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Mitophagy Inhibition Promotes Survival and Mitochondrial Function in MYC-driven HCC
Biorxiv : the Preprint Server for Biology
|July 29, 2026
Summary
Hepatocellular carcinoma (HCC) driven by MYC amplification shows altered mitochondrial metabolism. Targeting mitochondrial turnover, particularly mitophagy, offers a potential therapeutic strategy for this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Mitochondrial Biology
Background:
- Hepatocellular carcinoma (HCC) is a heterogeneous cancer often driven by MYC amplification or CTNNB1 mutations.
- MYC-driven HCC exhibits complex changes in mitochondrial gene expression, with decreased mtDNA-encoded genes but increased nuclear-encoded mitochondrial genes.
Purpose of the Study:
- To investigate the role of aberrant mitochondrial metabolism in MYC- and CTNNB1-driven HCC.
- To identify potential therapeutic targets within the mitochondrial pathways dysregulated in HCC.
Main Methods:
- Generation of MYC- and CTNNB1-driven murine HCC models.
- Analysis of mitochondrial metabolism, including oxidative phosphorylation (OXPHOS) and TCA cycle activity.
- Assessment of mitochondrial turnover, reactive oxygen species (ROS) levels, mitochondrial fission, and mitophagy.
- Investigation of the role of Nuclear Respiratory Factor 1 (NRF1) and Dynamin-related protein 1 (DRP1) in mitophagy.
Main Results:
- MYC-driven HCC tumors displayed reduced OXPHOS and TCA cycle activity, correlating with increased ROS levels.
- Elevated mitochondrial turnover, characterized by increased mitochondrial fission and mitophagy, was observed in MYC-driven HCC.
- MYC upregulates NRF1, which in turn promotes mitophagy via DRP1.
- DRP1 knockout reduced mitophagy and ROS, leading to improved survival in HCC-bearing mice.
Conclusions:
- Aberrant mitochondrial metabolism, specifically increased mitochondrial turnover via mitophagy, is a hallmark of MYC-driven HCC.
- Targeting mitochondrial quality control mechanisms, such as mitophagy, represents a promising therapeutic strategy for MYC-driven HCC.
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