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Mitochondrial pyruvate carrier 1 (MPC1) is a key metabolic protein that regulates the transport of pyruvate into the mitochondrial inner membrane. MPC1 deficiency may cause metabolic reprogramming. However, whether and how MPC1 controls mitochondrial oxidative capacity in cancer are still relatively unknown. MPC1 deficiency was recently found to be strongly associated with various diseases and cancer hallmarks. We utilized online databases and uncovered that MPC1 expression is lower in many cancer tissues than in adjacent normal tissues. In addition, MPC1 expression was found to be substantially altered in five cancer types: breast-invasive carcinoma (BRCA), kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), and prostate adenocarcinoma (PRAD). However, in KIRC, LUAD, PAAD, and PRAD, high MPC1 expression is closely associated with favourable prognosis. Low MPC1 expression in BRCA is significantly associated with shorter overall survival time. MPC1 expression shows strong positive and negative correlations with immune cell infiltration in thymoma (THYM) and thyroid carcinoma (THCA). Furthermore, we have comprehensively summarized the current literature regarding the metabolic reprogramming effects of MPC1 in various cancers. As shown in the literature, MPC1 expression is significantly decreased in cancer tissue and associated with poor prognosis. We discuss the potential metabolism-altering effects of MPC1 in cancer, including decreased pyruvate transport ability; impaired pyruvate-driven oxidative phosphorylation (OXPHOS); and increased lactate production, glucose consumption, and glycolytic capacity, and the underlying mechanisms. These activities facilitate tumour progression, migration, and invasion. MPC1 is a novel cancer biomarker and potentially powerful therapeutic target for cancer diagnosis and treatment. Further studies aimed at slowing cancer progression are in progress.

Xiang Zhou,1 Zhu-juan Xiong,2 Shuo-meng Xiao,1 Jin Zhou,3 Zhi Ding,1 Ling-chao Tang,1 Xiao-dong Chen,1 Rui Xu,1 Ping Zhao1 1Department of Gastrointestinal Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 2Nutritional Center, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 3Department of Thoracic Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China Abstract: Invasion and metastasis are major malignant characteristics of human gastric cancer (GC), but the molecular mechanisms underlying the invasion and metastasis of GC cells remain elusive. MPC1, a key factor that controls pyruvate transportation through the inner mitochondrial membrane, was reported to be downregulated and correlated with poor prognosis in several cancers. However, the effects of MPC1 on human GC have not been illustrated. In this study, we investigated the potential role of MPC1 in the proliferation, migration, invasion, and stem cell-like properties of human GC cells and evaluated its prognostic significance for patients with GC. We found that MPC1 protein and mRNA levels were significantly decreased in GC tissues and cell lines. Low MPC1 expression was associated with tumor T stage, N stage, and advanced tumor node metastasis stage. Decreased MPC1 expression was an independent prognostic marker and correlated with poor overall survival of patients with GC. Furthermore, overexpression of MPC1 inhibited the proliferation, migration, invasion, and stem cell-like properties of GC cells. These findings suggest that MPC1 may be a novel prognostic marker and a potential therapeutic target in human GC. Keywords: gastric cancer, invasion, migration, MPC1, proliferation

// Xiaoli Li 1, 2 , Yaqing Li 1, 2 , Gaoyang Han 3 , Xiaoran Li 2 , Yasai Ji 1 , Zhirui Fan 1 , Yali Zhong 1 , Jing Cao 1, 4 , Jing Zhao 1 , Goscinski Mariusz 5 , Mingzhi Zhang 1 , Jianguo Wen 6 , Jahn M. Nesland 2 , Zhenhe Suo 1, 2 1 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China 2 Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Montebello, Oslo, Norway 3 Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui City, Henan Province, China 4 Department of Pathology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China 5 Department of Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway 6 The Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China Correspondence to: Zhenhe Suo, email: zhenhes@medisin.uio.no, zhenhesuo@aliyun.com Keywords: MPC1, CRISPR/Cas9, diabetes, gene knockout, reproductive capability Received: June 13, 2016 Accepted: October 19, 2016 Published: November 08, 2016 ABSTRACT Pyruvate plays a critical role in the mitochondrial tricarboxylic acid (TCA) cycle, and it is the center product for the synthesis of amino acids, carbohydrates and fatty acids. Pyruvate transported across the inner mitochondrial membrane appears to be essential in anabolic and catabolic intermediary metabolism. The mitochondrial pyruvate carrier (MPC) mounted in the inner membrane of mitochondria serves as the channel to facilitate pyruvate permeating. In mammals, the MPC is formed by two paralogous subunits, MPC1 and MPC2. It is known that complete ablation of MPC2 in mice causes death on the 11th or 12th day of the embryonic period. However, MPC1 deletion and the knowledge of gene function in vivo are lacking. Using the new technology of gene manipulation known as Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9 (CRISPR/Cas9) systems, we gained stable MPC1 gene heterozygous mutation mice models, and the heterozygous mutations could be stably maintained in their offsprings. Only one line with homozygous 27 bases deletion in the first exon was established, but no offsprings could be obtained after four months of mating experiments, indicating infertility of the mice with such homozygous deletion. The other line of MPC1 knockout (KO) mice was only heterozygous, which mutated in the first exon with a terminator shortly afterwards. These two lines of MPC1 KO mice showed lower fertility and significantly higher bodyweight in the females. We concluded that heterozygous MPC1 KO weakens fertility and influences the metabolism of glucose and fatty acid and bodyweight in mice.

