1. A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.
- Author
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Xiaolei Liu, Devadiga, Sudhish A., Stanley, Robert F., Morrow, Ryan M., Janssen, Kevin A., Quesnel-Vallières, Mathieu, Pomp, Oz, Moverley, Adam A., Chenchen Li, Skuli, Nicolas, Carroll, Martin, Jian Huang, Wallace, Douglas C., Lynch, Kristen W., Abdel-Wahab, Omar, and Klein, Peter S.
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HEMATOLOGIC malignancies , *GLYCOGEN synthase kinase , *MITOCHONDRIA , *ACUTE myeloid leukemia , *CELL physiology , *MITOCHONDRIAL pathology - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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