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Transcriptional control of cardiac fuel metabolism and mitochondrial function.

Abstract

As a persistent pump, the mammalian heart demands a high-capacity mitochondrial system. Significant progress has been made in delineating the gene regulatory networks that control mitochondrial biogenesis and function in striated muscle. The PPARγ coactivator-1 (PGC-1) coactivators serve as inducible boosters of downstream transcription factors that control the expression of genes involved in mitochondrial energy transduction, ATP synthesis, and biogenesis. PGC-1 gain-of-function and loss-of-function studies targeting two PGC-1 family members, PGC-1α and PGC-1β, have provided solid evidence that these factors are both necessary and sufficient for perinatal mitochondrial biogenesis and maintenance of high-capacity mitochondrial function in postnatal heart. In humans, during the development of heart failure owing to hypertension or obesity-related diabetes, the activity of the PGC-1 coactivators, and several downstream target transcription factors, is altered. Gene targeting studies in mice have demonstrated that loss of PGC-1α and PGC-1β in heart leads to heart failure. Interestingly, the pattern of dysregulation within the PGC-1 transcriptional regulatory circuit distinguishes the heart disease caused by hypertension from that caused by diabetes. This transcriptional regulatory cascade and downstream metabolic pathways should be considered as targets for novel etiology-specific therapeutics aimed at the early stages of heart failure.

Authors+Show Affiliations

Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Review

Language

eng

PubMed ID

22096028

Citation

Leone, T C., and D P. Kelly. "Transcriptional Control of Cardiac Fuel Metabolism and Mitochondrial Function." Cold Spring Harbor Symposia On Quantitative Biology, vol. 76, 2011, pp. 175-82.
Leone TC, Kelly DP. Transcriptional control of cardiac fuel metabolism and mitochondrial function. Cold Spring Harb Symp Quant Biol. 2011;76:175-82.
Leone, T. C., & Kelly, D. P. (2011). Transcriptional control of cardiac fuel metabolism and mitochondrial function. Cold Spring Harbor Symposia On Quantitative Biology, 76, 175-82. https://doi.org/10.1101/sqb.2011.76.011965
Leone TC, Kelly DP. Transcriptional Control of Cardiac Fuel Metabolism and Mitochondrial Function. Cold Spring Harb Symp Quant Biol. 2011;76:175-82. PubMed PMID: 22096028.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transcriptional control of cardiac fuel metabolism and mitochondrial function. AU - Leone,T C, AU - Kelly,D P, Y1 - 2011/11/17/ PY - 2011/11/19/entrez PY - 2011/11/19/pubmed PY - 2012/10/18/medline SP - 175 EP - 82 JF - Cold Spring Harbor symposia on quantitative biology JO - Cold Spring Harb. Symp. Quant. Biol. VL - 76 N2 - As a persistent pump, the mammalian heart demands a high-capacity mitochondrial system. Significant progress has been made in delineating the gene regulatory networks that control mitochondrial biogenesis and function in striated muscle. The PPARγ coactivator-1 (PGC-1) coactivators serve as inducible boosters of downstream transcription factors that control the expression of genes involved in mitochondrial energy transduction, ATP synthesis, and biogenesis. PGC-1 gain-of-function and loss-of-function studies targeting two PGC-1 family members, PGC-1α and PGC-1β, have provided solid evidence that these factors are both necessary and sufficient for perinatal mitochondrial biogenesis and maintenance of high-capacity mitochondrial function in postnatal heart. In humans, during the development of heart failure owing to hypertension or obesity-related diabetes, the activity of the PGC-1 coactivators, and several downstream target transcription factors, is altered. Gene targeting studies in mice have demonstrated that loss of PGC-1α and PGC-1β in heart leads to heart failure. Interestingly, the pattern of dysregulation within the PGC-1 transcriptional regulatory circuit distinguishes the heart disease caused by hypertension from that caused by diabetes. This transcriptional regulatory cascade and downstream metabolic pathways should be considered as targets for novel etiology-specific therapeutics aimed at the early stages of heart failure. SN - 1943-4456 UR - https://www.unboundmedicine.com/medline/citation/22096028/Transcriptional_control_of_cardiac_fuel_metabolism_and_mitochondrial_function_ L2 - http://symposium.cshlp.org/cgi/pmidlookup?view=long&pmid=22096028 DB - PRIME DP - Unbound Medicine ER -