On the mechanism underlying ethanol-induced mitochondrial dynamic disruption and autophagy response

Abstract

We have explored the mechanisms underlying ethanol-induced mitochondrial dynamics disruption and mitophagy. Ethanol increases mitochondrial fission in a concentration-dependent manner through Drp1 mitochondrial translocation and OPA1 proteolytic cleavage. ARPE-19 (a human retinal pigment epithelial cell line) cells challenged with ethanol showed mitochondrial potential disruptions mediated by alterations in mitochondrial complex IV protein level and increases in mitochondrial reactive oxygen species production. In addition, ethanol activated the canonical autophagic pathway, as denoted by autophagosome formation and autophagy regulator elements including Beclin1, ATG5-ATG12 and P-S6 kinase. Likewise, autophagy inhibition dramatically increased mitochondrial fission and cell death, whereas autophagy stimulation rendered the opposite results, placing autophagy as a cytoprotective response aimed to remove damaged mitochondria. Interestingly, although ethanol induced mitochondrial Bax translocation, this episode was associated to cell death rather than mitochondrial fission or autophagy responses. Thus, Bax required 600 mM ethanol to migrate to mitochondria, a concentration that resulted in cell death. Furthermore, mouse embryonic fibroblasts lacking this protein respond to ethanol by undergoing mitochondrial fission and autophagy but not cytotoxicity. Finally, by using the specific mitochondrial-targeted scavenger MitoQ, we revealed mitochondria as the main source of reactive oxygen species that trigger autophagy activation. These findings suggest that cells respond to ethanol activating mitochondrial fission machinery by Drp1 and OPA1 rather than bax, in a manner that stimulates cytoprotective autophagy through mitochondrial ROS.

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

“…Our findings are substantiated by a study, where Drp-1 inhibition reduces aberrant mitochondrial fission and neurotoxicity in neuronal culture (55). Similarly, ethanol, a well established neurotoxicant also induced mitochondrial fission through enhanced Drp-1 mitochondrial translocation (56). In addition, manganese disrupted the mitochondrial network toward to an exacerbated fragmentation by enhancing the levels of Drp-1 (41,57).…”

FoxO1‐AMPK‐ULK1 Regulates Ethanol‐Induced Autophagy in Muscle by Enhanced ATG14 Association with the BECN1‐PIK3C3 Complex

“…For example, enhanced ULK1 phosphorylation at S555 increases mitophagy under energy stress conditions (Egan et al, 2011). The increased phosphorylation at this site, coupled with a reduction in SQSTM1 led us to speculate that EtOH enhances autophagy in myoblasts by specifically targeting organelles, such as mitochondria, as reported in other cell types (Bonet-Ponce et al, 2015, Flores-Bellver et al, 2014, Ding et al, 2010). Furthermore, decreased ULK1 phosphorylation at S757 has been correlated with an induction of nonspecific autophagy as reported in studies during acute nutrient deprivation (Shang et al, 2011).…”

Continuous exposure to non-lethal doses of sodium iodate induces retinal pigment epithelial cell dysfunction

“…Moreover, the upregulation in autophagy pathway could also be associated with the reduced RPE cell viability (Fig. 1B), which the increase in autophagy can lead to decreased mitochondrial activity by mitophagy in RPE cells38, leading to the reduction in the cell viability signal. These indicate that continuous oxidative stress exposure would attenuate RPE cell physiological functions.…”