Overexpression of carnitine palmitoyltransferase 1A promotes mitochondrial fusion and differentiation of glioblastoma stem cells

The authors demonstrate that carnitine palmitoyltransferase 1A (CPT1A) expression is reduced in glioma stem cells (GSCs) in comparison with non-stem tumor cells. CPT1A overexpression promotes mitochondrial fusion and GSC differentiation by increasing the phosphorylation of dynamin-related protein 1 (Drp1) at Ser-637, thus impairing GSC-derived xenograft growth and prolonging survival in tumor-bearing mice. These results suggest that CPT1A could be a molecular target for GSC differentiation therapy. Glioma stem cells (GSCs) are self-renewing tumor cells with multi-lineage differentiation potential and the capacity of construct glioblastoma (GBM) heterogenicity. Mitochondrial morphology is associated with the metabolic plasticity of GBM cells. Previous studies have revealed distinct mitochondrial morphologies and metabolic phenotypes between GSCs and non-stem tumor cells (NSTCs), whereas the molecules regulating mitochondrial dynamics in GBM cells are largely unknown. Herein, we report that carnitine palmitoyltransferase 1A (CPT1A) is preferentially expressed in NSTCs, and governs mitochondrial dynamics and GSC differentiation. Expressions of CPT1A and GSC marker CD133 were mutually exclusive in human GBMs. Overexpression of CPT1A inhibited GSC self-renewal but promoted mitochondrial fusion. In contrast, disruption of CPT1A in NSTCs promoted mitochondrial fission and reprogrammed NSTCs toward GSC feature. Mechanistically, CPT1A overexpression increased the phosphorylation of dynamin-related protein 1 at Ser-637 to promote mitochondrial fusion. In vivo, CPT1A overexpression decreased the percentage of GSCs, impaired GSC-derived xenograft growth and prolonged tumor-bearing mice survival. Our work identified CPT1A as a critical regulator of mitochondrial dynamics and GSC differentiation, indicating that CPT1A could be developed as a molecular target for GBM cell-differentiation strategy.