Xiang Zhou,1 Zhu-juan Xiong,2 Shuo-meng Xiao,1 Jin Zhou,3 Zhi Ding,1 Ling-chao Tang,1 Xiao-dong Chen,1 Rui Xu,1 Ping Zhao1 1Department of Gastrointestinal Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 2Nutritional Center, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 3Department of Thoracic Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China Abstract: Invasion and metastasis are major malignant characteristics of human gastric cancer (GC), but the molecular mechanisms underlying the invasion and metastasis of GC cells remain elusive. MPC1, a key factor that controls pyruvate transportation through the inner mitochondrial membrane, was reported to be downregulated and correlated with poor prognosis in several cancers. However, the effects of MPC1 on human GC have not been illustrated. In this study, we investigated the potential role of MPC1 in the proliferation, migration, invasion, and stem cell-like properties of human GC cells and evaluated its prognostic significance for patients with GC. We found that MPC1 protein and mRNA levels were significantly decreased in GC tissues and cell lines. Low MPC1 expression was associated with tumor T stage, N stage, and advanced tumor node metastasis stage. Decreased MPC1 expression was an independent prognostic marker and correlated with poor overall survival of patients with GC. Furthermore, overexpression of MPC1 inhibited the proliferation, migration, invasion, and stem cell-like properties of GC cells. These findings suggest that MPC1 may be a novel prognostic marker and a potential therapeutic target in human GC. Keywords: gastric cancer, invasion, migration, MPC1, proliferation

Background Stomata are micropores surrounded by pairs of guard cells, and their opening is finely controlled to balance water vapor loss as transpiration and CO2 absorption for photosynthesis. The regulatory signaling network for stomatal movement is complicated, and increasing numbers of new genes have been shown to be involved in this process. Our previous study indicated that a member of the plant putative mitochondrial pyruvate carrier (MPC) family, NRGA1, is a negative regulator of guard cell abscisic acid (ABA) signaling. In this study, we identified novel physiological roles of pyruvate and MPC1, another member of the MPC family, in the regulation of stomatal closure in Arabidopsis. Results Loss-of-function mutants of MPC1 (mpc1) were hypersensitive to ABA-induced stomatal closure and ABA-activated guard cell slow-type anion currents, and showed a reduced rate of water loss upon drought treatment compared with wild-type plants. In contrast, plants overexpressing MPC1 showed a hyposensitive ABA response and increased sensitivity to drought stress. In addition, mpc1 mutants accumulated more pyruvate after drought or ABA treatment. The increased pyruvate content also induced stomatal closure and activated the slow-type anion channels of guard cells, and this process was dependent on the function of RbohD/F NADPH oxidases and reactive oxygen species concentrations in guard cells. Conclusions Our findings revealed the essential roles of MPC1 and pyruvate in stomatal movement and plant drought resistance. Electronic supplementary material The online version of this article (10.1186/s12870-017-1175-3) contains supplementary material, which is available to authorized users.

Introduction: Cancer cells may exhibit outsourcing of their high energy need in order to avoid the intrinsic mitochondrial apoptosis. Reduced mitochondrial respiration and accumulation of mitochondrial genome mutations are among metabolic transformations in this regard. Mitochondrial humanin (MT-RNR2) is a small peptide with anti-apoptotic activities attributed to binding some pro-apoptotic proteins. Aim of the work: The current study aims at investigating the expression of mitochondrial humanin in bladder tumor cells and the possible casting of humanin anti-apoptotic action through orchestrating some of the mitochondrial metabolic enzymes. Material and methods: Here messenger RNA of humanin, succinate dehydrogenase, glutaminase, isocitrate dehydrogenase were compared in tissues from patients with T2 bladder carcinoma in comparison to tumor associated normal tissues from the same patients. Levels of lactate and mitochondrial pyruvate carrier (MPC1) mRNA were determined to scrutinize the prevalence of aerobic glycolysis. Results: The present study found that tumor cells had suppressed aerobic glycolysis, augmented mitochondrial respiration and interrupted tricarboxylic acid cycle, all of which were suggested to serve tumor aggressiveness. MT-RNR2 was found closely related to the alterations in mitochondrial activity. Conclusion: MT-RNR2 plays its anti-apoptotic role partly by avoiding deploying energy from complete oxidation of organic compounds to inorganic wastes. Thus MT-RNR2 can potentially serve as a new biomarker in the diagnosis of bladder carcinoma especially that it is present in blood circulation.

Background Cancer cells exhibit an altered metabolism, which is characterized by a preference for aerobic glycolysis more than mitochondrial oxidation of pyruvate. Mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2) play a bottleneck role by transporting pyruvate into mitochondrial through the mitochondrial inner membrane. Therefore, their protein expression in cancers may be of clinical consequences. There are studies showing low levels of MPC1 expression in colon, kidney and lung cancers, and the expression of MPC1 correlates with poor prognosis. However, the expression status of MPC1 and MPC2 in prostate cancer (PCA) is unclear. Methods In this study, expression of MPC1 and MPC2 in LNCaP and DU145 prostate cancer cell lines was examined by immunocytochemistry (ICC) and Western blotting. Compared to the LNCaP cells, lower levels of MPC1 and MPC2 expression in the DU145 cell line was identified. We then extended our study to 88 patients with prostate cancer who underwent transurethral electro-vaporization of prostate or radical prostatectomy at the First Affiliated Hospital of Zhengzhou University, Henan, China. Patient-derived paraffin embedded PCA specimens were collected for immunohistochemistry (IHC). Correlations with clinicopathologic factors were evaluated by Chi-square or Fisher´s exact probability tests. Overall survival (OS) rates were determined using the Kaplan-Meier estimator. The Cox proportional hazard regression model was used in univariate analysis and multivariate analysis to identify factors significantly correlated with prognosis. Results Linear regression analysis revealed that MPC1 expression level was positively correlated with MPC2 expression (r = 0.375, P = 0.006) in the prostate cancers. MPC1 expression was negatively associated with UICC stage (P = 0.031). While UICC stage (P