Sirtuin 3 regulates mitochondrial protein acetylation and metabolism in tubular epithelial cells during renal fibrosis.
Sirtuin 3 regulates mitochondrial protein acetylation and metabolism in tubular epithelial cells during renal fibrosis.
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Sirtuin 3 在肾纤维化过程中调节肾小管上皮细胞的线粒体蛋白乙酰化和代谢。
DOI：
10.1038/s41419-021-04134-4
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发表时间：
2021-09-13
影响因子：
9
通讯作者：
Jiang L
中科院分区：
文献类型：
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作者：
Zhang Y;Wen P;Luo J;Ding H;Cao H;He W;Zen K;Zhou Y;Yang J;Jiang L
近端肾小管上皮细胞（TEC）需要高能量，并依赖线粒体氧化磷酸化作为主要能量来源。然而，这在肾纤维化中受到干扰。乙酰化是线粒体代谢中重要的翻译后修饰。线粒体蛋白NAD+依赖性脱乙酰酶sirtuin 3（SIRT 3）调节线粒体代谢功能。因此，我们的目的是确定纤维化肾脏小管中乙酰组的变化，并确定它们与线粒体的关系。我们发现SIRT 3表达的降低伴随着在肾纤维化早期从TEC分离的线粒体中乙酰化的增加。Sirt 3基因敲除小鼠对高乙酰化线粒体蛋白和严重的肾纤维化易感。和厚朴对SIRT 3的激活改善了乙酰化并防止了肾纤维化。使用LC-MS/MS分析分离的肾小管中的乙酰组表明，单侧输尿管梗阻后，大多数肾脏蛋白质被过度乙酰化。增加的乙酰化蛋白（26.76%）是线粒体蛋白，其被映射到广泛的线粒体途径，包括脂肪酸β-氧化、三羧酸循环（TCA循环）和氧化磷酸化。丙酮酸脱氢酶E1α（PDHE 1 α）是糖酵解和TCA循环之间的主要联系，在TGF-β1刺激后TEC中赖氨酸385处高度乙酰化，并受SIRT 3调节。我们的研究结果表明，参与调节能量代谢的线粒体蛋白被乙酰化，并被TECs中的SIRT 3靶向。SIRT 3在赖氨酸385处对PDHE 1 α进行脱乙酰化在与肾纤维化相关的代谢重编程中起关键作用。
Proximal tubular epithelial cells (TECs) demand high energy and rely on mitochondrial oxidative phosphorylation as the main energy source. However, this is disturbed in renal fibrosis. Acetylation is an important post-translational modification for mitochondrial metabolism. The mitochondrial protein NAD+-dependent deacetylase sirtuin 3 (SIRT3) regulates mitochondrial metabolic function. Therefore, we aimed to identify the changes in the acetylome in tubules from fibrotic kidneys and determine their association with mitochondria. We found that decreased SIRT3 expression was accompanied by increased acetylation in mitochondria that have separated from TECs during the early phase of renal fibrosis. Sirt3 knockout mice were susceptible to hyper-acetylated mitochondrial proteins and to severe renal fibrosis. The activation of SIRT3 by honokiol ameliorated acetylation and prevented renal fibrosis. Analysis of the acetylome in separated tubules using LC–MS/MS showed that most kidney proteins were hyper-acetylated after unilateral ureteral obstruction. The increased acetylated proteins with 26.76% were mitochondrial proteins which were mapped to a broad range of mitochondrial pathways including fatty acid β-oxidation, the tricarboxylic acid cycle (TCA cycle), and oxidative phosphorylation. Pyruvate dehydrogenase E1α (PDHE1α), which is the primary link between glycolysis and the TCA cycle, was hyper-acetylated at lysine 385 in TECs after TGF-β1 stimulation and was regulated by SIRT3. Our findings showed that mitochondrial proteins involved in regulating energy metabolism were acetylated and targeted by SIRT3 in TECs. The deacetylation of PDHE1α by SIRT3 at lysine 385 plays a key role in metabolic reprogramming associated with renal fibrosis.
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DOI：
10.1042/cs20120190
发表时间：
2013-02
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Kitada M;Kume S;Takeda-Watanabe A;Kanasaki K;Koya D
通讯作者：
Koya D
影响因子：
19.6
作者：
Johnson, ACM;Stahl, A;Zager, RA
通讯作者：
Zager, RA
影响因子：
1.1
作者：
Kwon Y;Kim J;Lee CY;Kim H
通讯作者：
Kim H
影响因子：
16
作者：
Fan, Jun;Shan, Changliang;Kang, Hee-Bum;Elf, Shannon;Xie, Jianxin;Tucker, Meghan;Gu, Ting-Lei;Aguiar, Mike;Lonning, Scott;Chen, Huaibin;Mohammadi, Moosa;Britton, Laura-Mae P.;Garcia, Benjamin A.;Aleckovic, Masa;Kang, Yibin;Kaluz, Stefan;Devi, Nara;Van Meir, Erwin G.;Hitosugi, Taro;Seo, Jae Ho;Lonial, Sagar;Gaddh, Manila;Arellano, Martha;Khoury, Hanna J.;Khuri, Fadlo R.;Boggon, Titus J.;Kang, Sumin;Chen, Jing
通讯作者：
Chen, Jing
影响因子：
82.9
作者：
通讯作者：
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