Neonatal hypoxic–ischemic encephalopathy (HIE) is a leading cause of infant mortality and long-term neurological disability. Current treatments offer limited efficacy, especially in premature or severely affected infants. The pathology of HIE involves a cascade of cellular damage initiated by oxygen and nutrient deprivation, followed by reperfusion injury characterized by excessive reactive oxygen species (ROS) production and mitochondrial dysfunction. Cardiolipin (CL), a mitochondria-specific phospholipid, plays a critical role in maintaining mitochondrial integrity, dynamics, and quality control through mitophagy and programmed cell death. In this study, we examined changes in CL subspecies in an in vitro ischemia/reperfusion model and small and large animal models of neonatal HIE. We observed a significant increase in the ratio of monolysocardiolipin (MLCL) to CL and significant increase in saturated CL species following injury. Genetic ablation of Tafazzin protein using conditional Taz knockout mice resulted in accumulation of MLCL and demonstrated larger brain infarct size following HIE in mice, but without affecting mitochondrial respiration or mitochondrial dynamics under basal conditions. These findings suggest that CL remodeling and MLCL accumulation contribute to the progression of neonatal HIE pathology. This study highlights an underexplored mechanism linking cardiolipin remodeling to brain injury severity, offering potential therapeutic targets for neonatal HIE.
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