亲爱的研友该休息了!由于当前在线用户较少,发布求助请尽量完整地填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!身体可是革命的本钱,早点休息,好梦!

Abstract P3185: ATP Citrate Lyase Regulates Cardiomyocyte Function By Controlling Mitochondrial Reductive Stress

ATP柠檬酸裂解酶 柠檬酸合酶 柠檬酸循环 胞浆 线粒体 生物化学 糖酵解 NAD+激酶 乳酸脱氢酶 化学 生物 细胞生物学
作者
Mariam Meddeb,Navid Koleini,Seungho Jun,Mohammad Keykhaei,Farnaz Farshidfar,Liang Zhao,Abigail Mulligan,Seoyoung Kwon,Lin Bo,Gizem Keceli,Kavita Sharma,Mark J Ranek,Nazareno Paolocci,Erika L. Pearce,David A. Kass
出处
期刊:Circulation Research [Lippincott Williams & Wilkins]
卷期号:133 (Suppl_1)
标识
DOI:10.1161/res.133.suppl_1.p3185
摘要

ATP citrate lyase (ACLY) is a cytosolic enzyme that converts citrate transported from the mitochondria into oxaloacetate and acetyl-CoA. It was recently reported to support a non-canonical TCA cycle, which is particularly important in immature and proliferating cells. Cardiomyocytes are both mature and non-proliferating and the role of ACLY in such cells is unknown. Using uniformly labeled C 13 glucose, we found that inhibiting ACLY using highly specific BMS-303141 (ACLY-I) significantly elevated M2 malate/M2 citrate ratio in adult cardiomyocytes in 1 hour, indicating their engagement in a non-canonical TCA cycle. In isolated hearts (Langendorff), we found both dP/dt max and dP/dt min markedly depressed after 40 minutes of ACLY-I. Isolated adult myocytes exposed to 1 hour of ACLY-I had depressed sarcomere shortening and prolonged relaxation. Reactive oxygen species was unchanged. BMS303141 at >10 μM was cardiotoxic while concentrations up to 50μM are not toxic in cardiac fibroblasts or hepatocytes. Untargeted metabolomics from ACLY-I treated hearts found significant decreases in TCA cycle intermediates citrate and α-ketoglutarate, accompanied by reduction in ATP production despite accumulation of NADH. The NAD/NADH ratio was reduced after 1-hr ACLY-I in cardiomyocytes, supporting its induction of reductive stress. Consistent with this, lactate was increased perhaps as a mechanism to oxidize NADH and alleviate reductive stress. These results have translational importance, as we find in human heart failure biopsies that ACLY is significantly downregulated at both transcript and protein levels. This finding is inversely related to body mass index, raising the hypothesis that exposure to high fat diet may reduce ACLY levels. This was tested in adult cardiomyocytes isolated from hearts 4 weeks after transaortic constriction and then treated with palmitate and oleate. ACLY mRNA declined post fatty acid treatment and paralleled a decline in ACLY promoter activity. These results identify a critical role of ACLY in normal myocyte NAD/NADH balance and mitochondrial function. ACLY reduction in heart failure particularly with obesity (e.g. heart failure with preserved ejection fraction) suggests a potentially new metabolic therapeutic target.

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
WerWu完成签到,获得积分10
1分钟前
彭于晏应助Dc采纳,获得10
1分钟前
2分钟前
情怀应助科研通管家采纳,获得10
2分钟前
3分钟前
Dc发布了新的文献求助10
3分钟前
Dc完成签到,获得积分10
3分钟前
3分钟前
幽默平安发布了新的文献求助10
4分钟前
科研通AI2S应助科研通管家采纳,获得10
4分钟前
5分钟前
5分钟前
6分钟前
小禾一定行完成签到 ,获得积分10
6分钟前
inkoin发布了新的文献求助10
6分钟前
科研通AI2S应助科研通管家采纳,获得10
6分钟前
inkoin完成签到,获得积分10
6分钟前
7分钟前
积极的台灯应助Akitten采纳,获得10
7分钟前
隐形曼青应助务实书包采纳,获得10
7分钟前
7分钟前
8分钟前
爱思考的小笨笨完成签到,获得积分10
8分钟前
GingerF应助科研通管家采纳,获得50
8分钟前
GingerF应助科研通管家采纳,获得50
8分钟前
上官若男应助闫雪采纳,获得10
8分钟前
8分钟前
9分钟前
Akitten发布了新的文献求助10
9分钟前
9分钟前
大写的LV完成签到 ,获得积分10
9分钟前
ffff完成签到 ,获得积分10
10分钟前
zsmj23完成签到 ,获得积分0
10分钟前
Owen应助科研通管家采纳,获得10
10分钟前
Owen应助hongtao采纳,获得10
10分钟前
11分钟前
哈哈哈完成签到 ,获得积分10
11分钟前
12分钟前
liu完成签到 ,获得积分10
12分钟前
33发布了新的文献求助10
12分钟前
高分求助中
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3990219
求助须知:如何正确求助?哪些是违规求助? 3532146
关于积分的说明 11256472
捐赠科研通 3271042
什么是DOI,文献DOI怎么找? 1805190
邀请新用户注册赠送积分活动 882302
科研通“疑难数据库(出版商)”最低求助积分说明 809234