Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions
Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions
复制标题
DOI：
10.1074/jbc.m116.754762
复制
发表时间：
2016-12-23
影响因子：
4.8
通讯作者：
Schnellmann, Rick G.
中科院分区：
文献类型：
--
作者：
Collier, Justin B.;Whitaker, Ryan M.;Schnellmann, Rick G.
先前的研究表明，细胞外信号调节激酶1/2（ERK 1/2）直接抑制细胞损伤过程中的线粒体功能。我们评估了ERK 1/2对过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1 α）基因表达的作用，PGC-1 α基因是线粒体功能的主要调节因子。在肾皮质和原代肾细胞培养物的生理条件下，强效特异性MEK 1/2抑制剂曲美替尼可快速阻断ERK 1/2磷酸化，降低胞质和核FOXO 3a/1磷酸化，并增加PGC-1 α基因表达及其下游线粒体生物合成（MB）靶点。表皮生长因子受体（EGFR）抑制剂厄洛替尼阻断ERK 1/2磷酸化并增加PGC-1 α基因表达，与曲美替尼治疗相似，将EGFR激活和FOXO 3a/1失活与通过ERK 1/2下调PGC-1 α和MB联系起来。曲美替尼预处理阻断缺血/再灌注肾损伤后早期ERK 1/2磷酸化，并减弱PGC-1 α和下游靶基因的下调。这些结果表明，ERK 1/2通过一种新的途径，EGFR/ERK 1/2/FOXO 3a/1/PGC-1 α，在生理和病理条件下快速调节线粒体功能。因此，ERK 1/2通过PGC-1 α上游调节因子的磷酸化直接下调线粒体功能，随后降低MB。
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 gamma coactivator-1 alpha (PGC-1 alpha) 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-1 alpha 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-1 alpha gene expression similar to treatment with trametinib, linking EGFR activation and FOXO3a/1 inactivation to the down-regulation of PGC-1 alpha and MB through ERK1/2. Pretreatment with trametinib blocked early ERK1/2 phosphorylation following ischemia/reperfusion kidney injury and attenuated the downregulation of PGC-1 alpha 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 alpha, under physiological and pathological conditions. As such, ERK1/2 down-regulates mitochondrial function directly by phosphorylation of upstream regulators of PGC-1 alpha and subsequently decreasing MB.