This article shows that mitochondrial respiratory dysfunction activates a stress signaling that induces Akt1 activation. Akt1 activation occurs through calcineurin-mediated IGF1R/PI3-K pathway. Akt1-mediated phosphorylation of hnRNPA2 is a key requirement for the propagation of stress signaling and activation of nuclear target genes

Amuthan G.

Arnould T.

Babcock D. F.

Biswas G.

Brunet A.

Chen R.

Cho H.

Crimi M.

Datta S. R.

Deberardinis R. J.

Delsite R.

Dey R.

Garayoa M.

Guha M.

He Y.

Higuchi M.

Horton T. M.

Hu Y.

Huang W. C.

Jahangir Tafrechi R. S.

Ji-Kang Fang

Johnston D. S.

Kim J. Y.

Kondapaka S. B.

Kroemer G.

Kulawiec M.

Lawlor M. A.

Lee M. S.

Lee S. B.

Lievre A.

Linnartz B.

Loeb L. A.

Lowry O. H.

Manti Guha

Mazurek S.

Meierhofer D.

Moro L.

Morris J. Birnbaum

Narayan G. Avadhani

Okochi O.

Park J. S.

Park S.

Parrella P.

Patry C.

Pelicano H.

Petros J. A.

Plas D. R.

Robert Monks

Semenza G. L.

Shidara Y.

Singh K. K.

Summers S. A.

Taylor R. W.

Thai M. V.

Thomas D. Fox

Trotman L. C.

Vandermoere F.

Whiteman E. L.

Yamaoka K.

Yu M.

English

PubMed

Mitochondrial respiratory stress (also called mitochondrial retrograde signaling) activates a Ca2+/calcineurin-mediated signal that culminates in transcription activation/repression of a large number of nuclear genes. This signal is propagated through activation of the regulatory proteins NFκB c-Rel/p50, C/EBPδ, CREB, and NFAT. Additionally, the heterogeneous ribonucleoprotein A2 (hnRNPA2) functions as a coactivator in up-regulating the transcription of Cathepsin L, RyR1, and Glut-4, the target genes of stress signaling. Activation of IGF1R, which causes a metabolic switch to glycolysis, cell invasiveness, and resistance to apoptosis, is a phenotypic hallmark of C2C12 myoblasts subjected to mitochondrial stress. In this study, we report that mitochondrial stress leads to increased expression, activation, and nuclear localization of Akt1. Mitochondrial respiratory stress also activates Akt1-gene expression, which involves hnRNPA2 as a coactivator, indicating a complex interdependency of these two factors. Using Akt1−/−mouse embryonic fibroblasts and Akt1 mRNA-silenced C2C12 cells, we show that Akt1-mediated phosphorylation is crucial for the activation and recruitment of hnRNPA2 to the enhanceosome complex. Akt1 mRNA silencing in mtDNA-depleted cells resulted in reversal of the invasive phenotype, accompanied by sensitivity to apoptotic stimuli. These results show that Akt1 is an important regulator of the nuclear transcriptional response to mitochondrial stress.</jats:p

Crossref

Molecular Biology of the Cell

Activation of Akt Is Essential for the Propagation of Mitochondrial Respiratory Stress Signaling and Activation of the Transcriptional Coactivator Heterogeneous Ribonucleoprotein A2

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http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2954122

Activation of Akt Is Essential for the Propagation of Mitochondrial Respiratory Stress Signaling and Activation of the Transcriptional Coactivator Heterogeneous Ribonucleoprotein A2

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