Hypoxia-induced elevated NDRG1 mediates apoptosis through reprograming mitochondrial fission in HCC.

Hypoxia, as a form of stress, plays a critical role in oncogenesis, including metabolic reprogramming. Mitochondrial, the centers of energy production, re-balance mitochondria dynamic to maintain cell survival during high levels of environmental stresses. NDRG1 is a hypoxia-inducible protein that is involved in various human cancers, including HCC. However, little is known about whether NDRG1 participants in the quality control of mitochondrial in times of stress. Here, we firstly showed that how NDRG1 exerted its role through mediating mitochondrial dynamic in HCC cells under hypoxia. Initially, we identified that NDRG1 expression varies with oxygen content. NDRG1 silencing notably induced cell apoptosis under hypoxia, while no obviously change of wildtype cells in hypoxia compared with that in normoxia. Further analysis revealed that NDRG1 silencing in HCC cells led to increase of pro apoptotic protein BAX and decrease in anti-apoptotic proteins Bcl-2 and Bclx, which meant mitochondrial damage were induced. In the analysis of mitochondria, we found that more released cytochrome c located in cytosolic with NDRG1 knockdown in hypoxia, which may be due to mitochondria division. And the following experiment proved that more fragmented mitochondria were presented in NDRG1 silencing cells, as well as destroyed mitochondrial membrane potential with evidence by JC-1 was verified. Moreover, these trends could be reversed by Mdivi1. Further research showed that NDRG1 silencing disrupt hypoxia-enhanced aerobic glycolysis through effectively decreased glucose uptake, lactate output and ECAR value. In sum, we provide the first direct evidence that NDRG1-driven change in mitochondrial dynamics and aerobic glycolysis maintain cells survival in HCC during hypoxia.

SMDT1-driven change in mitochondrial dynamics mediate cell apoptosis in PDAC.

Mitochondrial Ca2+ uptake, an important governing for Ca2+ homeostasis, is catalyzed by the mitochondrial calcium uniporter (MCU) complex. SMDT1, as a subunit of MCU complex, was essential for bridging the calcium-sensing role of MICU1 and MICU2 with the calcium-conducting role of MCU. However, the molecular mechanism and regulatory purpose of SMDT1 remain largely unexplored, especially no study was reported in cancer. Here, we firstly reported that how SMDT1 exerted its role through mediating mitochondrial dynamic in PDAC malignancy. In this study, by screening online of subunit of MCU complex, we confirmed that SMDT1 expression was significantly positive correlated with PDAC prognosis. The GEO datasets showed decreased SMDT1 expression in PDAC tumor compared with non-tumor tissues. SMDT1 overexpression could notably inhibit cell proliferation and induce cell apoptosis. Further analysis demonstrated that up-regulated SMDT1 in ASPC1 and Canpan1 cells led to increased accumulation of pro apoptotic protein BAX and decrease in anti-apoptotic proteins Bcl-2 and Bclx. And more releasing of cytochrome c located in cytosolic. Mechanistically, in the morphological analysis of mitochondria, more fragmented mitochondria were presented in SMDT1 overexpression cells by promting the phosphorylation of Drp1, increasing Fis and decreasing MFN1. Meanwhile, more Drp1 was translocated on the mitochondrial from the cytoplasm in up-regulated SMDT1 cells. On the basis of the evidence above we deduce that SMDT1-driven change in mitochondrial dynamics mediated cells apoptosis in PDAC. And, SMDT1 could serve as an important therapeutic target to normalize mitochondrial dynamic responsible for poor prognosis in PDAC.