期刊
CIRCULATION RESEARCH
卷 110, 期 9, 页码 1226-1237出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.111.246868
关键词
heart aging; telomere; mitochondria; metabolism; PGC-1 alpha; myocardial regeneration; telomerase; transcription factors; transcriptional coactivator
资金
- National Institutes of Health [K08HL097031]
- Brigham and Women's Hospital
- Deutsche Forschungsgemeinschaft
- NIH National Cancer Institute [R01CA84628, 1U01CA141508-01]
- Robert A. and Renee E. Belfer Foundation
- Ellison Foundation
- American Cancer Society
Studies in humans and in mice have highlighted the importance of short telomeres and impaired mitochondrial function in driving age-related functional decline in the heart. Although telomere and mitochondrial dysfunction have been viewed mainly in isolation, recent studies in telomerase-deficient mice have provided evidence for an intimate link between these two processes. Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 alpha and PGC-1 beta in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging. (Circ Res. 2012;110:1226-1237.)
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