Mitochondria and blood-brain barrier dysfunction: a promising target for cerebrovascular disorders

The blood-brain barrier (BBB) functions as a highly selective regulatory system governing molecular transport between systemic circulation and the central nervous system. The maintenance of this strict permeability relies on the continuous, high-energy interactions of the neurovascular unit (NVU) primarily fueled by mitochondria. Sustaining the electrochemical gradients and active transport systems essential for this regulation imposes an immense metabolic burden, rendering the NVU uniquely susceptible to bioenergetic failure. This review critically evaluates the mechanistic link between mitochondrial dysfunction and specific, aberrant BBB phenotypes. We detail evidence surmising how mitochondrial dynamics within multiple NVU cell populations, including brain microvascular endothelial cells, pericytes, astrocytes and microglia, govern barrier stability. We specifically examine how mitochondrial reactive oxygen species (mtROS), aberrant fission/fusion cycles and impaired quality control precipitate tight junction disassembly and inflammatory activation. Furthermore, we explore the emerging paradigm of “mitoceuticals,” a class of therapeutics engineered to correct these bioenergetic deficits. By targeting molecular mechanisms such as mitoNEET stability and mitochondrial dynamics, these agents offer a unique strategic opportunity to preserve NVU function. We conclude by evaluating the potential of these agents to therapeutically reinforce the bioenergetic infrastructure of the NVU as a vital, yet under-explored, avenue for treating ischemic and neurodegenerative disorders.