过氧化物酶体增殖物激活受体 γ 共激活因子 1 在出生后心脏生长过程中线粒体动力学控制中的作用。
A role for peroxisome proliferator-activated receptor γ coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth.
机构信息
From the Diabetes and Obesity Research Center, Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (O.J.M., L.L., M.M.S., T.C.L., D.P.K.); Institute for Research in Biomedicine, Barcelona, Spain (A.Z.); Department de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain (A.Z.); CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain (A.Z.); Department of Biochemistry, University of Wisconsin-Madison, WI (M.P.K., A.D.A.); and Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (D.M.M.).
出版信息
Circ Res. 2014 Feb 14;114(4):626-36. doi: 10.1161/CIRCRESAHA.114.302562. Epub 2013 Dec 23.
RATIONALE
Increasing evidence has shown that proper control of mitochondrial dynamics (fusion and fission) is required for high-capacity ATP production in the heart. Transcriptional coactivators, peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) α and PGC-1β, have been shown to regulate mitochondrial biogenesis in the heart at the time of birth. The function of PGC-1 coactivators in the heart after birth has been incompletely understood.
OBJECTIVE
Our aim was to assess the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts in mice.
METHODS AND RESULTS
Conditional gene targeting was used in mice to explore the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts. Marked mitochondrial structural derangements were observed in hearts of PGC-1α/β-deficient mice during postnatal growth, including fragmentation and elongation, associated with the development of a lethal cardiomyopathy. The expression of genes involved in mitochondrial fusion (Mfn1, Opa1) and fission (Drp1, Fis1) was altered in the hearts of PGC-1α/β-deficient mice. PGC-lα was shown to directly regulate Mfn1 gene transcription by coactivating the estrogen-related receptor α on a conserved DNA element. Surprisingly, PGC-1α/β deficiency in the adult heart did not result in evidence of abnormal mitochondrial dynamics or heart failure. However, transcriptional profiling demonstrated that PGC-1 coactivators are required for high-level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial dynamics and energy transduction in the adult heart.
CONCLUSIONS
These results reveal distinct developmental stage-specific programs involved in cardiac mitochondrial dynamics.
背景
越来越多的证据表明，适当控制线粒体动力学（融合和裂变）对于心脏中高容量 ATP 的产生是必需的。转录共激活因子过氧化物酶体增殖物激活受体 γ 共激活因子 1（PGC-1）α 和 PGC-1β 已被证明可在出生时调节心脏中的线粒体生物发生。PGC-1 共激活因子在出生后心脏中的功能尚未完全了解。
目的
我们的目的是评估 PGC-1 共激活因子在小鼠出生后心脏发育和成年心脏中的作用。
方法和结果
在小鼠中使用条件性基因靶向来探索 PGC-1 共激活因子在出生后心脏发育和成年心脏中的作用。在出生后生长过程中，PGC-1α/β 缺陷小鼠的心脏观察到明显的线粒体结构紊乱，包括碎裂和伸长，与致命性心肌病的发展有关。PGC-1α/β 缺陷小鼠心脏中涉及线粒体融合（Mfn1、Opa1）和裂变（Drp1、Fis1）的基因表达发生改变。PGC-1α 被证明通过在保守的 DNA 元件上共激活雌激素相关受体 α 直接调节 Mfn1 基因的转录。令人惊讶的是，成年心脏中 PGC-1α/β 的缺失并未导致线粒体动力学异常或心力衰竭的证据。然而，转录谱分析表明 PGC-1 共激活因子是心脏中线粒体动力学和能量转导中涉及核编码和线粒体编码基因的高水平表达所必需的。
结论
这些结果揭示了心脏线粒体动力学中涉及的不同发育阶段特异性程序。
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