title: The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications.
abstract: The 'healthy cell bias of estrogen action' hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance aerobic glycolysis coupled to the citric acid cycle, mitochondrial respiration and ATP generation. Convergence of estrogen-induced signaling onto mitochondria is also a point of vulnerability when activated in diseased neurons which exacerbates degeneration through increased load on dysregulated calcium homeostasis. As the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess disparities in outcomes across basic and clinical science and on which to predict outcomes of estrogen interventions for sustaining neurological health and preventing age-associated neurodegenerative diseases such as Alzheimer's.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy Pharmaceutical Sciences Center, Los Angeles, CA 90033, USA. rbrinton@usc.edu
authors.forename: Roberta Diaz
authors.initials: RD
authors.lastname: Brinton
mesh_terms: D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects*; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D008954:Models, Biological; D009422:Nervous System Diseases / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure
chemical_list: D004967:Estrogens
references.citation: Neurology. 2000 Jan 25;54(2):295-301
references.pmid: 10668686
references.citation: JAMA. 2002 Nov 6;288(17):2170-2
references.pmid: 12413378
references.citation: Annu Rev Genet. 2005;39:359-407
references.pmid: 16285865
references.citation: Age (Dordr). 2009 Sep;31(3):199-210
references.pmid: 19277902
references.citation: Ann N Y Acad Sci. 1989;568:1-4
references.pmid: 2629579
references.citation: JAMA. 1998 Mar 4;279(9):688-95
references.pmid: 9496988
references.citation: Neuroscience. 2005;132(2):299-311
references.pmid: 15802184
references.citation: J Neurosci. 2006 Oct 11;26(41):10332-48
references.pmid: 17035515
references.citation: Endocrine. 2001 Apr;14(3):407-15
references.pmid: 11444439
references.citation: Neuroimage. 2008 Apr 15;40(3):1214-21
references.pmid: 18280754
references.citation: Endocrinology. 2008 Jul;149(7):3306-12
references.pmid: 18356271
references.citation: BMC Neurosci. 2006 Nov 03;7:74
references.pmid: 17083736
references.citation: J Neurosci. 2007 Mar 21;27(12):3098-110
references.pmid: 17376971
references.citation: J Nucl Med. 2008 Mar;49(3):390-8
references.pmid: 18287270
references.citation: Brain Res. 2002 Mar 15;930(1-2):216-34
references.pmid: 11879813
references.citation: Am J Epidemiol. 2008 Mar 15;167(6):692-700
references.pmid: 18218608
references.citation: J Neurosci. 2007 Dec 19;27(51):14069-77
references.pmid: 18094246
references.citation: Ann N Y Acad Sci. 2005 Jun;1052:57-74
references.pmid: 16024751
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19067-72
references.pmid: 18003925
references.citation: Eur J Nucl Med Mol Imaging. 2005 Dec;32(12):1463-5
references.pmid: 16283181
references.citation: Biochim Biophys Acta. 1992 Feb 3;1133(3):301-6
references.pmid: 1531302
references.citation: Ann N Y Acad Sci. 2005 Jun;1052:75-90
references.pmid: 16024752
references.citation: J Appl Physiol (1985). 2001 Oct;91(4):1860-7
references.pmid: 11568173
references.citation: Nat Med. 2002 Dec;8(12):1390-7
references.pmid: 12415260
references.citation: Brain Res Rev. 2008 Mar;57(2):421-30
references.pmid: 17512984
references.citation: JAMA. 2002 Nov 6;288(17):2123-9
references.pmid: 12413371
references.citation: J Pharmacol Exp Ther. 2008 Jun;325(3):782-90
references.pmid: 18354059
references.citation: Neurobiol Aging. 2000 Mar-Apr;21(2):373-83
references.pmid: 10867223
references.citation: Endocrinology. 2006 Nov;147(11):5303-13
references.pmid: 16916950
