Structure, function, and regulation of mitofusin-2 in health and disease

Abstract

Mitochondria are highly dynamic organelles that constantly migrate, fuse, and divide to regulate their shape, size, number, and bioenergetic function. Mitofusins (Mfn1/2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (Drp1), are key regulators of mitochondrial fusion and fission. Mutations in these molecules are associated with severe neurodegenerative and non-neurological diseases pointing to the importance of functional mitochondrial dynamics in normal cell physiology. In recent years, significant progress has been made in our understanding of mitochondrial dynamics, which has raised interest in defining the physiological roles of key regulators of fusion and fission and led to the identification of additional functions of Mfn2 in mitochondrial metabolism, cell signalling, and apoptosis. In this review, we summarize the current knowledge of the structural and functional properties of Mfn2 as well as its regulation in different tissues, and also discuss the consequences of aberrant Mfn2 expression.

Keywords: Charcot-Marie-Tooth disease; diabetes; mitochondria; mitochondrial dynamics; mitofusin-1; mitofusin-2; neurodegenerative disease; obesity; vascular disease.

Figure 1

Mitochondrial dynamics. (A) Mitochondrial fusion is a two‐step process that requires fusion of both outer (OM) and inner (IM) mitochondrial membranes mediated by mitofusins Mfn1/2 and optic atrophy 1 (OPA1), respectively. (B) Mitochondrial fission involves recruitment of dynamin‐related protein 1 (Drp1) by mitochondrial fission factor (Mff) and mitochondrial dynamics proteins (MiDs), followed by constriction of Drp1 on the outer mitochondrial membrane. Recent evidence has demonstrated that following partial constriction by Drp1, dynamin 2 mediates the final constriction of the mitochondrial membrane to achieve fission (Lee et al., 2016) (not shown in figure).

Figure 2

The functional domains of mitofusin‐2 (Mfn2). (A) The GTPase domains consists of five G motifs (G1–G5) shown in yellow. Heptad repeat (HR) coiled‐coil regions 1 and 2 are shown in green and red, respectively. The transmembrane (TM) domain is shown in black. (B) Mfn2 interacts in trans forming either homotypic or heterotypic (with Mfn1) dimers to produce mitochondrial tethering that precedes mitochondrial fusion.

Figure 3

Mitofusin‐2 (Mfn2) regulatory pathway. Peroxisome proliferator‐activated receptor gamma coactivator 1α (PGC‐1α) and PGC‐1β are positive regulators of Mfn2 activity. Mfn2 is induced by PGC‐1α in response to exercise, cold exposure or β3 adrenergic agonists, whereas under basal conditions PGC‐1β activates Mfn2. This involves activation of the Mfn2 promoter through an estrogen‐related receptor α (ERRα)‐binding element.

Figure 4

Diseases associated with mitofusin‐2 (Mfn2). Aberrant Mfn2 expression and function affects peripheral motor neurons, skeletal muscles and vascular smooth muscles leading to neurodegenerative diseases such as Charcot–Marie–Tooth type 2A (CMT2A), Alzheimer's (AD), Parkinson's (PD), and Huntington's (HD), as well as non‐neurological diseases.