Mitochondrial fusion and Bid-mediated mitochondrial apoptosis are perturbed by alcohol with distinct dependence on its metabolism

Authors

Shamim Naghdi, Thomas Jefferson UniversityFollow
William S. Slovinsky, Thomas Jefferson University
Muniswamy Madesh, Thomas Jefferson UniversityFollow
Emanual Rubin, Thomas Jefferson UniversityFollow
György Hajnóczky, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

10-9-2018

Comments

This article has been peer reviewed. It is the author’s final published version in Cell Death and Disease, Volume 9, Issue 10, October 2018, Article number 1028.

The published version is available at https://doi.org/10.1038/s41419-018-1070-3. Copyright © Naghdi et al.

Abstract

Environmental stressors like ethanol (EtOH) commonly target mitochondria to influence the cell’s fate. Recent literature supports that chronic EtOH exposure suppresses mitochondrial dynamics, central to quality control, and sensitizes mitochondrial permeability transition pore opening to promote cell death. EtOH-induced tissue injury is primarily attributed to its toxic metabolic products but alcoholism also impairs tissues that poorly metabolize EtOH. We embarked on studies to determine the respective roles of EtOH and its metabolites in mitochondrial fusion and tBid-induced mitochondrial apoptosis. We used HepG2 cells that do not metabolize EtOH and its engineered clone that expresses EtOH-metabolizing Cytochrome P450 E2 and alcohol dehydrogenase (VL-17A cells). We found that fusion impairment by prolonged EtOH exposure was prominent in VL-17A cells, probably owing to reactive oxygen species increase in the mitochondrial matrix. There was no change in fusion protein abundance, mitochondrial membrane potential or Ca²⁺ uptake. By contrast, prolonged EtOH exposure promoted tBid-induced outer mitochondrial membrane permeabilization and cell death only in HepG2 cells, owing to enhanced Bak oligomerization. Thus, mitochondrial fusion inhibition by EtOH is dependent on its metabolites, whereas sensitization to tBid-induced death is mediated by EtOH itself. This difference is of pathophysiological relevance because of the tissue-specific differences in EtOH metabolism. © 2018, The Author(s).

Recommended Citation

Naghdi, Shamim; Slovinsky, William S.; Madesh, Muniswamy; Rubin, Emanual; and Hajnóczky, György, "Mitochondrial fusion and Bid-mediated mitochondrial apoptosis are perturbed by alcohol with distinct dependence on its metabolism" (2018). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 247.
https://jdc.jefferson.edu/pacbfp/247

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

30301883

Language

English