Mitochondrial extracellular signal‐regulated kinases 1/2 (ERK1/2) are modulated during brain development

Abstract

Intracellular activation and trafficking of extracellular signalregulated protein kinases (ERK) play a significant role in cell cycle progression, contributing to developmental brain activities. Additionally, mitochondria participate in cell signalling through energy-linked functions, redox metabolism and activation of pro-or anti-apoptotic proteins. The purpose of the present study was to analyze the presence of ERK1/2 in mitochondria during rat brain development. Immunoblotting, immune electron microscopy and activity assays demonstrated that ERK1/2 are present in fully active brain mitochondria at the outer membrane/intermembrane space fraction. Besides, it was observed that ERK1/2 translocation to brain mitochondria follows a developmental pattern which is maximal between E19-P2 stages and afterwards declines at P3, just before maximal translocation to nucleus, and up to adulthood. Most of mitochondrial ERK1/2 were active; upstream phospho-MAPK/ERK kinases (MEK1/2) were also detected in the brain organelles. Mitochondrial phospho-ERK1/2 increased at 1 lM hydrogen peroxide (H 2 O 2 ) concentration, but it decreased at higher 50-100 lM H 2 O 2 , almost disappearing after the organelles were maximally stimulated to produce H 2 O 2 with antimycin. Our results suggest that developmental mitochondrial activation of ERK1/2 cascade contributes to its nuclear translocation effects, providing information about mitochondrial energetic and redox status to the proliferating/differentiating nuclear pathways. Keywords: development, extracellular signal-regulated kinases 1/2, hydrogen peroxide, MAPK/ ERK kinases 1/2, mitochondria, rat brain.

Dual effects of sodium tungstate on adipocyte biology: inhibition of adipogenesis and stimulation of cellular oxygen consumption

“…Increasing reports over the past few years suggest a direct regulation of mitochondrial activity by phosphorylation events in several cell types, in which some classical cytosolic kinases are found in mitochondria [32][33][34][35] acting on different subunits of the respiratory chain complexes. [36][37][38][39][40][41] We cannot exclude a direct regulation of mitochondrial activity by sodium tungstate.…”

The ERK Cascade: Distinct Functions within Various Subcellular Organelles

“…The decrease in mitochondrial ERK1/2 correlates with their increased nuclear translocation, providing information about mitochondrial energetic and redox status to the proliferating/differentiating cells. 140 In addition, phosphorylated ERK1/2 were found within a subset of mitochondria in degenerating neurons from patients with Parkinson disease and Lewy body dementia. 139 In the transformed Leydig-derived MA-10 cell line, presence of ERK1/2 in the mitochondria and their activation are obligatory for PKA-mediated steroidogenesis and thereby are probably associated with their oncogenic potential.…”

“…135,136 Additional cells in which ERK1/2 were identified in the mitochondria include murine cardiac myocytes, where the kinases are associated with enhanced Bad phosphorylation and cardioprotection, 137 and human alveolar macrophages, where ERK1/2 maintain mitochondrial membrane potential and M Monographs ATP production. 138 Finally, detailed immunoelectron microscopy studies have established the presence of phosphorylated ERK1/2 in the outer membrane and intermembrane space of brain mitochondria, 139,140 suggesting their role in multiple mitochondria functions.…”

6-Hydroxydopamine induces mitochondrial ERK activation

“…In addition to altered subcellular distributions of signaling proteins observed in PD neurons [20,21,29] normal mitochondrial functions for phosphoproteins traditionally thought of as nuclear regulators have begun to be elucidated [75]. Poderosos and colleagues have demonstrated the presence of mitochondrial ERK in the matrix, intermembrane space, and outer membrane of the rat CNS [39]. Interestingly, the levels of mitochondrial ERK peaked in the late in utero and early post natal periods, suggesting mitochondrial ERK may play a particularly important role in the developing nervous system.…”

“…Activated ERK has been identified in mitochondria in central nervous system tissue [39], including diseased neurons in patients with Parkinson's and Lewy Body Diseases [29]. We wished to characterize the effect of 6-OHDA on mitochondrial ERK.…”