TFAM

引言当细胞受到应激时，来自产生能量的线粒体的DNA如果不被清除，就会泄漏出来，引发炎症免疫反应。细胞采用一种称为自噬的质量控制系统来特异性地降解受损成分。2024年5月23日，广州医科大学冯杜团队在Nature Cell Biology 在线发表题为“TFAM is an autophagy receptor that limits  inflammation by binding to cytoplasmic mitochondrial DNA”的研究论文，该研究表明TFAM是一种自噬受体，通过结合细胞质线粒体DNA来限制炎症。该研究发现线粒体转录因子A (TFAM) -一种结合线粒体DNA (mtDNA)的蛋白质-通过自噬酶体途径(称之为核吞噬)与自噬蛋白LC3相互作用，帮助消除泄漏的mtDNA。TFAM包含一个称为LC3相互作用区(LIR)基序的分子邮政编码，使这种结合成为可能。虽然突变TFAM的LIR基序不会影响其正常的线粒体功能，但更多的mtDNA积聚在细胞质中，激活炎症信号通路。因此，TFAM介导泄漏mtDNA的自噬清除以限制炎症。确定这一机制有助于了解细胞如何利用自噬机制选择性地靶向和降解炎症mtDNA。这些发现可以为涉及线粒体损伤和炎症的疾病的研究提供信息。线粒体是通过氧化磷酸化产生ATP以支持细胞内稳态的重要细胞器。它们还参与各种生理或病理过程，如细胞死亡、炎症和活性氧(ROS)的生成。线粒体含有自己的DNA(即线粒体DNA (mtDNA))，这与核DNA不同。在哺乳动物中，mtDNA是一种环状双链DNA分子，大小约为16.5千碱基，编码氧化磷酸化复合物的基本亚基。线粒体DNA可以浓缩成一种叫做线粒体核苷的蛋白质-DNA复合物。线粒体转录因子A (Mitochondrial transcription factor A，TFAM)是类核的主要组成部分，在线粒体DNA的转录、复制和包装中起着关键作用。TFAM结合并包裹mtDNA的高迁移基团(HMG)盒，然后作为HMG蛋白执行其转录功能。在各种刺激下，mtDNA可以从线粒体释放到细胞质中。这是由于线粒体通透性破坏、电压依赖性阴离子通道(VDAC)低聚化或B细胞淋巴瘤2 (BCL2)拮抗剂/杀手和BCL2相关的X大孔的形成。之前报道过线粒体内膜蛋白禁止蛋白1调节炎症应激期间的通透性和mtDNA外排。此外，胞质内mtDNA的释放—被认为是一种损伤相关的分子模式—促进了DNA感知炎症途径的激活，包括干扰素基因的环GMP-AMP合成酶刺激物。(cGAS-STING)、Toll样受体9、NOD样受体蛋白3炎性小体和黑色素瘤2炎性小体中缺失的。自噬是哺乳动物细胞中物质周转和体内平衡的保守过程。细胞质mtDNA的去除是必要的，因为它具有促炎的性质。与受组蛋白保护的核DNA不同，mtDNA的类核结构缺乏组蛋白，使其容易受到压力或损伤。已经确定了一些线粒体自噬受体，包括含有FUN14结构域1 (FUNDC1)、BCL2相互作用蛋白3 (BNIP3)、BCL2相互作用蛋白3样(BNIP3L/NIX)，禁止蛋白2 (PHB2)和含有ATP酶家族AAA结构域3B (ATAD3B)。TFAM介导的核吞噬减轻cGAS-STING炎症通路的工作模型（Credit: Nature Cell Biology）虽然有研究调查了线粒体内mtDNA的降解，但分泌到细胞质中的mtDNA的去除机制尚不清楚。有证据表明，其他途径也可能清除mtDNA，包括那些涉及3 ' DNA外切酶3 '端修复外切酶1 (TREX1)和线粒体衍生囊泡((MDVs)的途径。然而，选择性胞质mtDNA降解的机制仍未被探索。该研究鉴定了主要的mtDNA结合蛋白TFAM作为类核清除的自噬受体。研究证明，在氧化或炎症应激期间，TFAM与微管相关蛋白1轻链3B (LC3B)相互作用，通过cGAS-STING途径减轻mtDNA诱导的炎症。因此，该研究研究为解释TFAM在这些疾病中的保护作用提供了一个潜在的途径，并表明TFAM可能是抗炎症治疗的潜在靶点。这表明mtDNA质量控制对了解mtDNA相关人类疾病的重要性。原文链接https://www-nature-com.libproxy1.nus.edu.sg/articles/s41556-024-01419-6责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

