bims-mibica 2020-04-19 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2020–04–19
forty papers selected by
Kelsey Fisher-Wellman, East Carolina University

Mitochondrial carrier homolog 2 (MTCH2) is necessary for AML survival.
Moderation of mitochondrial respiration mitigates metabolic syndrome of aging.
IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism.
Inhibition of Kv10.1 Channels Sensitizes Mitochondria of Cancer Cells to Antimetabolic Agents.
High expression of oxidative phosphorylation genes predicts improved survival in squamous cell carcinomas of the head and neck and lung.
Effects of psychoactive drugs on cellular bioenergetic pathways.
Blocking STAT3 by Pyrvinium Pamoate Causes Metabolic Lethality in KRAS-mutant lung cancer.
Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability.
Deletion of VDAC1 Hinders Recovery of Mitochondrial and Renal Functions After Acute Kidney Injury.
Sitagliptin ameliorates renal tubular injury in diabetic kidney disease via STAT3-dependent mitochondrial homeostasis through SDF-1α/CXCR4 pathway.
Mitochondrial complex II and reactive oxygen species in disease and therapy.
Metformin suppresses proliferation and invasion of drug-resistant breast cancer cells by activation of the Hippo pathway.
Enhanced cytotoxicity of imidacloprid by biotransformation in isolated hepatocytes and perfused rat liver.
Shedding New Light on Cancer Metabolism: A Metabolic Tightrope Between Life and Death.
Altered Sphingolipids Metabolism Damaged Mitochondrial Functions: Lessons Learned From Gaucher and Fabry Diseases.
Citrate synthase desuccinylation by SIRT5 promotes colon cancer cell proliferation and migration.
MCUb Induction Protects the Heart from Post-Ischemic Remodeling.
Mitochondrial localization of SESN2.
Mitochondrial disease disrupts hepatic allostasis and lowers the threshold for immune-mediated liver toxicity.
Study of Cinobufagin as a Promising Anticancer Agent in Uveal Melanoma Through Intrinsic Apoptosis Pathway.
Frataxin-deficient cardiomyocytes present an altered thiol-redox state which targets actin and pyruvate dehydrogenase.
PFKFB4 is critical for the survival of acute monocytic leukemia cells.
Histone deacetylases 1 and 2 silence cryptic transcription to promote mitochondrial function during cardiogenesis.
Alteration of the Mitochondrial Effects of Ceria Nanoparticles by Gold: An Approach for the Mitochondrial Modulation of Cells Based on Nanomedicine.
Effects of MOTS-c on the mitochondrial function of cells harboring 3243 A to G mutant mitochondrial DNA.
miR-181a regulates p62/SQSTM1, parkin, and protein DJ-1 promoting mitochondrial dynamics in skeletal muscle aging.
Evaluation of cell metabolic adaptation in wound and tumour by Fluorescence Lifetime Imaging Microscopy.
Decreased Triacylglycerol Content and Elevated Contents of Cell Membrane Lipids in Colorectal Cancer Tissue: A Lipidomic Study.
Leucine and branched chain amino acid metabolism contribute to the growth of bone sarcomas by regulating AMPK and mTORC1 signaling.
A common coupling mechanism for A-type heme-copper oxidases from bacteria to mitochondria.
Tumor cell-derived Angiopoietin-2 promotes metastasis in melanoma.
Niclosamide inhibits ovarian carcinoma growth by interrupting cellular bioenergetics.
Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence.
FAM84B, amplified in pancreatic ductal adenocarcinoma, promotes tumorigenesis through the Wnt/β-catenin pathway.
PCK1 Regulates Glycolysis and Tumor Progression in Clear Cell Renal Cell Carcinoma Through LDHA.
The Human Tumor Atlas Network: Charting Tumor Transitions across Space and Time at Single-Cell Resolution.
NNT in NSCLC: No need to worry?
The Complex Interplay between Antioxidants and ROS in Cancer.
Sex-associated molecular differences for cancer immunotherapy.
PGC1α suppresses metastasis of HCC by inhibiting Warburg effect via PPARγ-dependent WNT/β-catenin/PDK1 axis.

Blood. 2020 Apr 16. pii: blood.2019000106. [Epub ahead of print]

Mitochondrial carrier homolog 2 (MTCH2) is necessary for AML survival.

Dilshad H Khan, Michael Mullokandov, Yan Wu, Veronique Voisin, Marcela Victoria Gronda, Rose Hurren, Xiaoming Wang, Neil MacLean, Danny V Jeyaraju, Yulia Jitkova, G Wei Xu, Rob C Laister, Ayesh Seneviratne, Zachary Blatman, Troy Ketala, Gary D Bader, Sajid A Marhon, Daniel D De Carvalho, Mark D Minden, Atan Gross, Aaron D Schimmer.

Through a CRISPR screen to identify mitochondrial genes necessary for the growth of AML cells, we identified the mitochondrial outer membrane protein MTCH2 (Mitochondrial Carrier Homolog 2). In AML, knockdown of MTCH2 decreased growth, reduced engraftment potential of stem cells and induced differentiation. Inhibiting MTCH2 in AML cells increased nuclear pyruvate and pyruvate dehydrogenase that induced histone acetylation and subsequently promoted the differentiation of AML cells. Thus, we have defined a new mechanism by which mitochondria and metabolism regulate AML stem cells and gene expression.

DOI: https://doi.org/10.1182/blood.2019000106
Proc Natl Acad Sci U S A. 2020 Apr 17. pii: 201917948. [Epub ahead of print]

Moderation of mitochondrial respiration mitigates metabolic syndrome of aging.

Mojdeh Tavallaie, Ramouna Voshtani, Xinxian Deng, Yixue Qiao, Faqin Jiang, James P Collman, Lei Fu.

  Deregulation of mitochondrial dynamics leads to the accumulation of oxidative stress and unhealthy mitochondria; consequently, this accumulation contributes to premature aging and alterations in mitochondria linked to metabolic complications. We postulate that restrained mitochondrial ATP synthesis might alleviate age-associated disorders and extend healthspan in mammals. Herein, we prepared a previously discovered mitochondrial complex IV moderate inhibitor in drinking water and orally administered to standard-diet-fed, wild-type C57BL/6J mice every day for up to 16 mo. No manifestation of any apparent toxicity or deleterious effect on studied mouse models was observed. The impacts of an added inhibitor on a variety of mitochondrial functions were analyzed, such as respiratory activity, mitochondrial bioenergetics, and biogenesis, and a few age-associated comorbidities, including reactive oxygen species (ROS) production, glucose abnormalities, and obesity in mice. It was found that mitochondrial quality, dynamics, and oxidative metabolism were greatly improved, resulting in lean mice with a specific reduction in visceral fat plus superb energy and glucose homeostasis during their aging period compared to the control group. These results strongly suggest that a mild interference in ATP synthesis through moderation of mitochondrial activity could effectively up-regulate mitogenesis, reduce ROS production, and preserve mitochondrial integrity, thereby impeding the onset of metabolic syndrome. We conclude that this inhibitory intervention in mitochondrial respiration rectified the age-related physiological breakdown in mice by protecting mitochondrial function and markedly mitigated certain undesired primary outcomes of metabolic syndrome, such as obesity and type 2 diabetes. This intervention warrants further research on the treatment of metabolic syndrome of aging in humans.

Keywords:  aging; cytochrome c oxidase; metabolic syndrome; mitochondria; mitogenesis

DOI:  https://doi.org/10.1073/pnas.1917948117
J Biol Chem. 2020 Apr 14. pii: jbc.RA120.013366. [Epub ahead of print]

IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism.

Atsuhito Tsuji, Takumi Akao, Takahiro Masuya, Masatoshi Murai, Hideto Miyoshi.

  The small molecule IACS-010759 has been reported to potently inhibit the proliferation of glycolysis-deficient hypoxic tumor cells by interfering with the functions of mitochondrial NADH-ubiquinone oxidoreductase (complex I) without exhibiting cytotoxicity at tolerated doses in normal cells. Considering the significant cytotoxicity of conventional quinone-site inhibitors of complex I, such as piericidin and acetogenin families, we hypothesized that the mechanism of action of IACS-010759 on complex I differs from that of other known quinone-site inhibitors. To test this possibility, here we investigated IACS-010759's mechanism in bovine heart submitochondrial particles. We found that IACS-010759, like known quinone-site inhibitors, suppresses chemical modification by the tosyl reagent AL1 of Asp-160 in the 49-kDa subunit, located deep in the interior of a previously proposed quinone-access channel. However, contrary to the other inhibitors, IACS-010759 direction-dependently inhibited forward and reverse electron transfer and did not suppress binding of the quinazoline-type inhibitor [125I]AzQ to the N-terminus of the 49-kDa subunit. Photoaffinity labeling experiments revealed that the photoreactive derivative [125I]IACS-010759-PD1 binds to the middle of the membrane subunit ND1 and that inhibitors that bind to the 49-kDa or PSST subunit cannot suppress the binding. We conclude that IACS-010759's binding location in complex I differs from that of any other known inhibitor of the enzyme. Our findings, along with those from previous study, reveal that the mechanisms of action of complex I inhibitors with widely different chemical properties are more diverse than can be accounted for by the quinone-access channel model proposed by structural biology studies.

Keywords:  Complex I; IACS-010759; bioenergetics; cancer; chemical biology; enzyme inhibitor; hypoxia; mitochondria; photoaffinity labeling; ubiquinone

DOI:  https://doi.org/10.1074/jbc.RA120.013366
Cancers (Basel). 2020 Apr 09. pii: E920. [Epub ahead of print]12(4):

Inhibition of Kv10.1 Channels Sensitizes Mitochondria of Cancer Cells to Antimetabolic Agents.

Ileana Hernández-Reséndiz, David Pacheu-Grau, Araceli Sánchez, Luis A Pardo.

