Iba Toshiaki, Helms Julie, Maier Cheryl L, Ferrer Ricard, Levy Jerrold H
Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan.
Inflamm Res. 2025 Jan 13;74(1):17. doi: 10.1007/s00011-025-01994-w.
Mitochondria generate the adenosine triphosphate (ATP) necessary for eukaryotic cells, serving as their primary energy suppliers, and contribute to host defense by producing reactive oxygen species. In many critical illnesses, including sepsis, major trauma, and heatstroke, the vicious cycle between activated coagulation and inflammation results in tissue hypoxia-induced mitochondrial dysfunction, and impaired mitochondrial function contributes to thromboinflammation and cell death.
A computer-based online search was performed using the PubMed and Web of Science databases for published articles concerning sepsis, trauma, critical illnesses, cell death, mitochondria, inflammation, coagulopathy, and organ dysfunction.
Mitochondrial outer membrane permeabilization triggers apoptosis by releasing cytochrome c and activating caspases. Apoptosis is a non-inflammatory programmed cell death but requires sufficient ATP supply. Therefore, conversion to inflammatory necrosis may occur due to a lack of ATP in critical illness. Severely damaged mitochondria release excess reactive oxygen species and injurious mitochondrial DNA, inducing cell death. Besides non-programmed necrosis, mitochondrial damage can trigger programmed inflammatory cell death, including necroptosis, pyroptosis, and ferroptosis. Additionally, a unique form of DNA-ejecting cell death, known as etosis, occurs in monocytes and granulocytes following external stimuli and mitochondrial damage. The type of cell death chosen remains uncertain but is known to depend on the cell type, the nature of the injury, and the degree of damage.
Mitochondria damage is the major contributor to the cell death mechanism that leads to organ damage in critical illnesses. Regulating and restoring mitochondrial function holds promise for developing new therapeutic approaches for mitigating critical diseases.
线粒体产生真核细胞所需的三磷酸腺苷（ATP），作为其主要能量供应者，并通过产生活性氧参与宿主防御。在许多危重病中，包括脓毒症、重大创伤和中暑，激活的凝血与炎症之间的恶性循环导致组织缺氧诱导的线粒体功能障碍，而线粒体功能受损又会导致血栓炎症和细胞死亡。
利用PubMed和Web of Science数据库进行基于计算机的在线搜索，以查找有关脓毒症、创伤、危重病、细胞死亡、线粒体、炎症、凝血病和器官功能障碍的已发表文章。
线粒体外膜通透性改变通过释放细胞色素c和激活半胱天冬酶触发细胞凋亡。细胞凋亡是一种非炎症性程序性细胞死亡，但需要充足的ATP供应。因此，在危重病中，由于ATP缺乏可能会转变为炎症性坏死。严重受损的线粒体释放过量的活性氧和有害的线粒体DNA，诱导细胞死亡。除了非程序性坏死外，线粒体损伤还可触发程序性炎症细胞死亡，包括坏死性凋亡、焦亡和铁死亡。此外，一种独特的DNA排出性细胞死亡形式，即噬红细胞作用，在外源刺激和线粒体损伤后发生于单核细胞和粒细胞中。所选择的细胞死亡类型尚不确定，但已知取决于细胞类型、损伤性质和损伤程度。
线粒体损伤是导致危重病中器官损伤的细胞死亡机制的主要因素。调节和恢复线粒体功能有望为开发减轻危重病的新治疗方法带来希望。