New research provides insight about the bedrock scientific principle that mitochondrial DNA -- the distinct genetic code embedded in the organelle that serves as the powerplant of every cell in the body -- is exclusively passed down by the mother. New research provides insight about the bedrock scientific principle that mitochondrial DNA -- the distinct genetic code embedded in the organelle that serves as the powerplant of every cell in the body -- is exclusively passed down by the mother. The study, a collaboration among Oregon Health & Science University and other institutions, published today in the journal Nature Genetics. Scientists have long recognized the fact that mitochondrial DNA, or mtDNA, comes exclusively from egg cells in humans, meaning only the mother contributes the genetic code carried by thousands of mitochondria necessary for energy production in every cell in the body. Previously, it was believed that paternal mtDNA was eliminated soon after a sperm fuses with an oocyte, or developing egg, during fertilization, possibly through an immune-like search-and-destroy response. However, the study found that while mature sperm do carry a small number of mitochondria, they lack intact mtDNA. "We found that each sperm cell does bring 100 or so mitochondria as organelles when it fertilizes an egg, but there is no mtDNA in them," said co-author Shoukhrat Mitalipov, Ph.D., director of the Center for Embryonic Cell and Gene Therapy at OHSU. Researchers found that sperm cells are not only devoid of intact mtDNA, but they also lacked a protein essential for mtDNA maintenance, known as mitochondrial transcription factor A, or TFAM. Scientists aren't sure why sperm are not allowed to contribute mtDNA, but Mitalipov theorizes that it may relate to the fact that a sperm uses a lot of mitochondrial energy in its biological impetus to fertilize an egg. It would thus accumulate mutations in mtDNA. The developing eggs known as oocytes, by contrast, draw energy primarily from surrounding cells, not from their own mitochondria, so maintain relatively pristine mtDNA. "Eggs pass on really good mtDNA at least partly because they don't use mitochondria as a source of energy," Mitalipov said. The 100 or so organelles in sperm are swamped by hundreds of thousands of mitochondria embedded in each egg cell -- each carrying the 37 genes in mitochondrial DNA. The contribution of only maternal mtDNA is believed to confer an evolutionary advantage by limiting the risk of accumulations of mtDNA mutations that cause disease in offspring. Mitochondria control respiration and energy production within every cell of the body, so mutations in mtDNA can cause a range of potentially fatal disorders affecting organs with high-energy demands, such as the heart, muscle and brain. To help mothers prevent passing on known mtDNA disorders to their children, Mitalipov pioneered a method called mitochondrial replacement therapy to replace mutant mtDNA through in vitro fertilization using healthy mtDNA from donor eggs. Congress has prevented the Food and Drug Administration from overseeing clinical trials using the procedure in the U.S., so clinical trials are instead being conducted overseas, including clinical trials in the United Kingdom to prevent disease and in Greece to treat infertility. Researchers write that the new discovery has important implications for human fertility and germ cell therapy. "Understanding the role of TFAM during sperm maturation and its function during fertilization may hold keys to our ability to treat certain infertility disorders, and increase the efficiency of assisted reproductive technologies," said corresponding author Dmitry Temiakov, Ph.D., a molecular biologist with Thomas Jefferson University in Philadelphia. In addition to Mitalipov and Temiakov, co-authors include William Lee, Angelica Zamudio-Ochoa, Gina Buchel and Li Li of Thomas Jefferson University; Petar Podlesniy, Margalida Puigros, Anna Calderon and Ramon Trullas of the Institute of Biomedical Research of Barcelona; Nuria Marti Gutierrez, Aleksei Mikhalchenko and Amy Koski of OHSU; and Hsin-Yao Tang of The Wistar Institute of Philadelphia. Studies conducted at Oregon Health & Science University were supported by OHSU institutional funds.

Scientists have verified the anticancer effects of Kencur, a tropical plant of the ginger family, mainly grown in Southeast Asia, in cell and animal experiments. They found that Kencur extract and its main active components significantly inhibit cancer cell growth at the cellular and animal levels. Furthermore, the involvement of TFAM in the mechanism of action was confirmed. You may know it as an aromatic spice to add flavor to your dishes or as a soothing herbal remedy to use for upset stomachs, but researchers from Osaka Metropolitan University have uncovered promising findings that Kencur, a tropical plant in the ginger family native to Southeast Asia, possesses anti-cancer effects. Led by Associate Professor Akiko Kojima of the Graduate School of Human Life and Ecology, the researchers demonstrated that Kencur extract and its main active component, ethyl p-methoxycinnamate (EMC), significantly suppressed cancer cell growth at the cellular and animal levels. While previous studies on EMC indicated its anti-cancer potential by decreasing the expression of mitochondrial transcription factor A (TFAM), which is associated with cancer cell proliferation, the exact mechanism remained unclear until now. "The results of this study confirm the anti-cancer effects of Kencur extract and its main active ingredient, EMC. It is highly expected that TFAM will become a new marker for anti-cancer effects in the future as research advances in related fields," Professor Kojima stated. Their findings were published in Heliyon.