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

• Published in: Biochimica et biophysica acta Vol. 1820; no. 5; pp. 577 - 585
• Main Authors: Piao, Ying, Kim, Hyo Geun, Oh, Myung Sook, Pak, Youngmi Kim
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2012
• Subjects: 1-Methyl-4-phenylpyridinium - toxicity; Animals; Apoptosis; Blotting, Western; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Corpus Striatum - drug effects; Corpus Striatum - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; electron transport chain; Female; genes; Herbicides - toxicity; Humans; insulin; insulin resistance; Insulin signaling; Male; metabolic syndrome; metabolites; Mice; Mice, Inbred C57BL; mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial dysfunction; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mouse; MPP; Neuroblastoma - drug therapy; Neuroblastoma - metabolism; Neuroblastoma - pathology; neurons; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; NF-E2-Related Factor 1 - genetics; NF-E2-Related Factor 1 - metabolism; Parkinson disease; patients; phosphorylation; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; SH-SY5Y; Signal Transduction; Substantia Nigra - drug effects; Substantia Nigra - metabolism; transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; transfection; Tyrosine 3-Monooxygenase - metabolism; ST; SH-SY5Y; Mitochondrial dysfunction; CM; DN; MPP; CMAPS; TH; Mouse; NRF-1; TFAM; MPTP; SN; SDM; Insulin signaling
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2011.08.007

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. 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. Mitochondrial activation by TFAM, NRF-1, and myr-AKT abrogated MPP+-mediated damages on mitochondria and insulin signaling, leading to recovery of nigrostriatal neurodegeneration. 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. ► 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.