Antioxidants Modulate Mitochondrial PKA and Increase CREB Binding to D-loop DNA of the Mitochondrial Genome in Neurons

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Sep 20

PMID 16169904

Citations 81

Authors

Hoon Ryu

Junghee Lee

Soren Impey

Rajiv R Ratan

Robert J Ferrante

Affiliations

Soon will be listed here.

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.

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References

Bevilaqua L, Cammarota M, Paratcha G, de Stein M, Izquierdo I, Medina J . Experience-dependent increase in cAMP-responsive element binding protein in synaptic and nonsynaptic mitochondria of the rat hippocampus. Eur J Neurosci. 1999; 11(10):3753-6. DOI: 10.1046/j.1460-9568.1999.00830.x. View

Harada H, Becknell B, Wilm M, Mann M, Huang L, Taylor S . Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell. 1999; 3(4):413-22. DOI: 10.1016/s1097-2765(00)80469-4. View

Mayr B, Montminy M . Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol. 2001; 2(8):599-609. DOI: 10.1038/35085068. View

Reynolds I . Mitochondrial membrane potential and the permeability transition in excitotoxicity. Ann N Y Acad Sci. 2000; 893:33-41. DOI: 10.1111/j.1749-6632.1999.tb07816.x. View

Zaragoza A, Diez-Fernandez C, Alvarez A, Andres D, Cascales M . Mitochondrial involvement in cocaine-treated rat hepatocytes: effect of N-acetylcysteine and deferoxamine. Br J Pharmacol. 2001; 132(5):1063-70. PMC: 1572648. DOI: 10.1038/sj.bjp.0703909. View

Suzuki T, Usuda N, Ishiguro H, Mitake S, Nagatsu T, Okumura-Noji K . Occurrence of a transcription factor, cAMP response element-binding protein (CREB), in the postsynaptic sites of the brain. Brain Res Mol Brain Res. 1998; 61(1-2):69-77. DOI: 10.1016/s0169-328x(98)00199-5. View

Kroemer G, Dallaporta B, Resche-Rigon M . The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol. 1998; 60:619-42. DOI: 10.1146/annurev.physiol.60.1.619. View

Borthwick G, Johnson M, Ince P, Shaw P, Turnbull D . Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol. 1999; 46(5):787-90. DOI: 10.1002/1531-8249(199911)46:5<787::aid-ana17>3.0.co;2-8. View

Alam T, Kanki T, Muta T, Ukaji K, Abe Y, Nakayama H . Human mitochondrial DNA is packaged with TFAM. Nucleic Acids Res. 2003; 31(6):1640-5. PMC: 152855. DOI: 10.1093/nar/gkg251. View

10.

Green D, Reed J . Mitochondria and apoptosis. Science. 1998; 281(5381):1309-12. DOI: 10.1126/science.281.5381.1309. View

11.

Chandrasekaran K, Giordano T, Brady D, Stoll J, Martin L, Rapoport S . Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease. Brain Res Mol Brain Res. 1994; 24(1-4):336-40. DOI: 10.1016/0169-328x(94)90147-3. View

12.

Nantel F, Monaco L, Foulkes N, Masquilier D, Lemeur M, Henriksen K . Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice. Nature. 1996; 380(6570):159-62. DOI: 10.1038/380159a0. View

13.

Impey S, McCorkle S, Cha-Molstad H, Dwyer J, Yochum G, Boss J . Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell. 2004; 119(7):1041-54. DOI: 10.1016/j.cell.2004.10.032. View

14.

Schindler C, Fu X, Improta T, Aebersold R, Darnell Jr J . Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc Natl Acad Sci U S A. 1992; 89(16):7836-9. PMC: 49806. DOI: 10.1073/pnas.89.16.7836. View

15.

Blendy J, Kaestner K, Weinbauer G, Nieschlag E, Schutz G . Severe impairment of spermatogenesis in mice lacking the CREM gene. Nature. 1996; 380(6570):162-5. DOI: 10.1038/380162a0. View

16.

Sardanelli A, Technikova-Dobrova Z, Scacco S, Speranza F, Papa S . Characterization of proteins phosphorylated by the cAMP-dependent protein kinase of bovine heart mitochondria. FEBS Lett. 1995; 377(3):470-4. DOI: 10.1016/0014-5793(95)01407-1. View

17.

Beal M . Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol. 1995; 38(3):357-66. DOI: 10.1002/ana.410380304. View

18.

Kanki T, Ohgaki K, Gaspari M, Gustafsson C, Fukuoh A, Sasaki N . Architectural role of mitochondrial transcription factor A in maintenance of human mitochondrial DNA. Mol Cell Biol. 2004; 24(22):9823-34. PMC: 525493. DOI: 10.1128/MCB.24.22.9823-9834.2004. View

19.

Cammarota M, Paratcha G, Bevilaqua L, Levi de Stein M, Lopez M, PELLEGRINO DE IRALDI A . Cyclic AMP-responsive element binding protein in brain mitochondria. J Neurochem. 1999; 72(6):2272-7. DOI: 10.1046/j.1471-4159.1999.0722272.x. View

20.

Papa S, Sardanelli A, Cocco T, Speranza F, Scacco S, Technikova-Dobrova Z . The nuclear-encoded 18 kDa (IP) AQDQ subunit of bovine heart complex I is phosphorylated by the mitochondrial cAMP-dependent protein kinase. FEBS Lett. 1996; 379(3):299-301. DOI: 10.1016/0014-5793(95)01532-9. View