# Crosstalk of mitochondrial dysfunction and macrophage polarization in sepsis

## TL;DR

This review explores how mitochondrial dysfunction and macrophage behavior interact during sepsis, offering new insights into potential treatments.

## Contribution

The paper highlights new molecular insights into mitochondrial-macrophage crosstalk in sepsis and their therapeutic potential.

## Key findings

- Mitochondrial dysfunction contributes to sepsis progression by altering immune cell metabolism.
- Metabolites from mitochondria modulate immune signaling and macrophage polarization.
- Mitochondrial pathways show potential as biomarkers and therapeutic targets for sepsis.

## Abstract

Sepsis is a complex condition marked by significant dysregulation of immune and metabolic processes, leading to multi-organ failure. Macrophages, key mediators of immune activity, demonstrate functional flexibility by switching between pro- and anti-inflammatory phenotypes in response to inflammatory and metabolic signals in their local environment. During sepsis, pathogen-derived signals activate host defense responses that impair intercellular oxygen transport, increase oxygen consumption by immune cells within inflamed tissues, and promote a metabolic transition toward aerobic glycolysis. This metabolic transition supports immune defense mechanisms, and the metabolic by-products further regulate immune activation through feedback in key signaling cascades, promoting a transition toward tolerance during the resolution phase. Since mitochondria are central hubs for cellular energy homeostasis, they play a crucial role in this process. Mitochondrial dysfunction and metabolic changes are now recognized as major contributors to the progression of sepsis. The accumulation of mitochondria-derived metabolites can further modulate immune signaling pathways, actively influencing macrophage function. Therefore, this review emphasizes the crosstalk between macrophage polarization and mitochondrial changes, with a focus on new molecular insights and the potential of mitochondrial pathways as biomarkers or therapeutic targets. These concepts provide a foundation for advancing both experimental research and clinical applications, potentially guiding future interventions to better manage sepsis and its associated mortalities.