Mitochondrial dysfunction is a major cause of thromboinflammation and inflammatory cell death in critical illnesses.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.