title: Overexpression of TFAM, NRF-1 and myr-AKT protects the MPP(+)-induced mitochondrial dysfunctions in neuronal cells.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neuroscience, Neurodegeneration Control Research Center, South Korea.
authors.forename: Ying
authors.initials: Y
authors.lastname: Piao
authors.forename: Hyo Geun
authors.initials: HG
authors.lastname: Kim
authors.forename: Myung Sook
authors.initials: MS
authors.lastname: Oh
authors.forename: Youngmi Kim
authors.initials: YK
authors.lastname: Pak
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006540:Herbicides / Q000633:toxicity; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D051265:NF-E2-Related Factor 1 / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006540:Herbicides; D024101:Mitochondrial Proteins; D051265:NF-E2-Related Factor 1; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C499631:TFAM protein, human; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D051057:Proto-Oncogene Proteins c-akt; D015655:1-Methyl-4-phenylpyridinium