Mitochondrial Dysfunction and White Matter Injury

SUMMARY White matter injury (WMI) is the most common cause of cerebral palsy (CP) in children. Recently, a pathological pattern of WMI have shifted from necrotic brain damage to isolated or diffuse myelination failure associated with maturational defect of olygodendrocytes (OLs). While mechanisms for OLs, and other cells degeneration in WMI have been extensively studied, the mechanisms of OLs maturational failure are cryptic. We hypothesized, that maturational failure of OLs occurs secondary to their mitochondrial dysfunction to provide adequate energy supply for OLs differentiation. This bioenergetics crisis is not lethal and caused by multiple, brief episodes of hypoxemia-reoxygenation, the event very commonly seen in premature infants. To test this hypothesis we offer a novel mouse model of WM myelination failure in which physiological changes (systemic oxygenation, heart and respiratory rates) seen in premature infants during intermittent hypoxic events were closely reproduced in neonatal mice. This model reproduces sensorimotor deficit consistent with WMI phenotype in humans. Aim 1 will determine if in this model, OLs maturational failure is the main cellular mechanism of myelination deficit. Aim 2 determines the mechanism for mitochondrial dysfunction to support OLs maturation and cerebral myelination. We propose, that during hypoxic episodes mitochondrial membrane is transiently permeabilized. This transiently arrests ATP production, as the proton motive force is lost with permeabilization of mitochondrial membrane. Given that premature infants experience 50 - 200 (!) brief hypoxemic events a day, for several postnatal weeks, bioenergetics deficit to support adequate WM development represents conceivable mechanistic hypothesis. Aim 3 determines whether an inhibition of transient permeabilization of mitochondrial membrane during intermittent hypoxia attenuates severity of WMI. Using cyclophilin D KO mice we will determine a pathogenic role for mitochondrial permeabilization in bioenergetics crisis of OLs maturation. If the main hypothesis in this proposal is confirmed, then mitochondrial failure to support proper development will be claimed as the novel mechanism for WMI. This identifies novel therapeutic goals in prevention/treatment of WMI: (1) limit mitochondrial membrane permeabilization during hypoxic event.