Antioxidants modulate mitochondrial PKA and increase CREB binding to D-loop DNA of the mitochondrial genome in neurons

Hoon Ryu, Junghee Lee, Soren Impey, Rajiv R. Ratan, Robert J. Ferrante

Research output: Contribution to journalArticle

115 Scopus citations

Abstract

The protein kinase A (PKA) and the cAMP response element (CRE) binding protein (CREB) signaling pathways mediate plasticity and prosurvival responses in neurons through their ability to regulate gene expression. The PKA-CREB signaling mechanism has been well characterized in terms of nuclear gene expression. We show that the PKA catalytic and regulatory subunits and CREB are localized to the mitochondrial matrix of neurons. Mitochondrial CRE sites were identified by using both serial analyses of chromatin occupancy and chromatin immunoprecipitation. Deferoxamine (DFO), an antioxidant and iron chelator known to inhibit oxidative stress-induced death, activated mitochondrial PKA and increased mitochondrial CREB phosphorylation (Ser-133). DFO increased CREB binding to CRE in the mitochondrial D-loop DNA and D-loop CRE-driven luciferase activity. In contrast, KT5720, a specific inhibitor of PKA, reduced DFO-mediated neuronal survival against oxidative stress induced by glutathione depletion. Neuronal survival by DFO may be, in part, mediated by the mitochondrial PKA-dependent pathway. These results suggest that the regulation of mitochondrial function via the mitochondrial PKA and CREB pathways may underlie some of the salutary effects of DFO in neurons.

Original languageEnglish (US)
Pages (from-to)13915-13920
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number39
DOIs
StatePublished - Sep 27 2005

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