Abstract
Sepsis is a severe medical condition characterized by a systemic inflammatory response, often culminating in multiple organ dysfunction and high mortality rates. In recent years, there has been a growing recognition of the pivotal role played by mitochondrial damage in driving the progression of sepsis. Various factors contribute to mitochondrial impairment during sepsis, encompassing mechanisms such as reactive nitrogen/oxygen species generation, mitophagy inhibition, mitochondrial dynamics change, and mitochondrial membrane permeabilization. Damaged mitochondria actively participate in shaping the inflammatory milieu by triggering key signaling pathways, including those mediated by Toll-like receptors, NOD-like receptors, and cyclic GMP-AMP synthase. Consequently, there has been a surge of interest in developing therapeutic strategies targeting mitochondria to mitigate septic pathogenesis. This review aims to delve into the intricate mechanisms underpinning mitochondrial dysfunction during sepsis and its significant impact on immune dysregulation. Moreover, we spotlight promising mitochondria-targeted interventions that have demonstrated therapeutic efficacy in preclinical sepsis models.
Key Points:
- Mitochondria in Sepsis: Mitochondria are central to energy production and immune responses, but their dysfunction during sepsis exacerbates inflammation and organ failure.
- Mechanisms of Damage: Reactive nitrogen and oxygen species (RNS/ROS), impaired mitophagy, and altered mitochondrial membrane permeability are key pathways of mitochondrial damage.
- Immune Dysregulation: Damaged mitochondria activate inflammatory pathways, including NLRP3 inflammasome and cGAS-STING, worsening immune imbalances.
- Oxidative Stress: Excessive ROS overwhelms antioxidative defenses, damaging mitochondrial DNA, proteins, and lipids, and perpetuating the inflammatory cycle.
- Mitophagy Impairment: The inability to clear damaged mitochondria results in their accumulation, contributing to prolonged inflammation and cellular dysfunction.
- Therapeutic Targets: Strategies such as mitochondrial-targeted antioxidants (e.g., MitoQ) and mitophagy activators (e.g., Urolithin A) show promise in preclinical studies.
- Role of Antioxidants: Mitochondria-specific antioxidants mitigate ROS damage and support mitochondrial function, reducing sepsis-related mortality.
- Metabolic Reprogramming: Sepsis-induced shifts from oxidative phosphorylation to glycolysis are adaptive but may lead to energy deficits in vital organs.
- Clinical Translation: Preclinical successes underscore the need for clinical trials to validate mitochondrial therapies for sepsis.
- Future Directions: Research should focus on enhancing mitochondrial quality control and integrating these insights into sepsis management protocols.
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