Mitofusin-2 (MFN2) is a critical regulator of metabolic homeostasis in neuronal cells: A metabolomic and proteomic study

Abstract

The role of mitofusin 2 (Mfn2) in mitochondrial metabolism and neurodegeneration is largely unknown. The current study probes the role of Mfn2 in mitochondrial biogenesis and metabolism in SH-SY5Y neuronal cells using multi-omics strategies. Mfn2 knockdown (KD) by siRNA treatment resulted into diverse proteomic and metabolomic changes. Furthermore, a battery of cellular and molecular analyses associated Mfn2-KD with increased oxidative stress, perturbed mitochondrial membrane potential and reduced mtDNA copy numbers in the neuronal cells. In addition, Mfn2-KD induced dramatic alterations in cell cycle profiles inclusive of proliferation and apoptosis. SWATH-MS-based analysis showed downregulation and upregulation of 11 and 22 differentially expressed proteins (DEPs), respectively, that serve in ribosomal biogenesis, translation, apoptosis, aging, TCA, and OXPHOS metabolic pathways. Among these proteins, TARBP emerged as a hub protein. 1H NMR-based metabolomic analysis showed alterations in 7 metabolites in the Mfn2-KD cells, which were associated with mitochondrial metabolism. Among these metabolites, taurine, a neuromodulator, was significantly downregulated after Mfn2-KD. Interestingly, supplementation of taurine restored the Mfn2-KD-induced deleterious alterations in mitochondrial physiology and cellular metabolomics in the neuronal cells. These results suggest the vital role of Mfn2 in mitochondrial functions in neuronal cells, and taurine emerges as a potential metabolite in Mfn2-linked mitochondrial dysfunction.