了解多重线粒体功能障碍综合征2的分子基础:导致疾病的BOLA3的his96Arg突变
Beatrice Bargagna1,2, Lucia Banci1,2,3, Francesca Camponeschi1,2,3
1Department of Chemistry, University of Florence, Via Della Lastruccia 3, Sesto Fiorentino, 50019 Florence, Italy.
International journal of molecular sciences
|July 29, 2023
概括
在BOLA3中His96Arg突变导致严重的多重线粒体功能障碍综合征2型 (MMDS2) 通过创建一个有缺陷的铁-硫集群复合体,损害能量代谢和酶功能.
科学领域:
- 生物化学 生物化学
- 线粒体生物学 线粒体生物学
- 遗传学 是一个遗传学.
背景情况:
- 多重线粒体功能障碍综合征2型 (MMDS2) 是一种严重的代谢障碍,与BOLA3基因突变有关.
- 玻拉3对于铁硫 (Fe-S) 集群生物发生至关重要,对于线粒体 [4Fe-4S] 蛋白质成熟至关重要.
研究的目的:
- 研究BOLA3 p.His96Arg突变对蛋白质性质的结构和功能影响.
- 了解与这种突变相关的严重MMDS2表型的分子基础.
主要方法:
- 使用大小排除色谱,NMR,紫外线可见,圆形二元化和EPR光谱学进行蛋白质表征.
- 在 [4Fe-4S] 集群组合中分析BOLA3-GLRX5异构复合物的形成和功能.
主要成果:
- 这种His96Arg突变不会破坏BOLA3与其伴侣GLRX5.5的结合.
- 一个非功能性异常的BOLA3-[2Fe-2S]-GLRX5异构复合物形成,阻碍了NFU1.1上的 [4Fe-4S]集群组装.
- 观察到线粒体呼吸复合体和依赖脂酸的酶的缺陷.
结论:
- 在BOLA3中His96Arg突变导致MMDS2通过形成一个异常的异构复合体,损害Fe-S集群生物发生.
- 这项研究为MMDS2在患有His96Arg突变的患者中严重的临床表现提供了分子理由.
相关概念视频
Animal Mitochondrial Genetics
7.7K
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...
7.7K
Translocation of Proteins into the Mitochondria
3.2K
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,...
3.2K
Electron Transport Chain: Complex I and II
14.5K
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...
14.5K
Porin Insertion in the Outer Mitochondrial Membrane
3.1K
Porins are beta-barrel proteins translocated to the mitochondrial outer membrane through the TOM complex into the intermembrane space. Porin precursors bind TIM chaperones within the intermembrane space and are guided to the Sorting and Assembly Machinery complex or SAM complex on the outer mitochondrial membrane.
Three models describe the assembly of porins by the SAM complex and their insertion into the outer membrane. Model 1 suggests that porins are assembled outside the SAM channel as the...
Three models describe the assembly of porins by the SAM complex and their insertion into the outer membrane. Model 1 suggests that porins are assembled outside the SAM channel as the...
3.1K
Mitochondrial Membranes
11.6K
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,...
11.6K
ATP Synthase: Mechanism
14.8K
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
14.8K


