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

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.

Melatonin attenuates myocardial ischemia‐reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK‐OPA1 signaling pathways

“…To rectify excessive mitochondrial fission, mitochondrial fusion and mitophagy are the complementary regulatory systems to ensure mitochondrial quality and quantity . The antiapoptotic effects of mitochondrial fusion and mitophagy have been adequately explored in several types of cells in various disease models, such as alcohol liver disease, subarachnoid hemorrhage‐related brain injury, pancreatic cancer metastasis, and chronic kidney disease.…”

Tumor microenvironment-activatable Fe-doxorubicin preloaded amorphous CaCO 3 nanoformulation triggers ferroptosis in target tumor cells

“…From a molecular viewpoint, BID and EndoG are not only involved in the onset and execution of ferroptosis process but also have facilitative effect on the DOX-mediated apoptosis. For instance, BID up-regulation could increase the permeability of the mitochondrial membrane and facilitate the release of AIF from the mitochondrial compartment, both of which would enhance the tumor cell apoptosis (49,50). Alternatively, the mitochondrial EndoG would be released into the cytoplasm upon apoptosis-inducing stimulus and subsequently enter the cell nucleus to promote chromosomal DNA fragmentation (51), so the ferroptosis-induced EndoG up-regulation could also provide combinatorial benefit for enhancing the antitumor potency of DOX.…”

Gut bacteria signaling to mitochondria in intestinal inflammation and cancer

“…11 Through these proteins, fusion facilitates the sharing of mtDNA between mitochondria thereby providing more support for critical functions such as oxidative phosphorylation, mitophagy, apoptosis, cell proliferation, and migration. 12 Mitochondrial fission is the process by which mitochondria divide into smaller daughter mitochondria. 1 Mitochondrial fission is essential to generate adequate numbers of mitochondria for growing cells and is mediated by Dynamin-Related Protein1 (Drp1), Fission 1 (Fis1), Mitochondria Fission Factor (Mff), Mitochondrial Dynamics Protein (MID49) and MID51.…”

“… 11 Through these proteins, fusion facilitates the sharing of mtDNA between mitochondria thereby providing more support for critical functions such as oxidative phosphorylation, mitophagy, apoptosis, cell proliferation, and migration. 12 …”