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

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

Mariana Alonso; Mariana Melani; Daniela Converso; Ariel Jaitovich; Cristina Paz; M. Cecilia Carreras; Jorge H. Medina; Juan J. Poderoso

2006

Scholarcy highlights

  • Intracellular activation and trafficking of extracellular signal-regulated protein kinases play a significant role in cell cycle progression, contributing to developmental brain activities
  • To confirm the purity of the mitochondrial fraction, immunoblots were carried out in the rat brain subcellular fractions obtained at E17, E19, P2, P3 and adult with specific antibodies against synaptic membrane proteins, such as the metabotropic glutamate receptor type 1. mGluR1 was early detected in cytosol, synaptosomes and nucleus but it was absent in the mitochondrial fraction at any developmental stage; another synaptic protein, the GluR2 AMPA receptor subunit, was not detected in the mitochondrial fraction
  • Assessment of brain mitochondrial fraction identity and purity. Western blot using an antibody against receptor mGluR1 in the brain subcellular fractions obtained at different developmental stages, post-natal days 2 and 3 and adults. Lactate dehydrogenase activity was monitored spectrophotometrically in brain subcellular fractions at the same ages through oxidation of NADH at 340 nm. NADH-cytochrome c reductase activity was followed through reduction of cytochrome c at 550 nm. Data are expressed as mean ± SEM of three independent experiments
  • Our results show for the first time that: ERK1/2 subfamily of MAPK is localized in rat brain mitochondria; this finding confirms and extends a recent finding demonstrating the presence of mitochondrial ERK localization in murine heart; ERK1/2 are confined to the fraction containing the mitochondrial outer membrane and the intermembrane space; ERK1/2 protein expression, traffic to mitochondria and activity are under developmental modulation
  • The present results propose a similar process involving the mitochondrial compartment considering that: in the mitochondrial transit, ERK1/2 were predominantly found as phospho-ERK; mitochondria are targeted by upstream members of the ERK1/2 cascade like MEK1/2 and Raf-1, supporting the existence of a complete sequence for ERK1/2 activation in mitochondria; in accordance, we found activated phospho-MEK1/2 in the brain organelles
  • The activity of cytosolic lactate dehydrogenase was less than 5% in the mitochondrial fraction
  • Some adapters or scaffolding proteins which favour MAPK interactions like Grb 10 are localized in mitochondria, while others like 14.3.3 proteins are probably not, though they may contribute to mitochondrial protein import
  • In this study, mitochondrial ERK1/2 are subjected to modulatory effects of H2O2; preliminary data of our group, indicating that both phospho-ERK1/2 and phospho-MEK1/2 levels could be under redox influence in brain mitochondria

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