线粒体氨基胺降解成分1 (MARC1) 在人类和小鼠中的不同作用
Eriks Smagris1, Lisa M Shihanian1, Ivory J Mintah1
1Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America.
PLoS genetics
|March 4, 2024
概括
在MARC1基因的常见变异保护人类免受肝脏疾病. 然而,小鼠研究表明,Marc1缺乏不能防止肝脏问题,这显示了物种之间MARC1功能的显著差异.
科学领域:
- 遗传学 遗传学 是一个
- 肝病学 肝病学是一种肝病学.
- 生物化学 生物化学
背景情况:
- 人类全基因组关联研究将MARC1基因变异 (p.Ala165Thr,p.Met187Lys) 与减少肝脂肪和保护肝硬化相关联.
- 在MARC1中罕见的功能丧失变异也与人类类似的保护性表型有关.
研究的目的:
- 研究MARC1变异的功能后果,并探索该基因在肝脏健康中的作用.
- 用小鼠模型来确定MARC1的抑制或删除是否赋予肝脏保护.
主要方法:
- 在54万个个体中进行了exome-wide协会研究.
- 在实验室内对复合人类MARC1蛋白进行研究.
- 产生和分析Marc1淘汰赛小鼠.
主要成果:
- 人类研究证实MARC1变异与肝脏健康益处有关.
- 在体外研究表明,MARC1 p.Ala165Thr的替代导致蛋白质不稳定和错位.
- 马克1淘汰赛小鼠没有表现出对肝硬化症,炎症或纤维化的保护.
- 马克1在小鼠肝脏中起到较小的作用,而马克2是主要的对应物.
结论:
- 在人类中,MARC1变异赋予肝脏保护,可能是通过涉及蛋白质不稳定的机制.
- 在人类和小鼠中,MARC1的生理作用显著不同,而Marc2是小鼠的主要酶.
- 鼠标模型可能无法准确地复制人类对MARC1调节的反应,以治疗肝脏疾病.
相关概念视频
01:19Translocation of Proteins into the Mitochondria
3.1K
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
3.1K
01:46Electron Transport Chain: Complex I and II
13.3K
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
13.3K
01:45Mitochondrial Membranes
10.3K
A single mitochondrion is a bean-shaped organelle enclosed by a double-membrane system. The outer membrane of mitochondria is smooth and contains many porins - the integral membrane transporters. Porins enable free diffusion of ions and small uncharged molecules through the outer mitochondrial membrane but limit the transport of molecules larger than 5000 Daltons. Further, the outer mitochondrial membrane forms a unique structure called membrane contact sites with other subcellular organelles,...
10.3K
02:59Animal Mitochondrial Genetics
7.6K
Among all the organelles in an animal cell, only mitochondria have their own independent genomes. Animal mitochondrial DNA is a double-stranded, closed-circular molecule with around 20,000 base pairs. Mitochondrial DNA is unique in that one of its two strands, the heavy, or H, -strand is guanine rich, whereas the complementary strand is cytosine rich and called the light, or L, -strand. Compared to nuclear DNA, mitochondrial DNA has a very low percentage of non-coding regions and is marked by...
7.6K