Dynamin-1-Like Protein Inhibition Drives Megamitochondria Formation as an Adaptive Response in Alcohol-Induced Hepatotoxicity.
Journal
The American journal of pathology
ISSN: 1525-2191
Titre abrégé: Am J Pathol
Pays: United States
ID NLM: 0370502
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
31
01
2018
revised:
18
10
2018
accepted:
02
11
2018
pubmed:
17
12
2018
medline:
13
11
2019
entrez:
17
12
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30553835
pii: S0002-9440(18)30112-3
doi: 10.1016/j.ajpath.2018.11.008
pmc: PMC6436109
pii:
doi:
Substances chimiques
Ethanol
3K9958V90M
Dnm1l protein, mouse
EC 3.6.5.5
Dynamins
EC 3.6.5.5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
580-589Subventions
Organisme : NIAAA NIH HHS
ID : R01 AA020518
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM118247
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA024733
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103549
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM123266
Pays : United States
Informations de copyright
Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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