影响复合I功能的mtDNA点突变m.10191T>C的发病是多因素过程,导致线粒体的代谢重塑
Zeinab Alsadat Ahmadi1, Alfredo Cabrera-Orefice2, Marta Zaninello3
1Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands.
Biochimica et biophysica acta. Molecular basis of disease
|October 12, 2025
概括
一种线粒体DNA突变 (ND3S45P) 通过破坏复杂I调节而导致利氏综合征,而不仅仅是活动. 这导致NADH积累和严重疾病表型.
科学领域:
- 生物化学 生化学
- 遗传学 是一个遗传学.
- 细胞生物学 细胞生物学
背景情况:
- 遗传性线粒体疾病源于各种遗传原因,通常导致严重的表型.
- 关联分子缺陷与线粒体疾病临床表现的精确机制尚不清楚.
研究的目的:
- 研究线粒体DNA突变m.10191T>C (ND3S45P) 对复合I功能和细胞代谢的影响.
- 在利氏综合征的背景下,阐明影响复合体I的调节途径.
主要方法:
- 对人类线粒体中具有ND3S45P突变的复合I活性和氧化酸化的分析.
- 在完整的突变细胞中测量氧气消耗和NADH/NAD比率.
- 在cybrids,患者纤维细胞和肌肉活检中对线粒体复合体的全面分析.
主要成果:
- 突变线粒体 (ND3S45P) 保留了30-40%的复合I活动,但表现出最小的细胞氧气消耗.
- 完整的突变细胞显示NADH/NAD比率大大增加,表明电子传输受损.
- 对复合体I的Active/Deactive过渡的能量障碍降低表明了监管功能障碍,而不仅仅是活动的丧失.
结论:
- ND3S45P突变导致利氏综合征主要是通过控制复合体I的调节途径的故障导致的.
- 这种脱轨的调节会导致NADH的积累,这对疾病的严重表型有很大贡献.
- 对线粒体复合体的进一步研究是有必要的,以确定参与复合体I调节的因素.
相关概念视频
01:46Electron Transport Chain: Complex I and II
18.4K
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...
18.4K
01:19Translocation of Proteins into the Mitochondria
12.2K
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,...
12.2K
01:48ATP Synthase: Mechanism
16.7K
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...
16.7K
01:31Translation
155.3K
Lesson: Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
155.3K
01:31Translation
17.5K
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Proteins are...
Translation Produces the Building Blocks of Life
Proteins are...
17.5K
02:59Animal Mitochondrial Genetics
9.0K
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...
9.0K