TY - JOUR
T1 - Estrogen regulation of glucose metabolism and mitochondrial function
T2 - Therapeutic implications for prevention of Alzheimer's disease
AU - Brinton, Roberta Diaz
N1 - Funding Information:
The many contributions of the Brinton laboratory estrogen and mitochondria research team, especially Dr. Jon Nilsen, Dr. Ronald Irwin, Dr. Shuhua Chen, Dr. Ryan Hamilton, Dr. Liqin Zhao and Jia Yao are gratefully acknowledged. I also thank Dr. Enrique Cadenas for critique of this manuscript and helpful discussions. This study was supported by grants from the National Institute of Mental Health (1R01 MH67159), National Institute on Aging (P01 AG026572) and the Kenneth T. and Eileen L. Norris Foundation to RDB.
PY - 2008/10
Y1 - 2008/10
N2 - Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis and citric acid cycle-driven oxidative phosphorylation and ATP generation. Data derived from experimental and clinical paradigms investigating estrogen intervention in healthy systems and prior to neurodegenerative insult indicate enhanced neural defense and survival through maintenance of calcium homeostasis, enhanced glycolysis coupled to the citric acid cycle (aerobic glycolysis), sustained and enhanced mitochondrial function, protection against free radical damage, efficient cholesterol trafficking and beta amyloid clearance. The convergence of E2 mechanisms of action onto mitochondrial is also a potential point of vulnerability when activated in a degenerating neural system and could exacerbate the degenerative processes through increased load on dysregulated calcium homeostasis. The data indicate that as the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neuronal survival and neurological function. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the basic to clinical domains of scientific inquiry and on which to predict future applications of estrogen and hormone therapeutic interventions sustain neurological health and to prevent age-associated neurodegenerative diseases such as Alzheimer's. Overall, E2 promotes the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of Alzheimer's.
AB - Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis and citric acid cycle-driven oxidative phosphorylation and ATP generation. Data derived from experimental and clinical paradigms investigating estrogen intervention in healthy systems and prior to neurodegenerative insult indicate enhanced neural defense and survival through maintenance of calcium homeostasis, enhanced glycolysis coupled to the citric acid cycle (aerobic glycolysis), sustained and enhanced mitochondrial function, protection against free radical damage, efficient cholesterol trafficking and beta amyloid clearance. The convergence of E2 mechanisms of action onto mitochondrial is also a potential point of vulnerability when activated in a degenerating neural system and could exacerbate the degenerative processes through increased load on dysregulated calcium homeostasis. The data indicate that as the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neuronal survival and neurological function. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the basic to clinical domains of scientific inquiry and on which to predict future applications of estrogen and hormone therapeutic interventions sustain neurological health and to prevent age-associated neurodegenerative diseases such as Alzheimer's. Overall, E2 promotes the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of Alzheimer's.
KW - Aerobic glycolysis
KW - Alzheimer's disease
KW - Bioenergetics
KW - Brain metabolism
KW - Estrogen
KW - Hormone therapy
KW - Mitochondria
UR - http://www.scopus.com/inward/record.url?scp=51249114495&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=51249114495&partnerID=8YFLogxK
U2 - 10.1016/j.addr.2008.06.003
DO - 10.1016/j.addr.2008.06.003
M3 - Review article
C2 - 18647624
AN - SCOPUS:51249114495
VL - 60
SP - 1504
EP - 1511
JO - Advanced Drug Delivery Reviews
JF - Advanced Drug Delivery Reviews
SN - 0169-409X
IS - 13-14
ER -