Pathophysiological Role of Mitochondria in Sepsis

Dear Colleagues,

The objective of this Special Issue is to consolidate and advance the current understanding of the central role of mitochondria in the pathophysiology of sepsis and sepsis-induced organ dysfunction. Sepsis continues to be a leading cause of mortality in intensive care units worldwide, despite progress in antimicrobial therapy and organ support. It is increasingly recognized not only as an exaggerated inflammatory response to infection but also as a profound bioenergetic failure syndrome. This Special Issue will assemble original research, translational studies, and expert reviews that clarify mitochondrial dysfunction as a driver, biomarker, and therapeutic target in sepsis. The goal is to foster a shift from a hemodynamic-centered to a metabolism-centered paradigm in sepsis management.

Sepsis induces a life-threatening, dysregulated host response that results in cellular and organ dysfunction. Recent evidence indicates that organ failure in sepsis frequently occurs without significant cell death or tissue hypoperfusion, suggesting a functional cellular shutdown, referred to as "cytopathic hypoxia."

Mitochondria are central to this process:

1. Bioenergetic Failure: Inflammatory mediators, nitric oxide, and reactive oxygen species (ROS) inhibit key enzymes of the electron transport chain (ETC), reducing ATP synthesis even when oxygen delivery is sufficient. This energy deficit contributes to myocardial depression, immune paralysis, and renal or hepatic dysfunction.
2. Oxidative Stress and Damage: Damaged mitochondria become the primary source of mitochondrial ROS (mtROS), which amplify oxidative damage to mitochondrial DNA (mtDNA), proteins, and lipids, perpetuating a cycle of dysfunction.
3. Danger Signaling and Inflammation: Dysfunctional mitochondria release Damage-Associated Molecular Patterns (DAMPs), such as cell-free mtDNA, ATP, cardiolipin, and formyl-peptides. These molecules activate the NLRP3 inflammasome, TLR9, and cGAS-STING pathways, sustaining systemic inflammation and immunosuppression.
4. Dysregulated Dynamics and Quality Control: Sepsis disrupts mitochondrial dynamics, including the fusion and fission balance, and impairs quality control mechanisms such as mitophagy and mitochondrial biogenesis (regulated by PGC-1α and TFAM). This leads to the accumulation of dysfunctional organelles.
5. Therapeutic Frontier: Despite the significance of mitochondrial dysfunction, no current clinical therapy directly targets mitochondrial resuscitation. Advances in mitochondrial biology present new therapeutic opportunities, including mitochondria-targeted antioxidants (MitoQ, SS-31), NAD+ boosters, mitophagy inducers, and mesenchymal stem cell-derived mitochondrial transfer.

This research area is critically important because mitochondrial parameters may offer superior prognostic biomarkers compared to lactate or SOFA scores. Furthermore, mitochondrial protection represents a novel, disease-modifying strategy that could reduce the incidence of long-term post-sepsis syndrome characterized by persistent bioenergetic impairment.

Submissions are invited for original articles, review articles, systematic reviews, meta-analyses, brief communications, and experimental models addressing, but not limited to, the following topics:

• Molecular mechanisms of sepsis-induced mitochondrial dysfunction in specific organs (heart, lung, kidney, liver, brain, immune cells);
• Mitochondrial ROS, redox signaling, and oxidative phosphorylation failure in sepsis;
• Mitochondrial DAMPs (mtDNA, etc.) as biomarkers for sepsis diagnosis, severity stratification, and prognosis;
• Mitochondrial dynamics: fusion, fission (Drp1, Mfn1/2, OPA1), and mitophagy in sepsis
• Mitochondrial biogenesis and metabolic reprogramming in immune cells (immunometabolism);
• Crosstalk between mitochondria and inflammasome or innate immunity;
• Experimental models to assess mitochondrial function in vivo and in vitro (respirometry, imaging);
• Novel therapeutic strategies targeting mitochondria in sepsis and septic shock;
• Role of mitochondria in sepsis-induced long-term sequelae and post-sepsis immunosuppression;
• Translational and clinical studies evaluating mitochondrial function in septic patients.

Prof. Dr. Roberto Scatena
Guest Editor

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