在热应激下,ATP1A3调节蛋白质合成以保持线粒体稳定
Fumihiko Fujii1, Hikaru Kanemasa1, Sayaka Okuzono1
1Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Disease models & mechanisms
|May 28, 2024
概括
ATP1A3中的致病变体会导致儿童期交替性半 (AHC). 这项研究表明,ATP1A3功能受损导致蛋白质合成效率低下,增加了AHC患者对压力的脆弱性.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 编码Na+/K+-ATPase α3亚单元的ATP1A3中的致病变体,导致儿童期交替性半 (AHC).
- 在AHC患者中,压力下的过度症状背后的精确机制仍然不完全理解.
- Na+/K+-ATPase活动受损与AHC表型有关,但可能有其他因素的贡献.
研究的目的:
- 调查潜在的额外机制,有助于在压力条件下的AHC过度症状.
- 探索ATP1A3与RNA结合蛋白的相互作用及其在细胞应激反应中的作用.
- 阐明蛋白质合成对ATP1A3相关疾病中进展性表型的贡献.
主要方法:
- 在小鼠Neuro2a细胞中研究了ATP1A3细胞内循环 (ICL) 和RNA结合蛋白 (Eif4g,Pabpc1,Fmrp) 之间的相互作用.
- 在Neuro2a细胞中利用了siRNA介导的Atp1a3枯竭和ATP1A3-ICL p.R756C变异的异位表达.
- 在患者衍生的诱导多能干细胞 (iPSC) 和分化神经元中分析了热应激易感性,评估流反应.
主要成果:
- ATP1A3-ICL与RNA结合蛋白Eif4g,Pabpc1和Fmrp发生相互作用.
- Atp1a3 枯竭和 p.R756C 变体表达导致过度的核糖体蛋白 S6 酸化和增加热应激易感性.
- 来自患者的iPSC和神经元对热应激具有更高的脆弱性,并在ATP刺激时减少的流入.
- 这些发现表明,ATP1A3功能受损,蛋白质合成中断和细胞应激反应之间存在联系.
结论:
- 不高效的蛋白质合成是导致ATP1A3相关疾病患者,特别是p.R756C变异体患者的进展和恶化的表型的一个关键因素.
- ATP1A3与RNA结合蛋白的相互作用及其对蛋白质合成的影响代表了AHC病原发生的新机制.
- 准蛋白质合成途径可能为减轻AHC中压力诱导的恶化提供治疗策略.
相关概念视频
01:48ATP Synthase: Mechanism
14.5K
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...
14.5K
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
01:53RNA Stability
33.5K
Intact DNA strands can be found in fossils, while scientists sometimes struggle to keep RNA intact under laboratory conditions. The structural variations between RNA and DNA underlie the differences in their stability and longevity. Because DNA is double-stranded, it is inherently more stable. The single-stranded structure of RNA is less stable but also more flexible and can form weak internal bonds. Additionally, most RNAs in the cell are relatively short, while DNA can be up to 250 million...
33.5K
01:37Energy to Drive Translocation
2.1K
Mitochondrial protein import is powered by two distinct energy sources: ATP hydrolysis and electrochemical potential across the inner membrane. Newly synthesized precursors are bound by cytosolic chaperones of the Hsp70 family, which guide them to the import receptors on the mitochondrial surface. Utilizing the energy of ATP hydrolysis, Hsp70 chaperones transfer these precursors to the TOM receptors on the mitochondrial outer membrane.
Generally, polypeptides are unfolded by two distinct...
Generally, polypeptides are unfolded by two distinct...
2.1K
01:39Mitochondrial Protein Sorting
4.3K
Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death. Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
4.3K
01:39Mitochondrial Precursor Proteins
2.6K
Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70 chaperones are targetted to TOM20-TOM22 receptor complexes.
Most of the mitochondrial...
Most of the mitochondrial...
2.6K