  Reprogramming of energy metabolism constitutes one of the hallmarks of cancer and is, therefore, an emerging therapeutic target. We describe here that the potassium channel Kv10.1, which is frequently overexpressed in primary and metastatic cancer, and has been proposed a therapeutic target, participates in metabolic adaptation of cancer cells through regulation of mitochondrial dynamics. We used biochemical and cell biological techniques, live cell imaging and high-resolution microscopy, among other approaches, to study the impact of Kv10.1 on the regulation of mitochondrial stability. Inhibition of Kv10.1 expression or function led to mitochondrial fragmentation, increase in reactive oxygen species and increased autophagy. Cells with endogenous overexpression of Kv10.1 were also more sensitive to mitochondrial metabolism inhibitors than cells with low expression, indicating that they are more dependent on mitochondrial function. Consistently, a combined therapy using functional monoclonal antibodies for Kv10.1 and mitochondrial metabolism inhibitors resulted in enhanced efficacy of the inhibitors. Our data reveal a new mechanism regulated by Kv10.1 in cancer and a novel strategy to overcome drug resistance in cancers with a high expression of Kv10.1.

Keywords:  cancer metabolism; drug resistance; mitochondrial dynamics; potassium channel

DOI:  https://doi.org/10.3390/cancers12040920
Sci Rep. 2020 Apr 14. 10(1): 6380

High expression of oxidative phosphorylation genes predicts improved survival in squamous cell carcinomas of the head and neck and lung.

Mitchell Frederick, Heath D Skinner, Sawad A Kazi, Andrew G Sikora, Vlad C Sandulache.

Mitochondrial activity is a critical component of tumor metabolism, with profound implications for tumorigenesis and treatment response. We analyzed clinical, genomic and expression data from patients with oral cavity squamous cell carcinoma (OCSCC) in order to map metabologenomic events which may correlate with clinical outcomes and identified nuclear genes involved in oxidative phosphorylation and glycolysis (OXPHOG) as a critical predictor of patient survival. This correlation was validated in a secondary unrelated set of lung squamous cell carcinoma (LUSC) and was shown to be driven largely by over-expression of nuclear encoded components of the mitochondrial electron transport chain (ETC) coordinated with an increase in tumor mitochondrial DNA copy number and a strong threshold effect on patient survival. OCSCC and LUSC patients with a favorable OXPHOG signature demonstrated a dramatic (>2fold) improvement in survival compared to their counterparts. Differential OXPHOG expression correlated with varying tumor immune infiltrates suggesting that the interaction between tumor metabolic activity and tumor associated immunocytes may be a critical driver of improved clinical outcomes in this patient subset. These data provide strong support for studies aimed at mechanistically characterizing the interaction between tumor mitochondrial activity and the tumor immune microenvironment.

DOI: https://doi.org/10.1038/s41598-020-63448-z
World J Biol Psychiatry. 2020 Apr 16. 1-35

Effects of psychoactive drugs on cellular bioenergetic pathways.

Chiara Cristina Bortolasci, Briana Spolding, Shayini Kidnapillai, Mark F Richardson, Nina Vasilijevic, Sheree Dawn Martin, Laura Gray, Sean Lindsay McGee, Michael Berk, Ken Walder.

  Objectives: To investigate the actions of lithium, valproate, lamotrigine and quetiapine on bioenergetic pathways in cultured NT2-N neuronal-like cells and C8-B4 microglial cells. Methods: NT2-N and C8-B4 cells were cultured and treated with lithium (2.5mM), valproate (0.5mM), quetiapine (0.05mM) or lamotrigine (0.05mM) for 24 hours. Gene expression and the mitochondrial bioenergetic profile were measured in both cell lines. Results: In NT2-N cells, valproate increased oxidative phosphorylation (OXPHOS) gene expression, mitochondrial uncoupling and maximal respiratory capacity, while quetiapine decreased OXPHOS gene expression and respiration linked to ATP turnover, as well as decreasing the expression of genes in the citric acid cycle. Lamotrigine decreased OXPHOS gene expression but had no effect on respiration, while lithium reduced the expression of genes in the citric acid cycle. In C8-B4 cells, valproate and lithium increased OXPHOS gene expression, and valproate increased basal respiratory rate and maximal and spare respiratory capacities. In contrast, quetiapine significantly reduced basal respiratory rate and maximal and spare respiratory capacities. Conclusions: Overall our data suggest that some drugs used to treat neuropsychiatric and affective disorders have actions on a range of cellular bioenergetic processes, which could impact their effects in patients.

Keywords:  bioenergetic; microglia; mitochondria; neurons; psychoactive drugs

DOI:  https://doi.org/10.1080/15622975.2020.1755450
Biochem Pharmacol. 2020 Apr 13. pii: S0006-2952(20)30188-X. [Epub ahead of print] 113960

Blocking STAT3 by Pyrvinium Pamoate Causes Metabolic Lethality in KRAS-mutant lung cancer.

JuanJuan Feng, Wenhao Jiang, Yanan Liu, Wanfeng Huang, Kewen Hu, Kun Li, Jing Chen, Chengbin Ma, Zhenliang Sun, Xiufeng Pang.

