Dynamic changes of mitochondrial homeostasis and immune-inflammatory signaling during hemorrhagic shock resuscitation associated ischemia-reperfusion injury

Traumatic hemorrhagic shock is a common and life-threatening condition following severe trauma, characterized by reduced effective circulating blood volume and insufficient tissue perfusion, ultimately leading to an imbalance between oxygen supply and demand as well as progressive multi-organ dysfunction. Fluid resuscitation is essential for restoring hemodynamic stability; however, it may simultaneously trigger or aggravate ischemia-reperfusion injury (IRI). Emerging evidence suggests that disruption of mitochondrial homeostasis represents not only a critical cellular basis underlying organ injury during hemorrhagic shock resuscitation, but also an important driver of immune activation and inflammatory amplification. At the level of mitochondrial homeostasis regulation, the ischemia-reperfusion process exhibits distinct phasic alterations across the ischemic phase, early reperfusion, and late reperfusion stages. These dynamic changes are primarily characterized by metabolic reprogramming, excessive oxidative stress, mitochondrial dynamics imbalance, impaired mitophagy, loss of mitochondrial membrane integrity, and the release of mitochondria-derived damage-associated molecular patterns (DAMPs). Collectively, these events contribute to the initiation and progression of IRI and further promote dysregulated inflammatory responses. This review summarizes the phasic alterations of mitochondrial homeostasis and their interactions with immune-inflammatory pathways during hemorrhagic shock resuscitation. Understanding these temporal mechanisms may provide a rationale for stage-specific mitochondrial-targeted therapeutic strategies aimed at improving organ protection and modulating dysregulated immune-inflammatory responses.