Antioxidants modulate mitochondrial PKA and increase CREB binding to D-loop DNA of the mitochondrial genome in neurons.
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.
Ryu
Hoon
H
Geriatric Research Education and Clinical Center, Veteran's Affairs Medical Center, Bedford, MA 01730, USA. hoonryu@bu.edu
Lee
Junghee
J
Impey
Soren
S
Ratan
Rajiv R
RR
Ferrante
Robert J
RJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D020134:Catalytic Domain; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000032:analysis / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D021122:Protein Subunits / Q000032:analysis / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction
D000975:Antioxidants; D002227:Carbazoles; D017362:Cyclic AMP Response Element-Binding Protein; D004272:DNA, Mitochondrial; D007211:Indoles; D021122:Protein Subunits; D011758:Pyrroles; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases; D003676:Deferoxamine