Hypoxic-Ischemic Encephalopathy and Mitochondrial Dysfunction: Facts, Unknowns, and Challenges.

Hypoxic-ischemic events due to intrapartum complications represent the second cause of neonatal mortality and initiate an acute brain disorder known as hypoxic-ischemic encephalopathy (HIE). In HIE, the brain undergoes primary and secondary energy failure phases separated by a latent phase in which partial neuronal recovery is observed. A hypoxic-ischemic event leads to oxygen restriction causing ATP depletion, neuronal oxidative stress, and cell death. Mitochondrial dysfunction and enhanced oxidant formation in brain cells are characteristic phenomena associated with energy failure. Mitochondrial sources of oxidants in neurons include complex I of the mitochondrial respiratory chain, as a key contributor to O production succinate by a reverse electron transport mechanism. The reaction of O with nitric oxide (NO) yields peroxynitrite, a mitochondrial and cellular toxin. Quantitation of the redox state of cytochrome oxidase, through broadband near-infrared spectroscopy, represents a promising monitoring approach to evaluate mitochondrial dysfunction in humans, in conjunction with the determination of cerebral oxygenation and their correlation with the severity of brain injury. The energetic failure being a key phenomenon in HIE connected with the severity of the encephalopathy, measurement of mitochondrial dysfunction provides an approach to assess evolution, prognosis, and adequate therapies. Restoration of mitochondrial redox homeostasis constitutes a key therapeutic goal. While hypothermia is the only currently accepted therapy in clinical management to preserve mitochondrial function, other mitochondria-targeted and/or redox-based treatments are likely to synergize to ensure further efficacy.