Mitochondrial complex I controls blood brain barrier permeability

Abstract Mitochondrial electron transport chain (ETC) complexes are key mediators of energy metabolism in astrocytes and neurons, with subsequent effects on memory, behaviour and neurodegeneration. Mitochondrial dysfunction and increased blood brain barrier (BBB) permeability are known pathologies in Parkinson’s and Alzheimer’s diseases. However, knowledge of how ETC activities regulate metabolic flux and influence permeability in the BBB is lacking. Using metabolic flux control analysis we show that complex I is a critical control point for oxidative flux and permeability in brain microvascular endothelial cells derived from human induced pluripotent stem cells. Inhibition of complex I activity immediately reduced the transendothelial electrical resistance (TEER) by 60%, leading to an increase in protein transport across the BBB. These events were accompanied by a transient reduction in ATP that was recovered, along with TEER values, over an extended time period. Furthermore, while inhibition of downstream complexes III or IV decreased oxygen respiration rates, no effects on BBB permeability were identified, due to compensatory glycolytic flux and maintenance of ATP synthesis. These data show that mitochondrial complex I is critical for maintaining energy production in endothelial cells and transiently controls BBB permeability, which may contribute to brain disorders where complex I dysfunction is a hallmark.