A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.

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 SRSF2^P95H/+ 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. SRSF2^P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2^P95H/+

SUBMITTER: Liu X 

PROVIDER: S-EPMC11071312 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature