Identification of homocysteine-suppressive mitochondrial ETC complex genes and tissue expression profile - Novel hypothesis establishment.
Identification of homocysteine-suppressive mitochondrial ETC complex genes and tissue expression profile - Novel hypothesis establishment.
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同型半胱氨酸抑制线粒体 ETC 复合体基因和组织表达谱的鉴定 - 新假设的建立
DOI：
10.1016/j.redox.2018.03.015
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发表时间：
2018-07
期刊：
影响因子：
11.4
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Cueto R;Zhang L;Shan HM;Huang X;Li X;Li YF;Lopez J;Yang WY;Lavallee M;Yu C;Ji Y;Yang X;Wang H
高同型半胱氨酸血症（HHcy）是心血管疾病（CVD）的独立危险因素，与线粒体（Mt）功能障碍有关。本研究通过LC-ESI-MS/MS分析表征小鼠组织中Hcy代谢，通过数据库挖掘建立了20个人和19个小鼠组织中84个核编码Mt电子传递链复合物（nMt-ETC-Com）基因的组织表达谱，并建立了HHcy对Mt- etc功能的影响模型。小鼠肾、肺、脾、肝组织中Hcy水平较高（24 ~ 14 nmol/g），而脑、心组织中Hcy水平较低（~5 nmol/g）。s -腺苷型同型半胱氨酸（SAH）水平在肝/肾高（59 ~ 33 nmol/g），肺/心/脑中等（7 ~ 4 nmol/g），脾低（1 nmol/g）。s -腺苷甲硫氨酸（SAM）在所有组织中具有可变性（42 ~ 18 nmol/g）。脾SAM/SAH比值高达25.6，而心/肺/脑/肾/肝的SAM/SAH比值较低（7-0.6）。nMt-ETC-Com基因在人的肌肉/脑垂体/心脏/BM和小鼠的淋巴结/心脏/胰腺/脑中高度表达。我们发现15个Hcy抑制基因nMt-ETC-Com mRNA水平与组织Hcy水平呈负相关，包括11个complex-I、1个complex-IV和2个complex-V基因。在11个hcy抑制复合物- 1基因中，有4个是复合物- 1核心亚基。基于这些基因的组织表达模式，我们将组织分为三级（高/中/低hcy反应），并将人类和小鼠的心脏/眼睛/胰腺/脑/肾脏/肝脏/睾丸/胚胎组织定义为第一级（高hcy反应）组织。此外，通过广泛的文献挖掘，我们发现大多数抑制hcy的nMt-ETC-Com基因在HHcy条件下被抑制，并与人类疾病和实验模型中Mt复合物的组装/活性损伤有关。我们假设HHcy抑制Mt复合体I基因表达导致Mt功能障碍。Hcy在小鼠组织中代谢有差异。nMt-ETC-Com基因在人和小鼠组织中表达不同，并根据hcy反应性分为3层。15个nMt-ETC-Com基因与组织Hcy水平呈负相关。hcy抑制基因nMt-ETC-Com影响Mt复合体的组装和活性。HHcy通过Com I核心亚基V1/2和S3/7抑制破坏Mt氧化还原稳态。
Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease (CVD) which has been implicated in matochondrial (Mt) function impairment. In this study, we characterized Hcy metabolism in mouse tissues by using LC-ESI-MS/MS analysis, established tissue expression profiles for 84 nuclear-encoded Mt electron transport chain complex (nMt-ETC-Com) genes in 20 human and 19 mouse tissues by database mining, and modeled the effect of HHcy on Mt-ETC function. Hcy levels were high in mouse kidney/lung/spleen/liver (24–14 nmol/g tissue) but low in brain/heart (~5 nmol/g). S-adenosylhomocysteine (SAH) levels were high in the liver/kidney (59–33 nmol/g), moderate in lung/heart/brain (7–4 nmol/g) and low in spleen (1 nmol/g). S-adenosylmethionine (SAM) was comparable in all tissues (42–18 nmol/g). SAM/SAH ratio was as high as 25.6 in the spleen but much lower in the heart/lung/brain/kidney/liver (7–0.6). The nMt-ETC-Com genes were highly expressed in muscle/pituitary gland/heart/BM in humans and in lymph node/heart/pancreas/brain in mice. We identified 15 Hcy-suppressive nMt-ETC-Com genes whose mRNA levels were negatively correlated with tissue Hcy levels, including 11 complex-I, one complex-IV and two complex-V genes. Among the 11 Hcy-suppressive complex-I genes, 4 are complex-I core subunits. Based on the pattern of tissue expression of these genes, we classified tissues into three tiers (high/mid/low-Hcy responsive), and defined heart/eye/pancreas/brain/kidney/liver/testis/embryonic tissues as tier 1 (high-Hcy responsive) tissues in both human and mice. Furthermore, through extensive literature mining, we found that most of the Hcy-suppressive nMt-ETC-Com genes were suppressed in HHcy conditions and related with Mt complex assembly/activity impairment in human disease and experimental models. We hypothesize that HHcy inhibits Mt complex I gene expression leading to Mt dysfunction. Hcy is differentially metabolized in mouse tissues. nMt-ETC-Com genes are differentially expressed in human and mouse tissues and classified into 3 tiers for Hcy-responsiveness. Fifteen nMt-ETC-Com genes are negatively correlated with tissue Hcy levels. Hcy-suppressive nMt-ETC-Com genes impact on Mt complex assembly and activity. HHcy disrupts Mt redox homeostasis via Com I core subunits V1/2 and S3/7 suppression.
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