Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Cell Metab. 2019 May 7;29(5):1182-1191.e4. doi: 10.1016/j.cmet.2019.01.022. Epub 2019 Feb 21.
In Caenorhabditis elegans, mitochondrial dysfunction caused by mutation or toxins activates programs of detoxification and immune response. A genetic screen for mutations that constitutively induce C. elegans mitochondrial defense revealed reduction-of-function mutations in the mitochondrial chaperone hsp-6/mtHSP70 and gain-of-function mutations in the Mediator component mdt-15/MED15. The activation of detoxification and immune responses is transcriptionally mediated by mdt-15/MED15 and nuclear hormone receptor nhr-45. Mitochondrial dysfunction triggers redistribution of intestinal mitochondria, which requires the mitochondrial Rho GTPase miro-1 and its adaptor trak-1/TRAK1, but not nhr-45-regulated responses. Disabling the mdt-15/nhr-45 pathway renders animals more susceptible to a mitochondrial toxin or pathogenic Pseudomonas aeruginosa but paradoxically improves health and extends lifespan in animals with mitochondrial dysfunction caused by a mutation. Thus, some of the health deficits in mitochondrial disorders may be caused by the ineffective activation of detoxification and immune responses, which may be inhibited to improve health.
在秀丽隐杆线虫中，由突变或毒素引起的线粒体功能障碍会激活解毒和免疫反应程序。一个针对持续诱导线虫线粒体防御的突变的遗传筛选揭示了线粒体伴侣 hsp-6/mtHSP70 的功能丧失突变和介体成分 mdt-15/MED15 的功能获得性突变。解毒和免疫反应的激活是由 mdt-15/MED15 和核激素受体 nhr-45 转录介导的。线粒体功能障碍触发肠道线粒体的重新分布，这需要线粒体 Rho GTPase miro-1 和它的接头 trak-1/TRAK1，但不需要 nhr-45 调节的反应。使 mdt-15/nhr-45 途径失活会使动物更容易受到线粒体毒素或致病性铜绿假单胞菌的侵害，但矛盾的是，它会改善因突变引起的线粒体功能障碍动物的健康并延长其寿命。因此，线粒体疾病中的一些健康缺陷可能是由于解毒和免疫反应的无效激活引起的，为了改善健康，这些反应可能会受到抑制。