  Signal transducer and activator of transcription 3 (STAT3) exerts a profound role in regulating mitochondrial function and cellular metabolism. Mitochondrial STAT3 supports RAS-dependent malignant transformation and tumor growth. However, whether pharmacological blockade of STAT3 leads to metabolic lethality in KRAS-mutant lung cancer remains unclear. Pyrvinium pamoate, a clinical antihelminthic drug, preferentially inhibited the growth of KRAS-mutant lung cancer cells in vitro and in vivo. Mechanistic study revealed that pyrvinium dose-dependently suppressed STAT3 phosphorylation at tyrosine 705 and serine 727. Overexpression mitochondrial STAT3 prominently weakened the therapeutic efficacy of pyrvinium. As a result of targeting STAT3, pyrvinium selectively triggered reactive oxygen species release, depolarized mitochondrial membrane potential and suppressed aerobic glycolysis in KRAS-mutant lung cancer cells. Importantly, the cytotoxic effects of pyrvinium could be significantly augmented by glucose deprivation both in vitro and in a patient-derived lung cancer xenograft mouse model in vivo. The combined efficacy significantly correlated with intratumoural STAT3 suppression. Our findings reveal that KRAS-mutant lung cancer cells are vulnerable to STAT3 inhibition exerted by pyrvinium, providing a promising direction for developing therapies targeting STAT3 and metabolic synthetic lethality for the treatment of KRAS-mutant lung cancer.

Keywords:  KRAS; Metabolism; Pyrvinium pamoate; STAT3; Synthetic lethality

DOI:  https://doi.org/10.1016/j.bcp.2020.113960
Oncogene. 2020 Apr 14.

Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability.

Pui-Kei Wu, Seung-Keun Hong, Dmytro Starenki, Kiyoko Oshima, Hao Shao, Jason E Gestwicki, Susan Tsai, Jong-In Park.

The mitochondrial HSP70 chaperone mortalin (HSPA9/GRP75) is often upregulated and mislocalized in MEK/ERK-deregulated tumors. Here, we show that mortalin depletion can selectively induce death of immortalized normal fibroblasts IMR90E1A when combined with K-RasG12V expression, but not with wild-type K-Ras expression, and that K-RasG12V-driven MEK/ERK activity is necessary for this lethality. This cell death was attenuated by knockdown or inhibition of adenine nucleotide translocase (ANT), cyclophilin D (CypD), or mitochondrial Ca2+ uniporter (MCU), which implicates a mitochondria-originated death mechanism. Indeed, mortalin depletion increased mitochondrial membrane permeability and induced cell death in KRAS-mutated human pancreatic ductal adenocarcinoma (PDAC) and colon cancer lines, which were attenuated by knockdown or inhibition of ANT, CypD, or MCU, and occurred independently of TP53 and p21CIP1. Intriguingly, JG-98, an advanced MKT-077 derivative, phenocopied the lethal effects of mortalin depletion in K-RasG12V-expressing IMR90E1A and KRAS-mutated tumor cell lines in vitro. Moreover, JG-231, a JG-98 analog with improved microsomal stability effectively suppressed the xenograft of MIA PaCa-2, a K-RasG12C-expressing human PDAC line, in athymic nude mice. These data demonstrate that oncogenic KRAS activity sensitizes cells to the effects of mortalin depletion, suggesting that mortalin has potential as a selective therapeutic target for KRAS-mutated tumors.

DOI: https://doi.org/10.1038/s41388-020-1285-5
Biomolecules. 2020 Apr 10. pii: E585. [Epub ahead of print]10(4):

Deletion of VDAC1 Hinders Recovery of Mitochondrial and Renal Functions After Acute Kidney Injury.

Grazyna Nowak, Judit Megyesi, William J Craigen.

  Voltage-dependent anion channels (VDACs) constitute major transporters mediating bidirectional movement of solutes between cytoplasm and mitochondria. We aimed to determine if VDAC1 plays a role in recovery of mitochondrial and kidney functions after ischemia-induced acute kidney injury (AKI). Kidney function decreased after ischemia and recovered in wild-type (WT), but not in VDAC1-deficient mice. Mitochondrial maximum respiration, activities of respiratory complexes and FoF1-ATPase, and ATP content in renal cortex decreased after ischemia and recovered in WT mice. VDAC1 deletion reduced respiration and ATP content in non-injured kidneys. Further, VDAC1 deletion blocked return of activities of respiratory complexes and FoF1-ATPase, and recovery of respiration and ATP content after ischemia. Deletion of VDAC1 exacerbated ischemia-induced mitochondrial fission, but did not aggravate morphological damage to proximal tubules after ischemia. However, VDAC1 deficiency impaired recovery of kidney morphology and increased renal interstitial collagen accumulation. Thus, our data show a novel role for VDAC1 in regulating renal mitochondrial dynamics and recovery of mitochondrial function and ATP levels after AKI. We conclude that the presence of VDAC1 (1) stimulates capacity of renal mitochondria for respiration and ATP production, (2) reduces mitochondrial fission, (3) promotes recovery of mitochondrial function and dynamics, renal morphology, and kidney functions, and (4) increases survival after AKI.

