Dynamin-1-Like Protein Inhibition Drives Megamitochondria Formation as an Adaptive Response in Alcohol-Induced
Elena Palma1, Xiaowen Ma2, Antonio Riva1
1The Institute of Hepatology London, Foundation for Liver Research, London, United Kingdom; Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
Abstract:
Despite the growing global burden of alcoholic liver diseases, therapeutic options are limited, and novel targets are urgently needed. Accumulating evidence suggests that mitochondria adapt in response to ethanol and formation of megamitochondria in the livers of patients is recognized as a hallmark of alcoholic liver diseases. The processes involved in ethanol-induced hepatic mitochondrial changes, the impact on mitochondria-shaping proteins, and the significance of megamitochondria formation remain unknown. In this study, we investigated the mitochondrial and cellular response to alcohol in hepatoma cell line VL-17A. The mitochondrial architecture rapidly changed after 3 or 14 days of ethanol exposure with double-pronged presentation of hyperfragmentation and megamitochondria, and cell growth was inhibited. Dynamin-1-like protein (Drp1) was identified as the main mediator driving these mitochondrial alterations, and its genetic inactivation was determined to foster megamitochondria development, preserving the capacity of the cells to grow despite alcohol toxicity. The role of Drp1 in mediating megamitochondria formation in mice with liver-specific inactivation of Drp1 was further confirmed. Finally, when these mice were fed with ethanol, the presentation of hepatic megamitochondria was exacerbated compared with wild type fed with the same diet. Ethanol-induced toxicity was also reduced. Our study demonstrates that megamitochondria formation is mediated by Drp1, and this phenomenon is a beneficial adaptive response during alcohol-induced hepatotoxicity.
Insights
Alcoholic liver disease is a growing concern. This study reveals that megamitochondria formation, driven by Dynamin-1-like protein (Drp1), is a beneficial adaptation against alcohol-induced liver damage.
Area of Science:
- Hepatology
- Mitochondrial Biology
- Cellular Biology
Background:
- Alcoholic liver diseases (ALD) pose a significant global health challenge with limited therapeutic strategies.
- Mitochondrial adaptation, including megamitochondria formation, is a recognized hallmark in ALD patients.
- The precise mechanisms of ethanol-induced mitochondrial changes and the role of megamitochondria remain poorly understood.
Purpose of the Study:
- To investigate the cellular and mitochondrial responses to ethanol exposure in a hepatoma cell line.
- To identify the key proteins involved in ethanol-induced mitochondrial alterations.
- To elucidate the functional significance of megamitochondria formation in alcoholic hepatotoxicity.
Main Methods:
- Utilized VL-17A hepatoma cell line for in vitro studies of ethanol exposure.
- Analyzed mitochondrial morphology changes, including hyperfragmentation and megamitochondria.
- Employed genetic inactivation of Dynamin-1-like protein (Drp1) and liver-specific Drp1 knockout mice models.
- Assessed cell growth and alcohol-induced toxicity in response to Drp1 manipulation.
Main Results:
- Ethanol exposure induced rapid mitochondrial hyperfragmentation and megamitochondria formation in VL-17A cells, inhibiting cell growth.
- Dynamin-1-like protein (Drp1) was identified as the primary mediator of these mitochondrial alterations.
- Genetic inactivation of Drp1 promoted megamitochondria development, enhancing cell survival under alcohol stress.
- In vivo studies confirmed Drp1's role in megamitochondria formation and demonstrated reduced ethanol toxicity in Drp1-manipulated mice.
Conclusions:
- Megamitochondria formation in alcoholic liver disease is primarily mediated by Dynamin-1-like protein (Drp1).
- This megamitochondria formation represents a protective adaptive response against alcohol-induced hepatotoxicity.
- Targeting Drp1-mediated pathways may offer novel therapeutic avenues for alcoholic liver diseases.
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