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Saturated Fatty Acids Induce Ceramide-associated Macrophage Cell Death
Published on: October 31, 2017
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Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1
Tristen Wright1, Meghan E Turnis2, Christy R Grace3
1Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Molecular Cell
|March 19, 2024
Summary
MCL-1 protein supports long-chain fatty acid metabolism by binding to ACSL enzymes. Disrupting this interaction impairs fatty acid oxidation and may explain cardiac side effects of MCL-1 inhibitors.
Area of Science:
- Cellular Biology
- Biochemistry
- Cancer Research
Background:
- MCL-1 is crucial for cell survival and chemoresistance in cancer.
- MCL-1's role in mitochondrial metabolism is known but mechanistically unclear.
- Its function beyond apoptosis regulation requires further investigation.
Purpose of the Study:
- To elucidate the mechanism by which MCL-1 modulates mitochondrial metabolism.
- To investigate the link between MCL-1 and fatty acid oxidation.
- To explore the implications for cancer therapy and potential toxicities.
Main Methods:
- Investigated MCL-1 interactions with ACSL family members in cells and tissues.
- Utilized genetic manipulation (Mcl1 loss), mutagenesis, and BH3-mimetic inhibitors.
- Assessed long-chain fatty acid beta-oxidation (FAO) in cellular and mouse models (liver, heart).
Main Results:
- MCL-1 directly binds to ACSL1 via a non-conventional BH3-domain interaction.
- This interaction is essential for long-chain fatty acid beta-oxidation (FAO).
- Inhibition of this interaction reduces FAO in cells and in vivo, impacting mouse liver and heart.
Conclusions:
- MCL-1 facilitates mitochondrial metabolism, specifically long-chain FAO, through ACSL binding.
- Disruption of MCL-1's metabolic role may underlie cardiac toxicities observed with MCL-1 inhibitors.
- This provides a mechanistic link between MCL-1's anti-apoptotic function and its metabolic regulation.
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