Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia

Abstract

Transarterial embolization/transarterial chemoembolization (TAE/TACE) is the acceptable palliative treatment for hepatocellular carcinoma (HCC), mainly through ischemic necrosis induced by arterial embolization. However, how HCC cells survive under such ischemic hypoxic condition remains unclear, which can be exploited to potentiate TAE/ TACE treatment. We hypothesized that targeting mitophagy can increase HCC cell apoptosis during hypoxia. HCC cells were subjected to hypoxia and then mitophagy was quantified. The role of dynamin-related protein 1 (DRP1) in hypoxia-induced HCC mitophagy was determined. Moreover, the synergistic effect of hypoxia and DRP1 inhibitor on HCC apoptosis was assessed in vitro and in vivo. Clinical association between DRP1 expression and outcome for HCC patients was validated. HCC cells that survived hypoxia showed significantly increased DRP1-mediated mitochondrial fission and mitophagy compared with cells in normoxia. Hypoxia induced mitophagy in surviving HCC cells by enhancing DRP1 expression and its translocation into the mitochondria and excessive mitochondrial fission into fragments. Blocking the DRP1 heightened the possibility of hypoxic cytotoxicity to HCC cells due to impaired mitophagy and increased the mitochondrial apoptosis, which involved decreased in mitochondrial membrane potential and mitochondrial release of apoptosis-inducing factor and cytochrome c. Additionally, DRP1 inhibitor Mdivi-1 suppressed the in vivo growth of hypoxia-exposed HCC cells. High expression of DRP1 was significantly associated with shorter survival in HCC patients. In conclusion, our results demonstrate that blocking DRP1-mediated mitochondrial fission and mitophagy increases the incidence of mitochondrial apoptosis of HCC cells during hypoxia, suggesting the new approach of targeting mitophagy to potentiate TAE/TACE.

Roles of host mitochondria in the development of COVID-19 pathology: Could mitochondria be a potential therapeutic target?

“…Specifically, the open reading frame ORF9b protein of SARS-CoV bind the outer mitochondrial membrane in A549, HEK 293, and THP-1 cellular models and facilitate the degradation of Dynamin-related protein (Drp1) through ubiquitination that ultimately causes mitochondrial elongation [60]. Drp1 is a GTPase required for mitochondrial fission, an essential process by which dysfunctional mitochondria are eliminated through mitophagy [82][83][84][85][86]. However, the exact consequence of this mitochondrial elongation is unclear, but it is believed to alter mitochondrial dynamics, favoring viral replication.…”

Potential role of mitochondria in gastric cancer detection: Fission and glycolysis (Review)

“…The proliferation and invasion of tumor cells also require faster and increased energy supply ( 79 ). Thus, Drp1 expression is upregulated in several types of cancer cells, including liver ( 80 ), breast ( 81 ) and lung cancers ( 82 ), and may be considered as a biomarker for predicting poor survival in patients with these types of cancer. A study on ovarian cancer demonstrated that glycolysis is promoted by activating PI3K/AKT/HIF-1α signaling, while mitochondrial fission is enhanced by phosphorylation of Drp1 at Ser616 ( 83 ).…”

Mitochondrial Fission-Mediated Lung Development in Newborn Rats With Hyperoxia-Induced Bronchopulmonary Dysplasia With Pulmonary Hypertension

“…Combined with our findings, we speculated that lung injury caused by hyperoxia in newborn rats would increase mitochondrial fission, namely the expression of Drp1, due to oxidative stress. In addition, experiments have confirmed the relationship between hypoxia and Drp1, studies were not only involved in animal models about Lung Ischemia-reperfusion Injury (30) and lung vascular ischemic/hypoxic injury (31), but also in others like hepatocellular carcinoma cells in hypoxia (32), and Hypoxia-Reoxygenation Injury of Cardiomyocytes (33). Although hypoxia or hyperoxia can trigger similar pathological responses, such as oxidative stress and inflammation, these underlying mechanisms need to be further studied at the cellular level.…”