references.citation: J Neurosci. 2003 May 1;23(9):3807-19
references.pmid: 12736351
references.citation: JAMA. 2003 May 28;289(20):2717-9
references.pmid: 12771119
references.citation: JAMA. 2004 Jun 23;291(24):2947-58
references.pmid: 15213206
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9893-8
references.pmid: 8790427
references.citation: Neurobiol Aging. 2006 Feb;27(2):306-17
references.pmid: 15961189
references.citation: Learn Mem. 2001 May-Jun;8(3):121-33
references.pmid: 11390632
references.citation: Neurobiol Aging. 1987 Jul-Aug;8(4):346-7
references.pmid: 3627350
references.citation: Endocrinology. 2002 Jan;143(1):205-12
references.pmid: 11751611
references.citation: JAMA. 2003 May 28;289(20):2651-62
references.pmid: 12771112
references.citation: Mol Cell Endocrinol. 2008 Aug 13;290(1-2):51-9
references.pmid: 18571833
references.citation: Neuroscience. 2006;138(3):831-5
references.pmid: 16310320
references.citation: Curr Drug Targets CNS Neurol Disord. 2004 Aug;3(4):297-313
references.pmid: 15379606
references.citation: Mol Interv. 2006 Feb;6(1):26-35
references.pmid: 16507748
references.citation: Mol Pharmacol. 2005 Oct;68(4):959-65
references.pmid: 15994367
references.citation: J Neurosci. 2008 Feb 6;28(6):1410-20
references.pmid: 18256261
references.citation: Psychoneuroendocrinology. 2007 Aug;32 Suppl 1:S57-61
references.pmid: 17618061
references.citation: Trends Neurosci. 2004 Oct;27(10):614-20
references.pmid: 15374673
references.citation: Neurobiol Aging. 2000 May-Jun;21(3):475-96
references.pmid: 10858597
references.citation: Ann N Y Acad Sci. 2000 Apr;903:204-21
references.pmid: 10818509
references.citation: J Neurochem. 1992 May;58(5):1923-9
references.pmid: 1373180
references.citation: Nature. 2006 Oct 19;443(7113):787-95
references.pmid: 17051205
references.citation: Horm Behav. 1998 Oct;34(2):171-82
references.pmid: 9799627
references.citation: Annu Rev Biochem. 2007;76:781-821
references.pmid: 17506638
references.citation: FASEB J. 2001 Apr;15(6):907-15
references.pmid: 11292650
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2173-8
references.pmid: 14769913
references.citation: Neuroscience. 2005;135(1):59-72
references.pmid: 16084662
references.citation: Genes Dev. 2001 Jun 1;15(11):1406-18
references.pmid: 11390360
references.citation: J Neurol Sci. 2007 Jun 15;257(1-2):206-14
references.pmid: 17316694
references.citation: Nat Rev Neurosci. 2002 Nov;3(11):862-72
references.pmid: 12415294
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2842-7
references.pmid: 12604781
references.citation: Cell Death Differ. 2008 Mar;15(3):521-9
references.pmid: 18064042
references.citation: Neurobiol Aging. 2005 Feb;26(2):229-35
references.pmid: 15582750
references.citation: Front Biosci. 2008 Jan 01;13:1083-9
references.pmid: 17981614
references.citation: Cell. 2008 Jun 27;133(7):1149-61
references.pmid: 18585350
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):284-9
references.pmid: 14688411
references.citation: Front Biosci. 2007 Jan 01;12:1008-13
references.pmid: 17127355
references.citation: Mol Aspects Med. 2004 Feb-Apr;25(1-2):17-26
references.pmid: 15051313
references.citation: J Neurosci. 2006 Sep 13;26(37):9439-47
references.pmid: 16971528
references.citation: Mol Psychiatry. 2006 Aug;11(8):721-36
references.pmid: 16786033
references.citation: Psychoneuroendocrinology. 1986;11(3):337-45
references.pmid: 3786638
references.citation: Front Neuroendocrinol. 2008 Jan;29(1):88-113
references.pmid: 17980408
references.citation: JAMA. 2000 Feb 23;283(8):1007-15
references.pmid: 10697060
references.citation: Nature. 2004 Aug 5;430(7000):631-9
references.pmid: 15295589
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4441-6
references.pmid: 18332434