Sirtuin signaling controls mitochondrial function in glycogen storage disease type Ia.
Sirtuin signaling controls mitochondrial function in glycogen storage disease type Ia.
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DOI：
10.1007/s10545-018-0192-1
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发表时间：
2018-05-08
影响因子：
4.2
通讯作者：
Chou JY
中科院分区：
文献类型：
--
作者：
Cho JH;Kim GY;Mansfield BC;Chou JY
葡萄糖-6-磷酸酶-α（G6 α-phosphatase-α，G6 β-α）缺陷型糖原累积病Ia（Glycogen storage disease type Ia，GSD-Ia）是一种以糖稳态受损为特征的代谢性疾病，是肝细胞腺瘤/肝癌（hepatocellular adenoma/carcinoma，HCA/HCC）的长期并发症。线粒体功能障碍与GSD-Ia有关，但其潜在机制及其对HCA/HCC发展的贡献仍不清楚。我们已经证明，肝脏G6 α-α缺乏导致沉默调节蛋白1（SIRT 1）信号转导下调，这是GSD-Ia中肝脏自噬缺陷的基础。SIRT 1是一种NAD+依赖性脱乙酰酶，可以脱乙酰化并激活过氧化物酶体增殖物激活受体-γ共激活因子1α（PGC-1α），PGC-1 α是线粒体完整性、生物发生和功能的主要调节因子。我们假设，在G6 β-α缺乏的肝脏中，肝脏SIRT 1信号转导的下调损害了PGC-1a活性，导致线粒体功能障碍。在这里，我们发现G6 β-α缺乏的肝脏显示出PGC-1α信号传导缺陷，功能线粒体数量减少，氧化磷酸化受损。肝脏SIRT 1的过表达恢复PGC-1a活性，使电子传递链组分的表达正常化，并增加线粒体复合物IV活性。我们先前已经表明，肝脏G6 β-α表达的恢复使SIRT 1信号传导正常化。我们现在发现，肝脏G6 α表达的恢复也恢复了PGC-1a活性和线粒体功能。最后，我们发现，在G6 α-缺乏的肝脏中发现的HCA/HCC病变含有明显的线粒体和氧化DNA损伤。总之，我们的研究表明，肝脏SIRT 1/PGC-1α信号转导的下调是线粒体功能障碍的基础，受损线粒体引起的氧化DNA损伤可能有助于GSD-Ia中HCA/HCC的发展。
Glycogen storage disease type Ia (GSD-Ia) deficient in glucose-6-phosphatase-α (G6Pase-α) is a metabolic disorder characterized by impaired glucose homeostasis and a long-term complication of hepatocellular adenoma/carcinoma (HCA/HCC). Mitochondrial dysfunction has been implicated in GSD-Ia but the underlying mechanism and its contribution to HCA/HCC development remain unclear. We have shown that hepatic G6Pase-α deficiency leads to downregulation of sirtuin 1 (SIRT1) signaling that underlies defective hepatic autophagy in GSD-Ia. SIRT1 is a NAD+-dependent deacetylase that can deacetylate and activate peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial integrity, biogenesis, and function. We hypothesized that downregulation of hepatic SIRT1 signaling in G6Pase-α-deficient livers impairs PGC-1a activity, leading to mitochondrial dysfunction. Here we show that the G6Pase-α-deficient livers display defective PGC-1α signaling, reduced numbers of functional mitochondria, and impaired oxidative phosphorylation. Overexpression of hepatic SIRT1 restores PGC-1a activity, normalizes the expression of electron transport chain components, and increases mitochondrial complex IV activity. We have previously shown that restoration of hepatic G6Pase-α expression normalized SIRT 1 signaling. We now show that restoration of hepatic G6Pase-α expression also restores PGC-1a activity and mitochondrial function. Finally, we show that HCA/HCC lesions found in G6Pase-α-deficient livers contain marked mitochondrial and oxidative DNA damage. Taken together, our study shows that downregulation of hepatic SIRT1/PGC-1α signaling underlies mitochondrial dysfunction and that oxidative DNA damage incurred by damaged mitochondria may contribute to HCA/HCC development in GSD-Ia.
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影响因子：
64.5
作者：
Vyas S;Zaganjor E;Haigis MC
通讯作者：
Haigis MC
影响因子：
4.3
作者：
Sotgia, Federica;Whitaker-Menezes, Diana;Lisanti, Michael P.
通讯作者：
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DOI：
10.1038/nrendo.2010.189
发表时间：
2010-12
期刊：
Nature reviews. Endocrinology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1152/ajpgi.00270.2015
发表时间：
2016-02-01
影响因子：
4.5
作者：
Sun, Qian;Zhong, Wei;Zhou, Zhanxiang
通讯作者：
Zhou, Zhanxiang
影响因子：
4.6
作者：
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