Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies
Xiaolei Liu, … , Omar Abdel-Wahab, Peter S. Klein
Xiaolei Liu, … , Omar Abdel-Wahab, Peter S. Klein
Published May 7, 2024
Citation Information: J Clin Invest. 2024;134(12):e175619. https://doi.org/10.1172/JCI175619.
View: Text | PDF
Research Article Hematology Oncology Article has an altmetric score of 9

A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies

  • Text
  • PDF
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.

Authors

Xiaolei Liu, Sudhish A. Devadiga, Robert F. Stanley, Ryan M. Morrow, Kevin A. Janssen, Mathieu Quesnel-Vallières, Oz Pomp, Adam A. Moverley, Chenchen Li, Nicolas Skuli, Martin Carroll, Jian Huang, Douglas C. Wallace, Kristen W. Lynch, Omar Abdel-Wahab, Peter S. Klein

×

Figure 7

Targeting mitophagy in SRSF2-mutant hematologic malignancies.

Options: View larger image (or click on image) Download as PowerPoint
Targeting mitophagy in SRSF2-mutant hematologic malignancies.
(A and B) ...
(A and B) Quantification of mitochondrial parameters in WT and SRSF2P95H/+ cells treated with DMSO or 3 μM CHIR. (A) MMP per mitochondrion. (B) MTG. (C) GSEA showing mitochondria-related enrichment plots for CHIR- versus DMSO-treated WT and SRSF2P95H/+ cells. (D) Schematic of generation of WT and SRSF2P95H/+ stable lines overexpressing PINK1 for apoptosis assay with or without CHIR. (E) Percentages of viable and early- and late-apoptotic cells in PINK1-overexpressing WT and SRSF2P95H/+cells treated with DMSO or 3 μM CHIR in vitro for 8 days. (F) Quantification of mitochondrial mass by MTG staining in WT and SRSF2P95H/+ cells treated with vehicle or indicated concentrations of CQ for 6 days. (G and H) Percentage of viable cells based on 7-AAD and annexin V flow cytometric analysis of WT and SRSF2P95H/+ cells treated with vehicle, 20 μM CQ (G), or 2 μM Lys05 (H) in vitro. (I) Schematic representation of lentiviral delivery of SRSF2WT or SRSF2P95H to primary AML cells for CQ and Lys05 treatment followed by apoptosis assay. (J and K) Representative flow cytometric analysis (left) and quantification (right) of apoptosis in primary cells from patients with AML overexpressing either WT or SRSF2P95H, as measured by annexin V and 7-AAD staining in the absence or presence of 15 μM CQ (J) or 2 μM Lys05 (K) for 4 days. Data in A, B, and F–H are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 (2-way ANOVA with Šidák’s multiple-comparison test). For data in E, J, and K, statistical analysis was performed using a 2-tailed χ2 test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Blogged by 1
Posted by 3 X users
14 readers on Mendeley
See more details