ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: implications for Parkinson's disease.
Mitochondrial transcription factor A (TFAM) regulates mitochondrial biogenesis, which is downregulated by extracellular signal-regulated protein kinases (ERK1/2) in cells treated chronically with the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+). We utilized mass spectrometry to identify ERK1/2-dependent TFAM phosphorylation sites. Mutation of TFAM at serine 177 to mimic phosphorylation recapitulated the effects of MPP+ in decreasing the binding of TFAM to the light strand promoter, suppressing mitochondrial transcription. Mutant TFAM was unable to affect respiratory function or rescue the effects of MPP+ on respiratory complexes. These data disclose a novel mechanism by which ERK1/2 regulates mitochondrial function through direct phosphorylation of TFAM.
Department of Pathology, Division of Neuropathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Kent Z Q
KZ
Wang
Department of Pathology, Division of Neuropathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Jianhui
J
Zhu
Department of Pathology, Division of Neuropathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Ruben K
RK
Dagda
The Genomics and Proteomics Core Laboratories, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Guy
G
Uechi
Department of Pathology, Division of Neuropathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Salvatore J
SJ
Cherra
Department of Pathology, Division of Neuropathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Aaron M
AM
Gusdon
The Genomics and Proteomics Core Laboratories, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Manimalha
M
Balasubramani
Department of Pathology, Division of Neuropathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; The Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA; The Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA. Electronic address: ctc4@pitt.edu.
Charleen T
CT
Chu
D004268:DNA-Binding Proteins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D013058:Mass Spectrometry; D008928:Mitochondria / Q000737:chemistry / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000503:physiopathology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C499631:TFAM protein, human; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases
MAP kinases; Mitochondrial biogenesis; Parkinson disease; Phosphorylation; mtDNA