Abstract
Previous studies have shown that extracellular signal-regulated kinase 1/2 (ERK1/2) directly inhibits mitochondrial function during cellular injury. We evaluated the role of ERK1/2 on the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) gene, a master regulator of mitochondrial function. The potent and specific MEK1/2 inhibitor trametinib rapidly blocked ERK1/2 phosphorylation, decreased cytosolic and nuclear FOXO3a/1 phosphorylation, and increased PGC-1α gene expression and its downstream mitochondrial biogenesis (MB) targets under physiological conditions in the kidney cortex and in primary renal cell cultures. The epidermal growth factor receptor (EGFR) inhibitor erlotinib blocked ERK1/2 phosphorylation and increased PGC-1α gene expression similar to treatment with trametinib, linking EGFR activation and FOXO3a/1 inactivation to the down-regulation of PGC-1α and MB through ERK1/2. Pretreatment with trametinib blocked early ERK1/2 phosphorylation following ischemia/reperfusion kidney injury and attenuated the down-regulation of PGC-1α and downstream target genes. These results demonstrate that ERK1/2 rapidly regulates mitochondrial function through a novel pathway, EGFR/ERK1/2/FOXO3a/1/PGC-1α, under physiological and pathological conditions. As such, ERK1/2 down-regulates mitochondrial function directly by phosphorylation of upstream regulators of PGC-1α and subsequently decreasing MB.
Highlights
Previous studies have shown that extracellular signal-regulated kinase 1/2 (ERK1/2) directly inhibits mitochondrial function during cellular injury
ERK1/2 Inhibition Increases Levels of PGC-1␣ and Downstream Targets of mitochondrial biogenesis (MB) mRNA in renal proximal tubular cells (RPTC)—To test the hypothesis that ERK1/2 regulates PGC-1␣ and MB at a physiological level, we utilized the pharmacological MEK1/2 inhibitor trametinib and primary cultures of rabbit RPTC
The increase in PGC-1␣ mRNA was linked to increased nuclear encoded mediators of MB and gene targets of PGC-1␣, including mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF1), and NADH dehydrogenase Fe-S protein 1 (NDUFS1) at 1, 4 and 24 h after trametinib treatment (Fig. 1, C–E). These results reveal that ERK1/2 represses PGC-1␣ mRNA expression and its downstream target genes under physiological conditions and that inhibition of ERK1/2 activation results in a rapid induction of PGC-1␣ mRNA and other downstream MB genes
Summary
Previous studies have shown that extracellular signal-regulated kinase 1/2 (ERK1/2) directly inhibits mitochondrial function during cellular injury. The potent and specific MEK1/2 inhibitor trametinib rapidly blocked ERK1/2 phosphorylation, decreased cytosolic and nuclear FOXO3a/1 phosphorylation, and increased PGC-1␣ gene expression and its downstream mitochondrial biogenesis (MB) targets under physiological conditions in the kidney cortex and in primary renal cell cultures. Pretreatment with trametinib blocked early ERK1/2 phosphorylation following ischemia/reperfusion kidney injury and attenuated the downregulation of PGC-1␣ and downstream target genes. These results demonstrate that ERK1/2 rapidly regulates mitochondrial function through a novel pathway, EGFR/ERK1/2/ FOXO3a/1/PGC-1␣, under physiological and pathological conditions. In renal proximal tubular cells (RPTC), phosphorylated ERK1/2 was shown to reduce mitochondrial respiration and ATP production by decreasing complex I electron transport chain activity in response to tert-butyl hydroperoxide (TBHP), a model oxidant [7].
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