Elevated Acetylation of MFN2 is Accompanied by the Disruption of Mitochondrial Energy Metabolism and Inflammation in a Mouse Model of Depression.

Abstract

Mitofusin-2 (MFN2) is recognized as an important regulator of mitochondrial function. The activity of MFN2 is increased by deacetylation, but while MFN2 levels have been reported to be increased in major depressive disorder, the relationship between acetylation status of MFN2, mitochondrial energy production, and inflammation in depression-like disease in rodents has not been studied. Here, we induced a depression-like syndrome in mice with a 14-day-long chronic restraint stress (CRS) model, and the levels of acetylated MFN2 and SIRT1 activity were measured. The interaction of MFN2 with complex I was identified by immunoprecipitation, and the levels of mitochondrial metabolites were measured by GC-MS. MFN2 levels were unaltered by CRS, but SIRT1 expression and activity were reduced in the CRS-exposed mice, and levels of acetylated MFN2 were significantly increased. CRS affected mitochondrial energy metabolism by reducing the expression and activity of complexes I-V, decreasing levels of NAD⁺ and ATP synthase, and diminishing ATP production. Thus, while the expression of Mfn2 was unchanged by CRS, the inhibition of MFN2 deacetylation, via loss of SIRT1 activity, was associated with impaired mitochondrial oxidative phosphorylation, increased oxidative stress markers, and increased levels of inflammatory markers under the control of the SIRT1 target NFκB. The results presented here highlight the profound influence of acetylation/deacetylation-mediated control associated with depression-like behaviors.