The Charcot–Marie–Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system

Abstract

Mitofusin-2 (Mfn2) is a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells and mutations in the Mfn2 gene cause Charcot-Marie-Tooth neuropathy type 2A. Here, we show that Mfn2 loss-of-function inhibits pyruvate, glucose and fatty acid oxidation and reduces mitochondrial membrane potential, whereas Mfn2 gain-of-function increases glucose oxidation and mitochondrial membrane potential. As to the mechanisms involved, we have found that Mfn2 loss-of-function represses nuclear-encoded subunits of OXPHOS complexes I, II, III and V, whereas Mfn2 overexpression induced the subunits of complexes I, IV and V. Obesity-induced Mfn2 deficiency in rat skeletal muscle was also associated with a decrease in the subunits of complexes I, II, III and V. In addition, the effect of Mfn2 overexpression on mitochondrial metabolism was mimicked by a truncated Mfn2 mutant that is inactive as a mitochondrial fusion protein. Our results indicate that Mfn2 triggers mitochondrial energization, at least in part, by regulating OXPHOS expression through signals that are independent of its role as a mitochondrial fusion protein.

Mitochondrial dynamics in the regulation of neuronal cell death

“…Mfn2 can also interact directly with Ced9 or BclxL in HEK293 cells suggesting a mechanism for crosstalk with antiapoptotic Bcl family proteins [71]. Mfn2 has been shown to modulate metabolism [104,105] and cell cycle [106]. We therefore suggest that Mfn2, unlike Mfn1, may be able to provide additional protection against neuronal apoptosis through mitochondrial fusion independent mechanism, such as metabolic and cell cycle control (Fig.…”

“…Mfn2 control of metabolism is not dependent on mitochondrial fusion, since expression of a truncated form of Mfn2 that is localized in cytoplasm can still increase mitochondrial respiration. This suggests that mitochondrial fusion and metabolic control by Mfn2 can be dissociated [105]. Mfn2 controls metabolic rate by increasing the expression of the oxidative phosphorylation proteins, however, the exact mechanism remains to be elucidated.…”

Genes involved in mitochondrial biogenesis/function are induced in response to bilio-pancreatic diversion in morbidly obese individuals with normal glucose tolerance but not in type 2 diabetic patients

“…Mitofusin-2 (MFN2) is a mitochondrial fusion protein that regulates mitochondrial metabolism [19,20]. MFN2 loss of function reduces glucose oxidation and mitochondrial membrane potential in muscle and non-muscle cells [19,20].…”

“…In the present study, we aimed to determine whether the expression of genes involved in mitochondrial biogenesis/function was induced in response to BPD. To this end we selected: (1) nuclear genes that regulate mitochondrial biogenesis such as PGC-1α (also known as PPARGC1A), PGC-1β (also known as PPARGC1B) and PPARδ (also known as PPARD); (2) genes that regulate mitochondrial metabolism and fusion such as MFN2 [19,20]; (3) genes that regulate peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1α) such as SIRT1 [21,22]; and (4) genes that encode for constitutive proteins such as porin or citrate synthase.…”

Mitochondria and cancer: is there a morphological connection?

“…Importantly, the respiration defect turns out to be reversible upon reintroduction of the wild-type fusion proteins. Another recent study reports that downregulation of Mfn2 in L6E9 myotubes reduces both the activity of the TCA and the ETC, while it enhances glucose transport, glycolysis and lactic fermentation (Pich et al, 2005). Conversely, the overexpression of Mfn2 stimulates OXPHOS activity, suggesting that its role is not limited to the control of organelle shape.…”