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

BackgroundMitochondrial 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 resultsUsing 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.ConclusionsMitochondrial activation by TFAM, NRF-1, and myr-AKT abrogated MPP+-mediated damages on mitochondria and insulin signaling, leading to recovery of nigrostriatal neurodegeneration.General significanceWe 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.

► MPP+ impaired mitochondrial activity and Akt signaling in neuronal cells. ► Overexpression of TFAM, NRF-1, and myr-AKT ameliorated the MPP+-induced damages. ► They may be critical targets for therapeutic intervention of parkinsonism.