A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.
J Clin Invest
; 134(12)2024 May 07.
Article
en En
| MEDLINE
| ID: mdl-38713535
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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Proteínas Quinasas
/
Leucemia Mieloide Aguda
/
Mitofagia
/
Factores de Empalme Serina-Arginina
/
Mitocondrias
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Clin Invest
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos