由PARL缺乏引起的线粒体缺陷导致精子生成和铁亡的停止
Enrico Radaelli1, Charles-Antoine Assenmacher1, Jillian Verrelle1
1Department of Pathobiology, Comparative Pathology Core, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United States.
eLife
|July 28, 2023
概括
男性不孕症中的线粒体功能障碍:PARL缺乏导致丸缩,通过阻止精子生成并触发细胞死亡途径铁亡. 这揭示了对线粒体疾病和男性生殖健康的新见解.
科学领域:
- 线粒体生物学 线粒体生物学
- 生殖生物学 生殖生物学
- 细胞死亡途径 细胞死亡途径
背景情况:
- 线粒体疾病与精子发生障碍和男性不孕症有关,但机制尚不清楚.
- 线粒体蛋白酶PARL与线粒体平衡和疾病有关.
- 利氏综合症小鼠模型中的PARL缺陷,为研究生殖过程中的线粒体功能障碍提供了一个模型.
研究的目的:
- 研究PARL在精子生成和男性生育能力中的作用.
- 阐明将PARL缺乏与丸功能障碍联系起来的分子机制.
- 探索铁病在PARL相关的男性不孕症中的潜在参与.
主要方法:
- 产生和分析缺乏PARL的小鼠.
- 对丸组织学和精子生成进展的评估.
- 线粒体功能分析,包括电子运输链活动和CoQ生物合成.
- 对GPX4表达和脂质过氧化标记物的评估.
- 研究精子细胞中的铁亡标记物.
主要成果:
- 帕尔缺乏导致早期丸缩和完全停止精子生成在介质前期I.
- 缺少PARL的精子细胞表现出线粒体超结构异常,电子转移链缺陷,并破坏了CoQ生物合成.
- 观察到GPX4表达的生殖细胞特异性下降,导致停止的精子细胞中的铁亡.
- 通过对GPX4和辅酶Q (CoQ) 的同时作用,PARL缺乏引发了铁亡.
结论:
- PARL对于精子生成和男性生育能力至关重要.
- 在缺乏PARL的小鼠中,线粒体缺陷会在初级精子细胞中启动铁亡.
- 这项研究强调了铁亡作为线粒体疾病和男性不孕症的病原体的关键参与者.
相关概念视频
01:20Inborn Errors of Metabolism
199
Phenylketonuria (PKU) is a protein metabolism disorder characterized by high blood levels of the amino acid phenylalanine. This results from a mutation in the gene responsible for phenylalanine hydroxylase, an enzyme that converts phenylalanine into tyrosine. When this enzyme is deficient, phenylalanine builds up in the blood, leading to symptoms such as vomiting, rashes, seizures, growth deficiency, and severe mental retardation. An early diagnosis and a diet restricting phenylalanine intake...
199
01:27Protein Import into the Peroxisomes
3.5K
Cells contain membrane-bound organelles called peroxisomes that oxidize organic molecules by transferring hydrogen atoms to oxygen, producing hydrogen peroxide. Peroxisomes enzymatically convert the released hydrogen peroxide into water and oxygen.
Peroxisomal Protein Import:
Peroxisomes lack the genetic machinery required to code for their own proteins. Hence, most peroxisomal membrane, lumenal and transmembrane proteins are synthesized in the cytoplasm or ER and transported to the peroxisome...
Peroxisomal Protein Import:
Peroxisomes lack the genetic machinery required to code for their own proteins. Hence, most peroxisomal membrane, lumenal and transmembrane proteins are synthesized in the cytoplasm or ER and transported to the peroxisome...
3.5K
01:48ATP 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
01:16Necrosis
4.6K
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
4.6K
01:07Teratogenicity
2.5K
The ability of a drug to produce structural deformations and functional abnormalities in the developing embryo or the fetus is called teratogenicity, and the drug producing this effect is known as a teratogen. Teratogenic effects include stillbirth, miscarriage, intrauterine growth restriction, and neurocognitive delay. A teratogen may affect the embryo at different stages of development, which is important in determining the type and extent of the damage. During blastocyst formation, the early...
2.5K
01:46Electron 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