations in activity have been reported to modify cell respiration, substrate oxidation, and oxidative phosphorylation subunit expression in cultured nonmuscle and muscle cells. Mfn2 expression in skeletal muscle is subject to regulation and conditions characterized by reduced mitochondrial activity, such as obesity or type 2 diabetes, and are associated with repressed Mfn2. In contrast, cold-exposure treatment with beta(3)-adrenergic agonists or exercise induce the expression of this gene in muscle. Estrogen-related receptor-alpha transcription factor is a key regulator of Mfn2 transcription and recruits peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 beta and PGC-1 alpha. These 2 nuclear coactivators are potent, positive regulators of Mfn2 expression in muscle cells, and ablation of PGC-1 beta causes Mfn2 downregulation in skeletal muscle and in the heart. We propose that PGC-1 beta is a regulator of normal expression of Mfn2 in muscle, whereas PGC-1 alpha participates in the stimulation of Mfn2 expression under a variety of conditions characterized by enhanced energy expenditure.