A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies Journal Article

   

Authors:	Liu, X.; Devadiga, S. A.; Stanley, R. F.; Morrow, R. M.; Janssen, K. A.; Quesnel-Vallières, M.; Pomp, O.; Moverley, A. A.; Li, C.; Skuli, N.; Carroll, M.; Huang, J.; Wallace, D. C.; Lynch, K. W.; Abdel-Wahab, O.; Klein, P. S.
Article Title:	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 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. Copyright: © 2024, Liu et al.
Journal Title:	Journal of Clinical Investigation
Volume:	134
Issue:	12
ISSN:	0021-9738
Publisher:	American Society for Clinical Investigation
Date Published:	2024-06-17
Start Page:	e175619
Language:	English
DOI:	10.1172/jci175619
PUBMED:	38713535
PROVIDER:	scopus
PMCID:	PMC11178535
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85196818409&doi=10.1172%2fJCI175619&partnerID=40&md5=d99a89f11c0683a82b548edfaa3bfa77
Notes:	Article -- Source: Scopus

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