酰基辅酶A合成酶短链家族成员1(acyl-CoA synthetase short-chain family member 1,ACSS1)是定位于线粒体基质的关键代谢酶,主要功能是通过催化乙酸与辅酶A合成乙酰辅酶A,进入三羧酸(TCA)循环,经氧化分解产生ATP,为机体供能。其在细胞...酰基辅酶A合成酶短链家族成员1(acyl-CoA synthetase short-chain family member 1,ACSS1)是定位于线粒体基质的关键代谢酶,主要功能是通过催化乙酸与辅酶A合成乙酰辅酶A,进入三羧酸(TCA)循环,经氧化分解产生ATP,为机体供能。其在细胞能量稳态、脂质合成和表观遗传调控中发挥主要作用。ACSS1具有明确的基因定位和组织特异性表达模式,其蛋白结构保守。在葡萄糖缺乏或应激状态下,ACSS1可利用乙酸等替代碳源合成乙酰辅酶A,为TCA循环提供底物,维持ATP生成,从而保障心、脑等高耗能组织的能量稳定。其分子结构包含保守的赖氨酸乙酰化位点(小鼠K635/人类K642),该位点受到沉默信息调节转录因子3(Silent information regulator transcript 3,SIRT3)去乙酰化酶的动态调控,尤其在营养剥夺(如禁食)或氧化应激条件下,SIRT3通过去乙酰化激活ACSS1酶活性,促进乙酸利用以维持能量平衡。在正常生理状态下,ACSS1参与饥饿能量维持、肝脏生酮及心脏ATP供应。在病理状态下,ACSS1功能紊乱与多种疾病相关:在肿瘤中支持癌细胞低营养生存;其功能下降可能导致神经退行性疾病中的能量衰竭;此外还与脂肪肝、肌肉减少症等代谢性疾病密切相关。通过对现有研究的系统梳理,本综述旨在为理解ACSS1在能量代谢中的调控通路及分子机制提供理论依据。展开更多
The symbiotic relationship between the host and microbiota is widely acknowledged as mutually beneficial.However,due to significant differences in metabolic substrates and products between prokaryotic bacteria and mam...The symbiotic relationship between the host and microbiota is widely acknowledged as mutually beneficial.However,due to significant differences in metabolic substrates and products between prokaryotic bacteria and mammalian cells,mechanisms must exist to reconcile the metabolic incompatibility between the host and microbiota.We report that host enzymes are required to detoxify gut microbiota-derived acetate to maintain male fertility in mice.The combined deletion of acetyl-CoA synthetase short-chain family member 1 and 2(ACSS1 and ACSS2),two enzymes consuming acetate in mammals,leads to excessive accumulation of acetate in circulation.This accumulation causes metabolic acidosis,blocking spermatogenesis and rendering male mice infertile.ACSS1/2-deficient germ cells exhibit comprehensive metabolic alterations with nicotinamide adenine dinucleotide(NAD+)deficiency that impairs betaine production.Supplementation with betaine restores spermatogenesis and fertility in ACSS1/2-deficient mice.Thus,the inevitable production of acetate by gut bacteria and its reproductive toxicity to the host represents an unappreciated metabolic incompatibility between the host and microbiota,which is reconciled by ACSS1/2.展开更多
文摘酰基辅酶A合成酶短链家族成员1(acyl-CoA synthetase short-chain family member 1,ACSS1)是定位于线粒体基质的关键代谢酶,主要功能是通过催化乙酸与辅酶A合成乙酰辅酶A,进入三羧酸(TCA)循环,经氧化分解产生ATP,为机体供能。其在细胞能量稳态、脂质合成和表观遗传调控中发挥主要作用。ACSS1具有明确的基因定位和组织特异性表达模式,其蛋白结构保守。在葡萄糖缺乏或应激状态下,ACSS1可利用乙酸等替代碳源合成乙酰辅酶A,为TCA循环提供底物,维持ATP生成,从而保障心、脑等高耗能组织的能量稳定。其分子结构包含保守的赖氨酸乙酰化位点(小鼠K635/人类K642),该位点受到沉默信息调节转录因子3(Silent information regulator transcript 3,SIRT3)去乙酰化酶的动态调控,尤其在营养剥夺(如禁食)或氧化应激条件下,SIRT3通过去乙酰化激活ACSS1酶活性,促进乙酸利用以维持能量平衡。在正常生理状态下,ACSS1参与饥饿能量维持、肝脏生酮及心脏ATP供应。在病理状态下,ACSS1功能紊乱与多种疾病相关:在肿瘤中支持癌细胞低营养生存;其功能下降可能导致神经退行性疾病中的能量衰竭;此外还与脂肪肝、肌肉减少症等代谢性疾病密切相关。通过对现有研究的系统梳理,本综述旨在为理解ACSS1在能量代谢中的调控通路及分子机制提供理论依据。
基金This research was supported by Tsinghua University Initiative Scientific Research Program (to M.P.) and funds from Tsinghua-Peking Center for Life Sciences and Institute forImmunology at Tsinghua University (to M.P.).
文摘The symbiotic relationship between the host and microbiota is widely acknowledged as mutually beneficial.However,due to significant differences in metabolic substrates and products between prokaryotic bacteria and mammalian cells,mechanisms must exist to reconcile the metabolic incompatibility between the host and microbiota.We report that host enzymes are required to detoxify gut microbiota-derived acetate to maintain male fertility in mice.The combined deletion of acetyl-CoA synthetase short-chain family member 1 and 2(ACSS1 and ACSS2),two enzymes consuming acetate in mammals,leads to excessive accumulation of acetate in circulation.This accumulation causes metabolic acidosis,blocking spermatogenesis and rendering male mice infertile.ACSS1/2-deficient germ cells exhibit comprehensive metabolic alterations with nicotinamide adenine dinucleotide(NAD+)deficiency that impairs betaine production.Supplementation with betaine restores spermatogenesis and fertility in ACSS1/2-deficient mice.Thus,the inevitable production of acetate by gut bacteria and its reproductive toxicity to the host represents an unappreciated metabolic incompatibility between the host and microbiota,which is reconciled by ACSS1/2.
