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

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.

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

“…Phosphorylated/active Erk was also increased in mitochondria of mutant cells. Recently, Erk was shown to phosphorylate and activate Drp1 resulting in increased mitochondrial fission [34], and to directly phosphorylate Tfam downregulating mitochondrial transcription [37].…”

“…While Akt was described to promote enhanced mitochondrial function, Erk1/2 might conduce an opposite effect [e.g. [34][35][36][37].…”

Mitochondrial pathways to cardiac recovery: TFAM

“…Extracellular signal-related kinase activation (ERK 1, 2) regulates mt function through direct phosphorylation of TFAM resulting in suppression of mt transcription [167]. TFAM phosphorylation impairs DNA binding and promotes degradation by Lon protease [81].…”

Development of Therapeutics That Induce Mitochondrial Biogenesis for the Treatment of Acute and Chronic Degenerative Diseases

“…215 Additionally, in models of Parkinson disease ERK1/2 activation leads to phosphorylation of TFAM, impairing its ability to bind to mitochondrial DNA. 216 MEK1/2 inhibitors, such as 29 and 30 , have been developed for cancer chemotherapy. In vitro models of renal oxidative stress indicate that ERK1/2 is a mediator of oxidative damage in proximal tubule cells, and that its inhibition by 29 prevents oxidative damage.…”