线粒体脂肪酸氧化导致衰老
Shota Yamauchi1,2, Yuki Sugiura3, Junji Yamaguchi4,5
1Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Science advances
|October 25, 2024
概括
对线粒体发出信号的DNA损伤反应触发了细胞衰老. 这个过程涉及到BNIP3,增强脂肪酸氧化和p16INK4a表达,突出线粒体.
科学领域:
- 细胞生物学 细胞生物学
- 线粒体代谢的代谢过程
- 衰老的研究研究.
背景情况:
- 细胞衰老是一种关键的压力诱导的细胞循环停止,与瘤抑制和衰老有关.
- 虽然已知核DNA损伤会诱导衰老,但将其与这个过程联系在一起的精确机制在很大程度上仍未知.
- 了解将DNA损伤与衰老联系在一起的信号通路对于衰老和癌症研究至关重要.
研究的目的:
- 阐明DNA损伤反应信号触发细胞衰老的机制.
- 研究线粒体在调解衰老对DNA损伤反应中的作用.
- 在与衰老相关的疾病中确定治疗干预的新目标.
主要方法:
- 利用全基因组的小干扰RNA屏幕来识别参与衰老诱导的关键蛋白质.
- 采用了包括西方涂抹,代谢学 (稳定同位素标记) 和基于细胞的测试来分析线粒体功能和基因表达的技术.
- 调查了在DNA损伤反应途径中,阿塔克西亚特朗基切塔西亚突变 (ATM) 激酶和BNIP3蛋白的作用.
主要成果:
- 鉴定了外层线粒体蛋白BNIP3作为DNA损伤后衰老诱导的关键媒介.
- 证明DNA损伤反应信号酸化物BNIP3,导致线粒体晶状体的增加和脂肪酸氧化 (FAO) 的增强.
- 显示增加的FAO增强了基因素乙化,并上调了依赖环林的激酶抑制剂p16INK4a的表达,从而导致衰老.
- 仅粮农组织的药理活性就足以在体外和体内诱导衰老.
结论:
- 线粒体能量代谢,特别是增强的脂肪酸氧化,在诱导细胞衰老中起着至关重要的作用.
- DNA损伤反应途径汇聚在线粒体上,利用BNIP3和FAO促进衰老.
- 线粒体能量代谢是控制衰老和癌症中细胞衰老的潜在治疗点.
相关概念视频
01:37Mitochondria
11.3K
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,...
11.3K
01:46Electron Transport Chain: Complex I and II
12.0K
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...
12.0K
01:45Mitochondrial Membranes
9.0K
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,...
9.0K
01:15Pyruvate Oxidation
158.5K
After glycolysis, the charged pyruvate molecules enter the mitochondria via active transport and undergo three enzymatic reactions. These reactions ensure that pyruvate can enter the next metabolic pathway so that energy stored in the pyruvate molecules can be harnessed by the cells.
First, the enzyme pyruvate dehydrogenase removes the carboxyl group from pyruvate and releases it as carbon dioxide. The stripped molecule is then oxidized and releases electrons, which are then picked up by NAD+...
First, the enzyme pyruvate dehydrogenase removes the carboxyl group from pyruvate and releases it as carbon dioxide. The stripped molecule is then oxidized and releases electrons, which are then picked up by NAD+...
158.5K
02:15Replicative Cell Senescence
3.6K
Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds...
3.6K
01:28Overview of Fatty Acid Metabolism
30.2K
Lipids also are sources of energy that power cellular processes. Like carbohydrates, lipids are composed of carbon, hydrogen, and oxygen, but these atoms are arranged differently. Most lipids are nonpolar and hydrophobic. Major types include fats and oils, waxes, phospholipids, and steroids.
Fatty acids are catabolized in a process called beta-oxidation, which takes place in the matrix of the mitochondria and converts their fatty acid chains into two-carbon units of acetyl groups. The acetyl...
Fatty acids are catabolized in a process called beta-oxidation, which takes place in the matrix of the mitochondria and converts their fatty acid chains into two-carbon units of acetyl groups. The acetyl...
30.2K