Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia–reperfusion: Therapeutic potential of mitochondrially targeted antioxidants

Mitochondrial reactive oxygen species generation has been implicated in the pathophysiology of ischemia–reperfusion (I/R) injury; however, its exact role and its spatial–temporal relationship with inflammation are elusive. Herein we explore the spatial–temporal relationship of oxidative/nitrative stress and inflammatory response during the course of hepatic I/R and the possible therapeutic potential of mitochondrial-targeted antioxidants, using a mouse model of segmental hepatic ischemia–reperfusion injury. Hepatic I/R was characterized by early (at 2 h of reperfusion) mitochondrial injury, decreased complex I activity, increased oxidant generation in the liver or liver mitochondria, and profound hepatocellular injury/dysfunction with acute proinflammatory response (TNF-α, MIP-1α/CCL3, MIP-2/CXCL2) without inflammatory cell infiltration, followed by marked neutrophil infiltration and a more pronounced secondary wave of oxidative/nitrative stress in the liver (starting from 6 h of reperfusion and peaking at 24 h). Mitochondrially targeted antioxidants, MitoQ or Mito-CP, dose-dependently attenuated I/R-induced liver dysfunction, the early and delayed oxidative and nitrative stress response (HNE/carbonyl adducts, malondialdehyde, 8-OHdG, and 3-nitrotyrosine formation), and mitochondrial and histopathological injury/dysfunction, as well as delayed inflammatory cell infiltration and cell death. Mitochondrially generated oxidants play a central role in triggering the deleterious cascade of events associated with hepatic I/R, which may be targeted by novel antioxidants for therapeutic advantage.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (426 K)Download as PowerPoint slideHighlights► Ischemia–reperfusion (I/R) injury is a pivotal mechanism of organ damage/dysfunction. ► The exact role and timing of mitochondrial oxidant generation in liver I/R are elusive. ► Mitochondrial oxidant generation triggers I/R-induced liver inflammation and injury. ► Mitochondrial antioxidants (MTAs) prevent I/R-induced oxidative/nitrative injury. ► MTAs prevent I/R-induced acute/delayed inflammatory response and cell death.