Keywords:  ATP content; ATP synthase; electron transport chain; ischemia and reperfusion; mitochondrial dysfunction; mitochondrial fission; respiratory complexes; voltage-dependent anion channel-1 (VDAC1)

DOI:  https://doi.org/10.3390/biom10040585
FASEB J. 2020 Apr 12.

Sitagliptin ameliorates renal tubular injury in diabetic kidney disease via STAT3-dependent mitochondrial homeostasis through SDF-1α/CXCR4 pathway.

Qunzi Zhang, Li He, Yang Dong, Yang Fei, Jiejun Wen, Xiaomei Li, Jian Guan, Feng Liu, Ting Zhou, Ze Li, Ying Fan, Niansong Wang.

  Mitochondrial abnormalities play critical roles in diabetic tubular injury progression. Dipeptidyl peptidase-4 (DPP4) inhibitors are widely used antihyperglycemic agents that exert renal protective and positive effects against mitochondrial dysfunction in diabetic kidney disease (DKD). However, their underlying mechanism remains unclear. In this study, DPP4 upregulation, mitochondrial fragmentation, and altered mitochondrial dynamics-associated protein expression were observed in the tubules of DBA2/J (D2) diabetic mice with unilateral nephrectomy and in albumin-stimulated tubular cells. The inhibition of DPP4 by sitagliptin (Sita) ameliorated these mitochondrial perturbations both in vivo and in vitro, whereas DPP4 overexpression aggravated mitochondrial fusion-fission disorder and tubular cell injury in albumin-treated HK-2 cells. Downstream of DPP4, the SDF-1α/CXCR4 pathway was significantly suppressed in diabetic tubules. After Sita treatment, this signaling pathway was restored, and the mitochondrial dynamics was improved. Furthermore, a direct interaction between STAT3 and OPA1 was found in the mitochondria of tubular cells, and this effect was weakened by overloading albumin and by CXCR4 siRNA treatment, suggesting a possible link between DPP4-mediated SDF-1α/CXCR4/STAT3 signaling and mitochondrial dysfunction in diabetic tubular cells. The results suggest that a novel mechanism links the DPP4 enzyme to impaired mitochondrial dynamics homeostasis during tubular injury in DKD and highlight that the SDF-1α/CXCR4/STAT3 signaling pathway could become a potential target for managing DKD.

Keywords:  CXCR4; SDF-1α; STAT3; diabetic kidney disease; mitochondria; sitagliptin

DOI:  https://doi.org/10.1096/fj.201903038R
Redox Rep. 2020 Dec;25(1): 26-32

Mitochondrial complex II and reactive oxygen species in disease and therapy.

Katerina Hadrava Vanova, Michal Kraus, Jiri Neuzil, Jakub Rohlena.

  Increasing evidence points to the respiratory Complex II (CII) as a source and modulator of reactive oxygen species (ROS). Both functional loss of CII as well as its pharmacological inhibition can lead to ROS generation in cells, with a relevant impact on the development of pathophysiological conditions, i.e. cancer and neurodegenerative diseases. While the basic framework of CII involvement in ROS production has been defined, the fine details still await clarification. It is important to resolve these aspects to fully understand the role of CII in pathology and to explore its therapeutic potential in cancer and other diseases.

Keywords:  OXPHOS; Respiratory complex II; cancer; mitochondria; reactive oxygen species; succinate; succinate dehydrogenase; tricarboxylic acid cycle

DOI:  https://doi.org/10.1080/13510002.2020.1752002
J Cell Mol Med. 2020 Apr 12.

Metformin suppresses proliferation and invasion of drug-resistant breast cancer cells by activation of the Hippo pathway.

Jie Liu, Juan Li, He Chen, Ruiqi Wang, Pingping Li, Yi Miao, Peijun Liu.

  Drug resistance limits the clinical efficacy of breast cancer therapies, and overexpression or activation of Yes-associated protein (YAP) is common in drug-resistant cancer cells. Thus, inhibition of YAP may reduce resistance to anti-cancer drugs. Metformin (MET), a first-line diabetes medication that also has anti-tumour activities, induces AMP-activated protein kinase (AMPK), directly phosphorylates YAP and inhibits YAP transcriptional activity. In this study, we determined the effect of MET on the proliferation and invasion of drug-resistant breast cancer cells and then investigated the underlying molecular mechanism. Our in vivo and in vitro experiments indicated that MET suppressed breast cancer by an AMPK-independent pathway to decrease YAP nuclear localization. In drug-sensitive cells, MET activated the Hippo pathway by increasing KIBRA and FRMD6 expression, but this did not occur in drug-resistant cells. Scribble (SCRIB), a cell polarity protein, was notably down-regulated in tamoxifen- and paclitaxel-resistant breast cancer cells relative to sensitive cells. We also found that MET suppressed the proliferation and invasion of drug-resistant breast cancer cells by increasing the expression and cell membrane localization of SCRIB, which enhanced the interaction of SCRIB with MST1 and LATS1, and inhibited YAP nuclear localization and transcriptional activity.

