A form of mitofusin 2 (Mfn2) lacking the transmembrane domains and the COOH-terminal end stimulates metabolism in muscle and liver cells.
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 (ΔMfn2). This form localized in mitochondria but did not alter mitochondrial morphology in cells or in skeletal muscle fibers. The expression of ΔMfn2 in mouse skeletal muscle stimulated glucose oxidation and enhanced respiratory control ratio, which occurred in the absence of changes in mitochondrial mass. ΔMfn2 did not stimulate mitochondrial respiration in Mfn2-deficient muscle cells. The expression of ΔMfn2 in mouse liver or in hepatoma cells stimulated gluconeogenesis. In addition, ΔMfn2 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.
Institute for Research in Biomedicine (IRB Barcelona Barcelona, Spain;
Jessica
J
Segalés
José C
JC
Paz
María Isabel
MI
Hernández-Alvarez
David
D
Sala
Juan Pablo
JP
Muñoz
Eduard
E
Noguera
Sara
S
Pich
Manuel
M
Palacín
José Antonio
JA
Enríquez
Antonio
A
Zorzano
D000818:Animals; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000502:physiology*; D015870:Gene Expression; D057809:HEK293 Cells; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000201:enzymology / Q000502:physiology*; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000502:physiology*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000502:physiology*; D018482:Muscle, Skeletal / Q000201:enzymology*; D020033:Protein Isoforms / Q000737:chemistry / Q000502:physiology; D017434:Protein Structure, Tertiary; D051381:Rats
D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human
diabetes; mitochondrial dynamics; mitochondrial fusion; mitochondrial respiration