Overexpression of TFAM, NRF-1 and myr-AKT protects the MPP(+)-induced mitochondrial dysfunctions in neuronal cells.

BACKGROUND Mitochondrial dysfunction is a prominent feature of neurodegenerative diseases including Parkinson's disease (PD), in which insulin signaling pathway may also be implicated because 50-80% of PD patients exhibited metabolic syndrome and insulin resistance. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its toxic metabolite, 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPP(+)), inhibit complex I in mitochondrial respiratory chain and are used widely to construct the PD models. But the precise molecular link between mitochondrial damage and insulin signaling remains unclear. METHODS AND RESULTS Using cell-based mitochondrial activity profiling system, we systemically demonstrated that MPP(+) suppressed mitochondrial activity and mitochondrial gene expressions mediated by nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (TFAM) in SH-SY5Y cells. MPP(+) fragmented mitochondrial networks and repressed phosphorylation of AKT. Similarly, the expressions of mitochondrial genes and tyrosine hydroxylase and AKT phosphorylation were reduced in substantia nigra and striatum of MPTP-injected mice. Transient transfection of TFAM, NRF-1, or myr-AKT reversed all aspects of the MPP(+)-mediated changes. CONCLUSIONS Mitochondrial activation by TFAM, NRF-1, and myr-AKT abrogated MPP(+)-mediated damages on mitochondria and insulin signaling, leading to recovery of nigrostriatal neurodegeneration. GENERAL SIGNIFICANCE We suggest that TFAM, NRF-1, and AKT may be the critical points of therapeutic intervention for PD. This article is part of a Special Issue entitled Biochemistry of Mitochondria.