Eukaryotic cells exhibit the operation of mitochondrial fusion and fission processes, which are catalyzed by distinct protein machineries. Mitochondrial fusion requires the activity of mitofusin-1 (Mfn1), mitofusin-2 (Mfn2) and OPA1, and mitochondrial fission depends on Drp1, and Fis1. Some of these proteins are mutated in certain human diseases, and it is likely that other proteins may participate in those processes.

The mitochondrial fusion protein Mfn2 has been reported to show additional cellular functions. More specifically, changes in Mfn2 in nonmuscle and muscle cells modulate the capacity of cells to oxidize substrates (glucose, pyruvate, fatty acids), and in parallel modulate the expression of subunits of the OXPHOS system.

Recent evidence indicated that proteins participating in mitochondrial fusion or fission also participate in metabolism. The mitochondrial fusion protein mitofusin 2 (Mfn2) stimulates respiration, substrate oxidation and OXPHOS subunits expression in cultured cells. In this regard, skeletal muscle of obese subjects and of type 2 diabetic patients shows reduced Mfn2 expression. Therefore, alterations in the activity of proteins involved in mitochondrial dynamics, and particularly Mfn2, may participate in the reduced mitochondrial function present in skeletal muscle in obesity and type 2 diabetes. Mfn2 expression in skeletal muscle is subject to regulation and conditions characterized by reduced mitochondrial activity, such as obesity or type 2 diabetes, are associated with repressed Mfn2. In contrast, cold-exposure, treatment with b₃-adrenergic agonists or exercise induce the expression of this gene in muscle. ERRa transcription factor is a key regulator of Mfn2 transcription and recruits nuclear co-activators PGC-1b and PGC-1a. These two nuclear co-activators are potent positive regulators of Mfn2 expression in muscle cells, and ablation of PGC-1b causes Mfn2 down-regulation in skeletal muscle and in heart. We propose that PGC-1b is a regulator of normal expression of Mfn2 in muscle, whereas PGC-1a participates in the stimulation of Mfn2 expression under a variety of conditions characterized by enhanced energy expenditure.