Tingting Ren

Bio: Tingting Ren is an academic researcher from Fourth Military Medical University. The author has contributed to research in topics: Mitochondrion & Mitochondrial fission. The author has an hindex of 10, co-authored 13 publications receiving 592 citations.

Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways.

Abstract: Mitochondrial morphology is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, especially in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying molecular mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degradation, and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a critical role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.

MCU-dependent mitochondrial Ca 2+ inhibits NAD +/SIRT3/SOD2 pathway to promote ROS production and metastasis of HCC cells

Abstract: Mitochondrial Ca2+ signaling, which is strongly dependent on the mitochondrial Ca2+ uniporter (MCU) complex, has a series of key roles in physiopathological processes, including energy metabolism, reactive oxygen species (ROS) production and cell apoptosis. However, a mechanistic understanding of how the mitochondrial Ca2+ signaling is remodeled and its functional roles remains greatly limited in cancers, especially in hepatocellular carcinoma. Here we demonstrated that the MCU complex was dysregulated in hepatocellular carcinoma (HCC) cells and significantly correlated with metastasis and poor prognosis of HCC patients. Upregulation of MCU clearly enhanced the Ca2+ uptake into mitochondria, which significantly promoted ROS production by downregulating nicotinamide adenine dinucleotide+ (NAD+)/reduced form of nicotinamide adenine dinucleotid (NADH) ratio and the NAD+-dependent deacetylase activity of sirtuin 3 to inhibit superoxide dismutase 2 (SOD2) activity. Moreover, our data indicated that the MCU-dependent mitochondrial Ca2+ uptake promotes matrix metalloproteinase-2 activity and cell motility by ROS-activated c-Jun N-terminal kinase pathway, and thus contributed to the increased ability of invasion and migration in vitro and intrahepatic and distal lung metastasis in vivo of HCC cells. In addition, treatment with the mitochondrial Ca2+-buffering protein parvalbumin significantly suppressed ROS production and the ability of HCC metastasis. Our study uncovers a mechanism that links the remodeling of mitochondrial Ca2+ homeostasis to ROS production, and provides evidence supporting a metastasis-promoting role for the MCU-dependent mitochondrial Ca2+ uptake in HCC. Our findings suggest that the mitochondrial Ca2+ uptake machinery may potentially be a novel therapeutic target for HCC metastasis.

MCUR1 facilitates epithelial-mesenchymal transition and metastasis via the mitochondrial calcium dependent ROS/Nrf2/Notch pathway in hepatocellular carcinoma

Abstract: Mitochondrial Ca2+ plays a critical role in tumorigenesis, including cell proliferation and metastasis. Mitochondrial calcium uniporter regulator 1 (MCUR1) has been shown to be frequently upregulated in HCC and promote cancer cell survival. However, whether MCUR1 is involved in the metastasis of HCC and its underlying mechanisms remain unknown. The effect of MCUR1 expression on epithelial-mesenchymal transition (EMT) in HCC cells was first evaluated by immunofluorescent staining and Western blot. Then, in vitro invasion and in vivo metastasis assays were used to evaluate the function of MCUR1 in HCC metastasis. The underlying mechanism has also been explored by investigating the effect of MCUR1 on ROS/Nrf2/Notch1 pathway. MCUR1 expression was significantly higher in HCC with metastasis and associated with tumor progression. MCUR1 promoted in vitro invasion and in vivo metastasis of HCC cells by promoting EMT via Snail. Mechanistically, MCUR1-mediated mitochondrial Ca2+ signaling promoted the EMT of HCC cells by activating ROS/Nrf2/Notch1 pathway. Inhibition of ROS production, mitochondrial Ca2+ uptake, Nrf2 expression or Notch1 activity significantly suppressed MCUR1-induced EMT of HCC cells. In addition, treatment with the mitochondrial Ca2+-buffering protein parvalbumin significantly inhibited ROS/Nrf2/Notch pathway and MCUR1-induced EMT and HCC metastasis. Our study provides evidence supporting a metastasis-promoting role for MCUR1-dependent mitochondrial Ca2+ uptake in HCC. Our findings suggest that MCUR1 may be a potential therapeutic target for HCC treatment.

Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress

Abstract: To date, mechanisms of tumour cell survival under energy stress are not well understood. Cumulative evidence is beginning to reveal that specific mitochondrial morphologies are often associated with energetic states and survival of cells. However, the functional roles of mitochondria in the metabolic adaptation of tumour cells to energy stress remain to be elucidated. In this study, we first investigated the changes in mitochondrial morphology induced by nutrition deprivation in tumour cells, and the underlying molecular mechanism. We then systematically explored glucose metabolism reprogramming by energy stress-induced alteration of mitochondrial morphology and its effect on tumour cell survival. Our results showed that starvation treatment resulted in a dramatic mitochondrial elongation, which was mainly mediated by DRP1S637 phosphorylation through protein kinase A activation and subsequent suppression of mitochondrial translocation of DRP1. We further observed that tumour cells under an energy stress condition exhibited a clear shift from glycolysis towards oxidative phosphorylation, which was reversed by the recovery of mitochondrial fission induced by forced expression of mutant DRP1S637A. Mechanistically, energy stress-induced mitochondrial elongation facilitated cristae formation and assembly of respiratory complexes to enhance oxidative phosphorylation, which in turn exhibited a feedback inhibitory effect on glycolysis through NAD+-dependent SIRT1 activation. In addition, our data indicated that DRP1S637-mediated mitochondrial elongation under energy stress was essential for tumour cell survival both in vitro and in vivo and predicted poor prognosis of hepatocellular carcinoma patients. Overall, our study demonstrates that remodelling of mitochondrial morphology plays a critical role in tumour cell adaptation to energy stress by reprogramming glucose metabolism.

Mitochondrial metabolism and cancer.

Abstract: Glycolysis has long been considered as the major metabolic process for energy production and anabolic growth in cancer cells. Although such a view has been instrumental for the development of powerful imaging tools that are still used in the clinics, it is now clear that mitochondria play a key role in oncogenesis. Besides exerting central bioenergetic functions, mitochondria provide indeed building blocks for tumor anabolism, control redox and calcium homeostasis, participate in transcriptional regulation, and govern cell death. Thus, mitochondria constitute promising targets for the development of novel anticancer agents. However, tumors arise, progress, and respond to therapy in the context of an intimate crosstalk with the host immune system, and many immunological functions rely on intact mitochondrial metabolism. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.

SARS-CoV-2 invades host cells via a novel route: CD147-spike protein

Abstract: SUMMARY Currently, COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been widely spread around the world; nevertheless, so far there exist no specific antiviral drugs for treatment of the disease, which poses great challenge to control and contain the virus. Here, we reported a research finding that SARS-CoV-2 invaded host cells via a novel route of CD147-spike protein (SP). SP bound to CD147, a receptor on the host cells, thereby mediating the viral invasion. Our further research confirmed this finding. First, in vitro antiviral tests indicated Meplazumab, an anti-CD147 humanized antibody, significantly inhibited the viruses from invading host cells, with an EC50 of 24.86 μg/mL and IC50 of 15.16 μg/mL. Second, we validated the interaction between CD147 and SP, with an affinity constant of 1.85×10−7M. Co-Immunoprecipitation and ELISA also confirmed the binding of the two proteins. Finally, the localization of CD147 and SP was observed in SARS-CoV-2 infected Vero E6 cells by immuno-electron microscope. Therefore, the discovery of the new route CD147-SP for SARS-CoV-2 invading host cells provides a critical target for development of specific antiviral drugs.

Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements.

Abstract: Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor microenvironment and is known to initiate cancer angiogenesis, metastasis, and survival at different concentrations. At moderate concentration, ROS activates the cancer cell survival signaling cascade involving mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1/2 (MAPK/ERK1/2), p38, c-Jun N-terminal kinase (JNK), and phosphoinositide-3-kinase/ protein kinase B (PI3K/Akt), which in turn activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF). At high concentrations, ROS can cause cancer cell apoptosis. Hence, it critically depends upon the ROS levels, to either augment tumorigenesis or lead to apoptosis. The major issue is targeting the dual actions of ROS effectively with respect to the concentration bias, which needs to be monitored carefully to impede tumor angiogenesis and metastasis for ROS to serve as potential therapeutic targets exogenously/endogenously. Overall, additional research is required to comprehend the potential of ROS as an effective anti-tumor modality and therapeutic target for treating malignancies.