Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development.

While deregulation of mitochondrial metabolism and cytosolic glycolysis has been well recognized in tumor cells, the role of coordinated mitochondrial oxidation and cytosolic fermentation of pyruvate, a key metabolite derived from glucose, in physiological processes is not well understood. Here, we report that knockout of PTPMT1, a mitochondrial phosphoinositide phosphatase, completely blocked postnatal cerebellar development. Proliferation of granule cell progenitors, the most actively replicating cells in the developing cerebellum, was only moderately decreased, and proliferation of Purkinje cell progenitors did not seem to be affected in knockout mice. In contrast, generation of functional Bergmann glia from multipotent precursor cells (radial glia), which is essential for cerebellar corticogenesis, was totally disrupted. Moreover, despite a low turnover rate, neural stem cells were impaired in self-renewal in knockout mice. Mechanistically, loss of PTPMT1 decreased mitochondrial aerobic metabolism by limiting utilization of pyruvate, which resulted in bioenergetic stress in neural precursor/stem cells but not in progenitor or mature cells, leading to cell cycle arrest through activation of the AMPK-p19/p21 pathway. This study suggests that mitochondrial oxidation of the carbohydrate fuel is required for postnatal cerebellar development, and identifies a bioenergetic stress-induced cell cycle checkpoint in neural precursor/stem cells.