Keywords:  Hippo pathway; Metformin; drug-resistant breast cancer; scribble

DOI:  https://doi.org/10.1111/jcmm.15241
Pestic Biochem Physiol. 2020 Mar;pii: S0048-3575(20)30019-5. [Epub ahead of print]164 183-190

Enhanced cytotoxicity of imidacloprid by biotransformation in isolated hepatocytes and perfused rat liver.

Paulo F V Bizerra, Anilda R J S Guimarães, Camila A Miranda, Rodrigo P Constantin, Karina S Utsunomiya, Eduardo H Gilglioni, Jorgete Constantin, Emy L Ishii-Iwamoto, Marcos A Maioli, Fábio E Mingatto.

  Imidacloprid (IMD) is a neonicotinoid insecticide widely used in crops, pets, and on farm animals for pest control, which can cause hepatotoxicity in animals and humans. In a previous study using isolated rat liver mitochondria, we observed that IMD inhibited the activity of FoF1-ATP synthase. The aim of this study was to evaluate the effects of IMD on rat isolated hepatocytes and perfused rat liver, besides the influence of its biotransformation on the toxicological potential. For the latter goal, rats were pretreated with dexamethasone or phenobarbital, two classical cytochrome P-450 stimulators, before hepatocytes isolation or liver perfusion. IMD (150 and 200 μM) reduced state 3 mitochondrial respiration in digitonin-permeabilized cells that were energized with glutamate plus malate but did not dissipate the mitochondrial membrane potential. In intact (non-permeabilized) hepatocytes, the intracellular ATP concentration and cell viability were reduced when high IMD concentrations were used (1.5-3.0 mM), and only in cells isolated from dexamethasone-pretreated rats, revealing that IMD biotransformation increases its toxicity and that IMD itself affects isolated mitochondria or mitochondria in permeabilized hepatocytes in concentrations that do not affect mitochondrial function in intact hepatocytes. Coherently, in the prefused liver, IMD (150 and 250 μM) inhibited gluconeogenesis from alanine, but without affecting oxygen consumption and urea production, indicating that such effect was not of mitochondrial origin. The gluconeogenesis inhibition was incomplete and occurred only when the rats were pretreated with phenobarbital, signs that IMD biotransformation was involved in the observed effect. Our findings reveal that changes in hepatic energy metabolism may be acutely implicated in the hepatotoxicity of IMD only when animals and humans are exposed to high levels of this compound, and that IMD metabolites seem to be the main cause for its toxicity.

Keywords:  Cellular structure; Energy metabolism; Gluconeogenesis; Insecticides; Liver; Toxicity

DOI:  https://doi.org/10.1016/j.pestbp.2020.01.011
Front Oncol. 2020 ;10 409

Shedding New Light on Cancer Metabolism: A Metabolic Tightrope Between Life and Death.

Matthias Läsche, Günter Emons, Carsten Gründker.

  Since the earliest findings of Otto Warburg, who discovered the first metabolic differences between lactate production of cancer cells and non-malignant tissues in the 1920s, much time has passed. He explained the increased lactate levels with dysfunctional mitochondria and aerobic glycolysis despite adequate oxygenation. Meanwhile, we came to know that mitochondria remain instead functional in cancer cells; hence, metabolic drift, rather than being linked to dysfunctional mitochondria, was found to be an active act of direct response of cancer cells to cell proliferation and survival signals. This metabolic drift begins with the use of sugars and the full oxidative phosphorylation via the mitochondrial respiratory chain to form CO2, and it then leads to the formation of lactic acid via partial oxidation. In addition to oncogene-driven metabolic reprogramming, the oncometabolites themselves alter cell signaling and are responsible for differentiation and metastasis of cancer cells. The aberrant metabolism is now considered a major characteristic of cancer within the past 15 years. However, the proliferating anabolic growth of a tumor and its spread to distal sites of the body is not explainable by altered glucose metabolism alone. Since a tumor consists of malignant cells and its tumor microenvironment, it was important for us to understand the bilateral interactions between the primary tumor and its microenvironment and the processes underlying its successful metastasis. We here describe the main metabolic pathways and their implications in tumor progression and metastasis. We also portray that metabolic flexibility determines the fate of the cancer cell and ultimately the patient. This flexibility must be taken into account when deciding on a therapy, since singular cancer therapies only shift the metabolism to a different alternative path and create resistance to the medication used. As with Otto Warburg in his days, we primarily focused on the metabolism of mitochondria when dealing with this scientific question.

Keywords:  cancer; metabolism; metastasis; microenvironment; therapy

DOI:  https://doi.org/10.3389/fonc.2020.00409
J Clin Med. 2020 Apr 14. pii: E1116. [Epub ahead of print]9(4):

Altered Sphingolipids Metabolism Damaged Mitochondrial Functions: Lessons Learned From Gaucher and Fabry Diseases.

Margarita Ivanova.

