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Dynamin-1-like protein inhibition drives megamitochondria formation as an adaptive response in alcohol-induced hepatotoxicity

Research output: Contribution to journalArticle

Elena Palma, Xiaowen Ma, Antonio Riva, Valeria Iansante, Anil Dhawan, Shaogui Wang, Hong-Min Ni, Hiromi Sesaki, Roger Williams, Wen-Xing Ding, Shilpa Chokshi

Original languageEnglish
JournalAmerican Journal of Pathology
Early online date14 Dec 2018
DOIs
Accepted/In press2 Nov 2018
E-pub ahead of print14 Dec 2018

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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 hyper-fragmentation 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 to 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.

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