代谢重新连接可以防止由慢性线粒体功能障碍引起的神经退行
Shlesha Richhariya1, Daniel Shin1, Matthias Schlichting1
1Howard Hughes Medical Institute, Department of Biology, Brandeis University, Waltham, MA 02454, USA.
Current biology : CB
|October 28, 2025
概括
线粒体融合对神经元的生存至关重要,其破坏与神经退行有关. 抑制乳酸脱酶 (Ldh) 能防止这种依赖于年龄的神经元损伤.
科学领域:
- 神经科学是一个神经科学.
- 细胞生物学 细胞生物学
- 遗传学 是一个遗传学.
背景情况:
- 线粒体分裂-融合循环对于神经元健康至关重要,但在长寿神经元中人们对其了解甚少.
- 这个循环中的功能障碍与神经退行性疾病有关.
- 人类线粒体融合基因Opa1的突变导致光学缩.
研究的目的:
- 为了研究线粒体分裂和融合在多索菲拉神经元中的作用.
- 描述线粒体融合缺陷的分子反应,特别是Opa1.1.
- 确定保护神经元免受由融合障碍引起的年龄相关变性退化的机制.
主要方法:
- 利用特定于细胞类型的CRISPR来敲除Drosophila神经元中的裂变和融合基因.
- 进行了转录基因分析,以研究对Opa1淘汰赛的年龄相关反应.
- 采用双淘汰策略来评估乳酸脱酶 (Ldh) 和ATF4.4的作用.
主要成果:
- 线粒体分裂和融合对于基本的神经元的生存和功能都不是必不可少的.
- 线粒体融合缺陷,特别是Opa1淘汰,比裂变缺陷的影响更大,特别是在老的神经元中.
- Opa1淘汰诱导了与年龄相关的转录基因转移,类似于癌细胞,包括Ldh上调.
- 发现Ldh上调具有神经保护作用,对于维持ATP水平和预防退化至关重要.
- 转录因子ATF4调节Ldh的神经保护性上调.
结论:
- 线粒体融合对神经元的生存能力比裂变更为关键,特别是在年龄增长时.
- 损坏的线粒体融合触发了神经元生存的代谢重编程 (类似于癌症中的沃堡效应).
- 准Ldh提供了一种潜在的治疗策略,可以对抗由线粒体功能障碍引起的依赖年龄的神经退行.
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
01:37Mitochondria
19.5K
Mitochondria are eukaryotic cellular organelles that are known to produce energy through a process called oxidative phosphorylation. Besides their primary function, mitochondria are involved in various cellular processes, including cell growth, differentiation, signaling, metabolism, and senescence. Age-related changes cause a decline in mitochondrial quality and integrity due to increased mitochondrial mutations and oxidative damage. Thus, aging can severely impact mitochondrial functions,...
19.5K
01:45Mitochondrial Membranes
16.6K
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,...
16.6K
01:15Neurogenesis and Regeneration of Nervous Tissue
1.5K
In the CNS, neurogenesis, the birth of new neurons from stem cells, is limited to the hippocampus in adults. In other regions of the brain and spinal cord, neurogenesis is almost non-existent due to inhibitory influences from neuroglia, especially oligodendrocytes, and the absence of growth-stimulating cues. The myelin produced by oligodendrocytes in the CNS inhibits neuronal regeneration. Furthermore, astrocytes proliferate rapidly after neuronal damage, forming scar tissue that physically...
1.5K