  Sphingolipids represent a class of bioactive lipids that modulate the biophysical properties of biological membranes and play a critical role in cell signal transduction. Multiple studies have demonstrated that sphingolipids control crucial cellular functions such as the cell cycle, senescence, autophagy, apoptosis, cell migration, and inflammation. Sphingolipid metabolism is highly compartmentalized within the subcellular locations. However, the majority of steps of sphingolipids metabolism occur in lysosomes. Altered sphingolipid metabolism with an accumulation of undigested substrates in lysosomes due to lysosomal enzyme deficiency is linked to lysosomal storage disorders (LSD). Trapping of sphingolipids and their metabolites in the lysosomes inhibits lipid recycling, which has a direct effect on the lipid composition of cellular membranes, including the inner mitochondrial membrane. Additionally, lysosomes are not only the house of digestive enzymes, but are also responsible for trafficking organelles, sensing nutrients, and repairing mitochondria. However, lysosomal abnormalities lead to alteration of autophagy and disturb the energy balance and mitochondrial function. In this review, an overview of mitochondrial function in cells with altered sphingolipid metabolism will be discussed focusing on the two most common sphingolipid disorders, Gaucher and Fabry diseases. The review highlights the status of mitochondrial energy metabolism and the regulation of mitochondria-autophagy-lysosome crosstalk.

Keywords:  Fabry disease; Gaucher disease; autophagy; mitochondria; sphingolipids

DOI:  https://doi.org/10.3390/jcm9041116
Biol Chem. 2020 Apr 01. pii: /j/bchm.just-accepted/hsz-2020-0118/hsz-2020-0118.xml. [Epub ahead of print]

Citrate synthase desuccinylation by SIRT5 promotes colon cancer cell proliferation and migration.

Mengmeng Ren, Xin Yang, Juntao Bie, Zhe Wang, Minghui Liu, Yutong Li, Genze Shao, Jianyuan Luo.

  Citrate synthase (CS), the rate-limiting enzyme in the TCA cycle, catalyzes the first step of the cycle, namely, the condensation of oxaloacetate and acetyl-CoA to produce citrate. The expression and enzymatic activity of CS are altered in cancers, but posttranslational modification (PTM) of CS and its regulation in tumorigenesis remain largely obscure. SIRT5 belongs to the nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase sirtuin family and plays vital roles in multiple biological processes via modulating various substrates. Here, we show that SIRT5 interacts with CS and that SIRT5 desuccinylates CS at the evolutionarily conserved residues K393 and K395. Moreover, hypersuccinylation of CS at K393 and K395 dramatically reduces its enzymatic activity and suppresses colon cancer cell proliferation and migration. These results provide experimental evidence in support of a potential therapeutic approach for colon cancer.

Keywords:  SIRT5; cancer; citrate synthase; succinylation

DOI:  https://doi.org/10.1515/hsz-2020-0118
Circ Res. 2020 Apr 17.

MCUb Induction Protects the Heart from Post-Ischemic Remodeling.

Jiuzhou Huo, Shan Lu, Jennifer Q Kwong, Michael J Bround, Kelly M Grimes, Michelle A Sargent, Milton E Brown, Michael E Davis, Donald M Bers, Jeffery D Molkentin.

  Rationale: Mitochondrial Ca2+ loading augments oxidative metabolism to match functional demands during times of increased work or injury. However, mitochondrial Ca2+ overload also directly causes mitochondrial rupture and cardiomyocyte death during ischemia-reperfusion injury by inducing mitochondrial permeability transition pore opening. The mitochondrial Ca2+ uniporter (MCU) mediates mitochondrial Ca2+ influx, and its activity is modulated by partner proteins in its molecular complex, including the MCUb subunit. Objective: Here we sought to examine the function of the MCUb subunit of the MCU-complex in regulating mitochondria Ca2+ influx dynamics, acute cardiac injury and long-term adaptation after ischemic injury. Methods and Results:Cardiomyocyte-specific MCUb overexpressing transgenic mice and Mcub gene-deleted (Mcub-/-) mice were generated to dissect the molecular function of this protein in the heart. We observed that MCUb protein is undetectable in the adult mouse heart at baseline, but mRNA and protein are induced after ischemia-reperfusion injury. MCUb overexpressing mice demonstrated inhibited mitochondrial Ca2+ uptake in cardiomyocytes and partial protection from ischemia-reperfusion injury by reducing mitochondrial permeability transition pore opening. Antithetically, deletion of the Mcub gene exacerbated pathologic cardiac remodeling and infarct expansion after ischemic injury in association with greater mitochondrial Ca2+ uptake. Furthermore, hindlimb remote ischemic pre-conditioning induced MCUb expression in the heart, which was associated with decreased mitochondrial Ca2+ uptake, collectively suggesting that induction of MCUb protein in the heart is protective. Similarly, mouse embryonic fibroblasts from Mcub-/- mice were more sensitive to Ca2+ overload. Conclusions: Our studies suggest that Mcub is a protective cardiac inducible gene that reduces mitochondrial Ca2+ influx and permeability transition pore opening after ischemic injury to reduce ongoing pathological remodeling.

