A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies

Area of Science:

• Molecular Biology
• Cellular Biology
• Cancer Biology

Background:

• Splicing factor mutations, particularly in SRSF2, are prevalent in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
• The functional consequences of these mutations on cellular processes, especially mitochondrial function, remain largely unknown.

Purpose of the Study:

• To elucidate how the pathogenic SRSF2P95H/+ mutation impacts cellular functions.
• To investigate the role of mitochondrial dysfunction and mitophagy in SRSF2-mutant MDS and AML.
• To identify potential therapeutic strategies targeting the observed cellular mechanisms.

Main Methods:

• Analysis of mitochondrial mRNA splicing in cells with SRSF2P95H/+ mutation.
• Assessment of mitochondrial complex I function and mitophagy levels.
• Investigation of the PINK1 splicing mechanism in response to mitochondrial stress.
• Pharmacological inhibition of splicing using a glycogen synthase kinase 3 inhibitor.

Main Results:

• The SRSF2P95H/+ mutation disrupts mitochondrial mRNA splicing, impairs mitochondrial complex I, and increases mitophagy.
• Mitochondrial dysfunction triggers a surveillance mechanism involving PINK1 splicing, enhancing PINK1 mRNA and protein levels.
• PINK1-mediated mitophagy is essential for the survival of SRSF2P95H/+ cells.
• Splicing inhibition promotes PINK1 poison intron retention, reduces mitophagy, and induces apoptosis in mutant cells.

Conclusions:

• A novel homeostatic mechanism links mitochondrial stress sensing to PINK1 splicing.
• Increased mitophagy is a key feature and a therapeutic vulnerability in SRSF2-mutant MDS and AML.
• Targeting splicing pathways offers a potential therapeutic avenue for these hematological malignancies.