MTFR2-dependent mitochondrial fission promotes HCC progression

Area of Science:

• Mitochondrial biology
• Oncology
• Genomics

Background:

• Mitochondrial dynamics (fission, fusion, mitophagy) are crucial in cancer, but their specific role in hepatocellular carcinoma (HCC) requires further investigation.
• Understanding mitochondrial dynamics in HCC can reveal new prognostic markers and therapeutic targets.

Purpose of the Study:

• To investigate the impact of mitochondrial dynamics on HCC progression.
• To develop a prognostic model based on mitochondrial dynamic genes for HCC patients.
• To explore the relationship between mitochondrial status, immune infiltration, and therapeutic response in HCC.

Main Methods:

• Mitochondrial dynamic genes from MitoCarta 3.0 and gene expression data from TCGA were analyzed.
• Patients were clustered based on gene expression, and a prognostic model was built using COX and LASSO regression.
• Immune infiltration, tumor mutational burden (TMB), tumor stemness indices (TSI), and immune checkpoint block (ICB) response were assessed.
• Morphological and protein expression analyses were performed using TEM, H&E, IHC, WB, and IF.

Main Results:

• Two patient clusters were identified, with Cluster 2 showing increased mitochondrial fission and worse prognosis.
• A ten-gene prognostic signature was developed, with all genes upregulated in the high-risk group and linked to MTFR2-mediated mitochondrial fission.
• High-risk patients exhibited unfavorable prognosis, higher TP53 mutation frequency, increased immune checkpoint expression, higher TIS, and lower TIDE scores.
• Increased mitochondrial fission and elevated MTFR2 and DNM1L expression were confirmed in HCC tissues and cell lines.

Conclusions:

• A novel ten-gene prognostic signature related to MTFR2 and mitochondrial fission was developed for HCC.
• These genes are crucial for mitochondrial fission and show potential as predictive biomarkers and therapeutic targets for HCC.