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.

ER membranes exhibit phase behavior at sites of organelle contact

“…Mfn1 and Mfn2 are mitochondrial outer membrane tethering proteins that are essential for mitochondrial fusion. Since Mfn2 has been shown to also localize to the ER, it has been proposed that it serves an additional role in ER-mitochondria tethering 22,28 . The mitofusins are enriched in cells at inter-mitochondrial contact sites through homotypic (Mfn1-Mfn1) or heterotypic (Mfn1-Mfn2) interactions 22,49,50 .…”

“…Contact sites represent only a small proportion of the overall surface area of an organelle, but they serve several fundamental functions, including being the sites of inter-organelle exchange of lipids, ions, ROS and other small molecules [17][18][19][20][21] . Contact sites also play an important role in organelle inheritance and fission 17,[20][21][22][23][24][25][26][27][28] . Even though known tethering, effector, and regulatory proteins involved in contact site organization have been uncovered, how contact sites assemble and whether they exhibit selforganizational properties of lipids and proteins is unclear 17 .…”

Mitofusin 2 regulates neutrophil adhesive migration and the actin cytoskeleton

“…Currently, over 100 dominant mutations in the MFN2 gene have been reported in CMT2A patients though how these mutations lead to disease is still largely unknown. The challenges in MFN2 research are that MFN2 regulates mitochondrial fusion and a plethora of cellular functions such as mitochondrial dynamics, transport, mtDNA stability, lipid metabolism and survival (Chandhok et al, 2018). In addition, gain-of-function and loss-of-function mutations are reported that affect different aspects of cellular functions (Chandhok et al, 2018).…”

Mitochondria could be a potential key mediator linking the intestinal microbiota to depression

“…29 Mitochondrial fusion is the merging of two mitochondria to form one functional entity, while mitochondrial fission refers to its division into two. 30 Fission is increased under nutrient rich conditions as well as with dying cells. A threestep process that includes organelle approximation, mitochondrial outmembrane tethering/fusion, and IMM fusion under control of mitofusion 1, 2 (Mfn1 and Mfn2), and dynamin-related GTPases.…”