Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis.
Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis.
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DOI：
10.1126/sciadv.adf0115
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发表时间：
2023-05-03
期刊：
影响因子：
13.6
通讯作者：
Wellen, Kathryn E.
中科院分区：
文献类型：
--
作者：
Izzo, Luke T.;Trefely, Sophie;Demetriadou, Christina;Drummond, Jack M.;Mizukami, Takuya;Kuprasertkul, Nina;Farria, Aimee T.;Nguyen, Phuong T. T.;Murali, Nivitha;Reich, Lauren;Kantner, Daniel S.;Shaffer, Joshua;Affronti, Hayley;Carrer, Alessandro;Andrews, Andrew;Capell, Brian C.;Snyder, Nathaniel W.;Wellen, Kathryn E.
代谢物乙酰辅酶A是细胞质中脂质合成和细胞核中组蛋白乙酰化所必需的。乙酰辅酶A在细胞核-细胞质区室中的两种典型前体是柠檬酸盐和乙酸盐，它们分别被ATP-柠檬酸盐裂解酶（ACLY）和酰基辅酶A合成酶短链2（ACSS 2）加工成乙酰辅酶A。目前尚不清楚是否存在其他实质性途径的核胞质乙酰辅酶A。为了研究这一点，我们产生了缺乏ACLY和ACSS 2的癌细胞系[双敲除（DKO）细胞]。使用稳定的同位素示踪，我们表明，葡萄糖和脂肪酸有助于乙酰辅酶A池和组蛋白乙酰化在DKO细胞和乙酰肉毒碱穿梭可以转移两个碳单位从线粒体到胞质溶胶。此外，在不存在ACLY的情况下，葡萄糖可以以肉毒碱响应性和肉毒碱乙酰转移酶（CrAT）依赖性方式供给脂肪酸合成。这些数据将乙酰肉毒碱定义为ACLY-和ACSS 2-独立的核-胞质乙酰辅酶A前体，其可以支持乙酰化、脂肪酸合成和细胞生长。乙酰肉毒碱从线粒体穿梭可以提供乙酰辅酶A的脂肪生成和乙酰化独立的ACLY和ACSS 2。
The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation in the nucleus. The two canonical precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It is unclear whether other substantial routes to nuclear-cytosolic acetyl-CoA exist. To investigate this, we generated cancer cell lines lacking both ACLY and ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing, we show that both glucose and fatty acids contribute to acetyl-CoA pools and histone acetylation in DKO cells and that acetylcarnitine shuttling can transfer two-carbon units from mitochondria to cytosol. Further, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and carnitine acetyltransferase (CrAT)-dependent manner. The data define acetylcarnitine as an ACLY- and ACSS2-independent precursor to nuclear-cytosolic acetyl-CoA that can support acetylation, fatty acid synthesis, and cell growth. Acetylcarnitine shuttling from mitochondria can supply acetyl-CoA for lipogenesis and acetylation independent of ACLY and ACSS2.
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影响因子：
28.2
作者：
Carrer, Alessandro;Trefely, Sophie;Wellen, Kathryn E.
通讯作者：
Wellen, Kathryn E.
DOI：
10.1038/s41573-021-00367-2
发表时间：
2022-04
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Batchuluun B;Pinkosky SL;Steinberg GR
通讯作者：
Steinberg GR
影响因子：
3.7
作者：
Kuo YM;Andrews AJ
通讯作者：
Andrews AJ
影响因子：
16.6
作者：
Calejman, C. Martinez;Trefely, S.;Guertin, D. A.
通讯作者：
Guertin, D. A.
影响因子：
64.5
作者：
Liu X;Cooper DE;Cluntun AA;Warmoes MO;Zhao S;Reid MA;Liu J;Lund PJ;Lopes M;Garcia BA;Wellen KE;Kirsch DG;Locasale JW
通讯作者：
Locasale JW