Sonic hedgehog (Shh) signaling is closely coupled with bioenergetics of medulloblastoma, the most common malignant pediatric brain tumor. Shh-associated medulloblastoma arises from cerebellar granule neuron precursors (CGNPs), a neural progenitor whose developmental expansion requires signaling by Shh, a ligand secreted by the neighboring Purkinje neurons. Previous observations show that Shh signaling inhibits fatty acid oxidation while driving increased fatty acid synthesis. Proliferating CGNPs and mouse Shh medulloblastomas feature high levels of glycolytic enzymes in vivo and in vitro. Since both of these metabolic processes are closely linked to mitochondrial bioenergetics, the role of Shh signaling in mitochondrial biogenesis was investigated. This report uncovers a surprising decrease in mitochondrial membrane potential (MMP) and overall ATP production in CGNPs exposed to Shh, consistent with increased glycolysis resulting in high intracellular acidity, leading to mitochondrial fragmentation. Ultrastructural examination of mitochondria revealed a spherical shape in Shh-treated cells, in contrast to the elongated appearance in vehicle-treated post-mitotic cells. Expression of mitofusin 1 and 2 was reduced in these cells, while their ectopic expression restored the mitochondrial membrane potential to the non-proliferating state and the morphology to a fused, interconnected state. Mouse Shh medulloblastoma cells featured drastically impaired mitochondrial morphology, restoration of which by ectopic mitofusin expression was also associated with a decrease in the expression of cyclin D2 protein, a marker for proliferation. Implications: This report exposes a novel role for Shh in regulating mitochondrial dynamics and rescue of the metabolic profile of tumor cells to that of non-transformed, non-proliferating cells and represents a potential avenue for development of medulloblastoma therapeutics.

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