title: Nuclear depletion of apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is an indicator of energy disruption in neurons.
abstract: Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is a multifunctional protein critical for cellular survival. Its involvement in adaptive survival responses includes key roles in redox sensing, transcriptional regulation, and repair of DNA damage via the base excision repair (BER) pathway. Ape1 is abundant in most cell types and central in integrating the first BER step catalyzed by different DNA glycosylases. BER is the main process for removal of oxidative DNA lesions in postmitotic brain cells, and after ischemic brain injury preservation of Ape1 coincides with neuronal survival, while its loss has been associated with neuronal death. Here, we report that in cultured primary neurons, diminution of cellular ATP by either oligomycin or H(2)O(2) is accompanied by depletion of nuclear Ape1, while other BER proteins are unaffected and retain their nuclear localization under these conditions. Importantly, while H(2)O(2) induces γH2AX phosphorylation, indicative of chromatin rearrangements in response to DNA damage, oligomycin does not. Furthermore, despite comparable diminution of ATP content, H(2)O(2) and oligomycin differentially affect critical parameters of mitochondrial respiration that ultimately determine cellular ATP content. Taken together, our findings demonstrate that in neurons, nuclear compartmentalization of Ape1 depends on ATP and loss of nuclear Ape1 reflects disruption of neuronal energy homeostasis. Energy crisis is a hallmark of stroke and other ischemic/hypoxic brain injuries. In vivo studies have shown that Ape1 deficit precedes neuronal loss in injured brain regions. Thus, our findings bring to light the possibility that energy failure-induced Ape1 depletion triggers neuronal death in ischemic brain injuries.
authors: Department of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
authors: Shilpee
authors: S
authors: Singh
authors: Ella W
authors: EW
authors: Englander
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology*; D002478:Cells, Cultured; D004249:DNA Damage; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004734:Energy Metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D010101:Oxygen Consumption; D000075223:Poly-ADP-Ribose Binding Proteins; D021381:Protein Transport; D000076105:X-ray Repair Cross Complementing Protein 1; D029867:Xenopus Proteins
chemical_list: D004268:DNA-Binding Proteins; D009840:Oligomycins; D016877:Oxidants; D000075223:Poly-ADP-Ribose Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; D029867:Xenopus Proteins; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D025261:Mitochondrial Proton-Translocating ATPases; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus