Our data demonstrate significantly greater sensitivity to mitophagy/autophagy inhibitors in SRSF2P95/+ cells, reveal a mechanism connecting this leukemogenic splicing factor mutation to mitochondrial dysfunction and increased mitophagy, and identify PINK1 splicing as a targetable vulnerability in SRSF2-mutated AML and MDS. Here, SRSF2 is linked to myelodysplastic syndrome.