ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: Implications for Parkinson's disease

Kent Z.Q. Wang; Jianhui Zhu; Ruben K. Dagda; Guy Uechi; Salvatore J. Cherra; Aaron M. Gusdon; Manimalha Balasubramani; Charleen T. Chu

doi:10.1016/j.mito.2014.04.008

ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: Implications for Parkinson's disease

Kent Z.Q. Wang, Jianhui Zhu, Ruben K. Dagda, Guy Uechi, Salvatore J. Cherra, Aaron M. Gusdon, Manimalha Balasubramani, Charleen T. Chu

Neuroscience

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	132-140
Number of pages	9
Journal	Mitochondrion
Volume	17
DOIs	https://doi.org/10.1016/j.mito.2014.04.008
State	Published - Jul 2014

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health ( R01 AG026389, R01 NS065789 and K18 DC009120 ). The Genomics and Proteomics Core Laboratories and Biomedical Mass Spectrometry Center were supported in part by UL1 RR024153, UL1 TR000005 and P30 CA047904. The funding agencies were not involved in the study design, collection and interpretation of the data, writing of the report, or the decision to submit for publication.

Keywords

MAP kinases
Mitochondrial biogenesis
MtDNA
Parkinson disease
Phosphorylation

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Cell Biology

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10.1016/j.mito.2014.04.008

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abstract = "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.",

keywords = "MAP kinases, Mitochondrial biogenesis, MtDNA, Parkinson disease, Phosphorylation",

author = "Wang, {Kent Z.Q.} and Jianhui Zhu and Dagda, {Ruben K.} and Guy Uechi and Cherra, {Salvatore J.} and Gusdon, {Aaron M.} and Manimalha Balasubramani and Chu, {Charleen T.}",

note = "Funding Information: This work was supported by the National Institutes of Health ( R01 AG026389, R01 NS065789 and K18 DC009120 ). The Genomics and Proteomics Core Laboratories and Biomedical Mass Spectrometry Center were supported in part by UL1 RR024153, UL1 TR000005 and P30 CA047904. The funding agencies were not involved in the study design, collection and interpretation of the data, writing of the report, or the decision to submit for publication.",

year = "2014",

month = jul,

doi = "10.1016/j.mito.2014.04.008",

language = "English",

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T2 - Implications for Parkinson's disease

AU - Wang, Kent Z.Q.

AU - Zhu, Jianhui

AU - Dagda, Ruben K.

AU - Uechi, Guy

AU - Cherra, Salvatore J.

AU - Gusdon, Aaron M.

AU - Balasubramani, Manimalha

AU - Chu, Charleen T.

N1 - Funding Information: This work was supported by the National Institutes of Health ( R01 AG026389, R01 NS065789 and K18 DC009120 ). The Genomics and Proteomics Core Laboratories and Biomedical Mass Spectrometry Center were supported in part by UL1 RR024153, UL1 TR000005 and P30 CA047904. The funding agencies were not involved in the study design, collection and interpretation of the data, writing of the report, or the decision to submit for publication.

PY - 2014/7

Y1 - 2014/7

N2 - 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.

AB - 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.

KW - MAP kinases

KW - Mitochondrial biogenesis

KW - MtDNA

KW - Parkinson disease

KW - Phosphorylation

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JO - Mitochondrion

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ER -

ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: Implications for Parkinson's disease

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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