A form of mitofusin 2 (Mfn2) lacking the transmembrane domains and the COOH-terminal end stimulates metabolism in muscle and liver cells

Abstract

A form of mitofusin 2 (Mfn2) lacking the transmembrane domains and the COOH-terminal end stimulates metabolism in muscle and liver cells. Am J Physiol Endocrinol Metab 305: E1208 -E1221, 2013. First published August 13, 2013; doi:10.1152/ajpendo.00546.2012.-Mitofusin 2 (Mfn2), a protein that participates in mitochondrial fusion, is required to maintain normal mitochondrial metabolism in skeletal muscle and liver. Given that muscle Mfn2 is repressed in obese or type 2 diabetic subjects, this protein may have a potential pathophysiological role in these conditions. To evaluate whether the metabolic effects of Mfn2 can be dissociated from its function in mitochondrial dynamics, we studied a form of human Mfn2, lacking the two transmembrane domains and the COOH-terminal coiled coil (⌬Mfn2). This form localized in mitochondria but did not alter mitochondrial morphology in cells or in skeletal muscle fibers. The expression of ⌬Mfn2 in mouse skeletal muscle stimulated glucose oxidation and enhanced respiratory control ratio, which occurred in the absence of changes in mitochondrial mass. ⌬Mfn2 did not stimulate mitochondrial respiration in Mfn2-deficient muscle cells. The expression of ⌬Mfn2 in mouse liver or in hepatoma cells stimulated gluconeogenesis. In addition, ⌬Mfn2 activated basal and maximal respiration both in muscle and liver cells. In all, we show that a form of Mfn2 lacking mitochondrial fusion activity stimulates mitochondrial function and enhances glucose metabolism in muscle and liver tissues. This study suggests that Mfn2 regulates metabolism independently of changes in mitochondrial morphology. mitochondrial dynamics; diabetes; mitochondrial respiration; mitochondrial fusion MITOCHONDRIAL MORPHOLOGY, response to apoptotic stimuli, mitochondrial metabolism, and mitochondrial quality control are all, in part, controlled through the balance between mitochondrial fusion and fission (33,47). Mitochondrial fusion in mammalian cells is controlled by mitofusin 1 and 2 (Mfn1, Mfn2) proteins and by OPA1. Mfn1 and Mfn2 explain outer mitochondrial membrane fusion, while OPA1 is responsible for inner mitochondrial membrane fusion. Mfn2 is an outer mitochondrial membrane protein of 757 residues in humans. The COOH-terminal part of the protein contains the transmembrane domains (residues 615-648 aa) and the coiled-coil 2 domain (HR2, residues 693-747 aa). The HR2 domain permits the tethering of Mfn2 with either Mfn2 or Mfn1 located in a neighboring mitochondrion (29). In addition to its participation in mitochondrial fusion, Mfn2 is also localized in endoplasmic reticulum (ER) mitochondrial contact sites and regulates the tethering of the ER to mitochondria and calcium homeostasis in mouse embryo fibroblasts (15). Thus, Mfn2 has pleiotropic cellular roles and regulates cell proliferation, oxidative metabolism, autophagy, and mitochondrial antiviral signaling protein (4, 13, 22, 37, 51). It has also been recently documented that ablation of Mfn1 and Mfn2 causes mitochondrial DNA depletion, an observation that indicat...

Mitofusin 2 Deficiency Affects Energy Metabolism and Mitochondrial Biogenesis in MEF Cells

“…In contrast to aforementioned data it has been shown here that MEF cells with deleted Mfn2 gene exhibit substantially faster oxygen consumption than control fibroblasts. The interesting effects were observed by Segales et al (2013) [ 28 ], who found increased routine (basal) but not maximal oxygen consumption in myotubes and hepatoma FAO cells with silenced Mfn2 gene. However, this effect was attributed to increased oligomycin-insensitive proton leak.…”

“…Similar stability of the ATP content was found in muscle cells depleted of Mfn2 gene. However, in those study oxidative metabolism was substantially reduced [ 26 , 28 ]. Moreover, recently Son et al (2015) have shown that in MEF cells Mfn1/2 depletion facilitates the glycolytic metabolic transition through the activation of the Ras-Raf and hypoxia-inducible factor 1α (HIF1α) signaling at an early stage of reprogramming [ 30 ].…”

Three‐dimensional reconstruction of the human skeletal muscle mitochondrial network as a tool to assess mitochondrial content and structural organization

“…A recent study shows that transgenic expression of a short form of Mfn2, which has no effect on mitochondrial morphology, stimulates glucose oxidation in skeletal muscle, and gluconeogenesis in liver, and enhances mitochondrial respiration in muscle and liver cells (Segales et al . ). Our results show that both type I and type II muscle fibres have profusion mitochondrial networks, with the diameter of the tubes and the fractional volume being larger in type I muscle fibres (Fig.…”

“…() reported that Mfn2 deficiency leads to fragmented mitochondria and impairs insulin signalling in liver and muscle; however, as discussed above, the same group (Segales et al . ) has recently shown that Mfn2 has an effect on glucose metabolism regardless of mitochondrial morphology. Therefore, future studies investigating mitochondrial network structural organization and dynamics in high resolution are needed to investigate the effect of mitochondrial dynamics on cell metabolism and the spatial organization of the key players on/in the mitochondrial network.…”

Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

“…Although Mfn2 is mostly known for its role in mitochondrial fusion, it also activates mitochondrial metabolism and increases the RC expression (Pich et al 2005). Specifically, mfn2 loss in skeletal muscle was characterized by reduced RC expression level and activity and impaired respiratory function (Segalés et al 2013). A loss of Kdm5a in Rb1 −/− MEFs resulted in a significant shift from glycolytic to oxidative metabolism.…”