Targeting mitophagy in SRSF2 mutant hematologic malignancies
Liu, X.; Devadiga, S. A.; Stanley, R. F.; Moroow, R.; Janssen, K.; Quesnel-Vallieres, M.; Pomp, O.; Moverley, A. A.; Li, C.; Skuli, N.; Carroll, M. P.; Huang, J.; Wallace, D. C.; Lynch, K. W.; Abdel-Wahab, O.; Klein, P. S.
Show abstract
Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2P95H mutant MDS and AML.
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