Keywords:  Ca2+ handling; ischemic injury; mitochondrial calcium; reperfusion injury

DOI:  https://doi.org/10.1161/CIRCRESAHA.119.316369
PLoS One. 2020 ;15(4): e0226862

Mitochondrial localization of SESN2.

Irina E Kovaleva, Artem V Tokarchuk, Andrei O Zheltukhin, Alexandra A Dalina, Grigoriy G Safronov, Alexandra G Evstafieva, Konstantin G Lyamzaev, Peter M Chumakov, Andrei V Budanov.

SESN2 is a member of the evolutionarily conserved sestrin protein family found in most of the Metazoa species. The SESN2 gene is transcriptionally activated by many stress factors, including metabolic derangements, reactive oxygen species (ROS), and DNA-damage. As a result, SESN2 controls ROS accumulation, metabolism, and cell viability. The best-known function of SESN2 is the inhibition of the mechanistic target of rapamycin complex 1 kinase (mTORC1) that plays a central role in support of cell growth and suppression of autophagy. SESN2 inhibits mTORC1 activity through interaction with the GATOR2 protein complex preventing an inhibitory effect of GATOR2 on the GATOR1 protein complex. GATOR1 stimulates GTPase activity of the RagA/B small GTPase, the component of RagA/B:RagC/D complex, preventing mTORC1 translocation to the lysosomes and its activation by the small GTPase Rheb. Despite the well-established role of SESN2 in mTORC1 inhibition, other SESN2 activities are not well-characterized. We recently showed that SESN2 could control mitochondrial function and cell death via mTORC1-independent mechanisms, and these activities might be explained by direct effects of SESN2 on mitochondria. In this work, we examined mitochondrial localization of SESN2 and demonstrated that SESN2 is located on mitochondria and can be directly involved in the regulation of mitochondrial functions.

DOI: https://doi.org/10.1371/journal.pone.0226862
Mol Metab. 2020 Mar 26. pii: S2212-8778(20)30055-7. [Epub ahead of print] 100981

Mitochondrial disease disrupts hepatic allostasis and lowers the threshold for immune-mediated liver toxicity.

Maxim Jestin, Senta M Kapnick, Tatyana N Tarasenko, Cassidy T Burke, Patricia M Zerfas, Francisca Diaz, Hilary Vernon, Larry N Singh, Ronald J Sokol, Peter J McGuire.

   OBJECTIVE: In individuals with mitochondrial disease, respiratory viral infection can result in metabolic decompensation with mitochondrial hepatopathy. Here, we used a mouse model of liver-specific Complex IV deficiency to study hepatic allostasis during respiratory viral infection.
METHODS: Mice with hepatic cytochrome c oxidase deficiency (LivCox10-/-) were infected with aerosolized influenza, A/PR/8 (PR8), and euthanized on day five after infection following three days of symptoms. This time course is marked by a peak in inflammatory cytokines and mimics the timing of a common clinical scenario in which caregivers may first attempt to manage the illness at home before seeking medical attention. Metabolic decompensation and mitochondrial hepatopathy in mice were characterized by serum hepatic testing, histology, electron microscopy, biochemistry, metabolomics, and bioenergetic profiling.
RESULTS: Following influenza infection, LivCox10-/- mice displayed marked liver disease including hepatitis, enlarged mitochondria with cristae loss, and hepatic steatosis. This pathophysiology was associated with viremia. Primary hepatocytes from LivCox10-/- mice cocultured with WT Kupffer cells in the presence of PR8 showed enhanced lipid accumulation. Treatment of hepatocytes with recombinant TNFα implicated Kupffer cell-derived TNFα as a precipitant of steatosis in LivCox10-/- mice. Eliminating Kupffer cells or blocking TNFα in vivo during influenza infection mitigated the steatosis and mitochondrial morphologic changes.
CONCLUSIONS: Taken together, our data shift the narrative of metabolic decompensation in mitochondrial hepatopathy beyond the bioenergetic costs of infection to include an underlying susceptibility to immune-mediated damage. Moreover, our work suggests that immune modulation during metabolic decompensation in mitochondrial disease represents a future viable treatment strategy needing further exploration.

Keywords:  Immunometabolism; Influenza; Kupffer cells; Mitochondrial disease; TNFα; Viral infection

DOI:  https://doi.org/10.1016/j.molmet.2020.100981
Front Oncol. 2020 ;10 325

Study of Cinobufagin as a Promising Anticancer Agent in Uveal Melanoma Through Intrinsic Apoptosis Pathway.

Leilei Zhang, Xiaolin Huang, Tao Guo, Huixue Wang, Haiyan Fan, Li Fang.

  Uveal melanoma (UM) is the most common primary intraocular carcinoma in adults. Cinobufagin, secreted by the Asiatic toad Bufo gargarizans, is a traditional Chinese medicine, widely used in tumor treatment. Here, we explored the potential antitumor function of cinobufagin and investigated its biochemical mechanisms in UM cells. The antitumor potential of cinobufagin was determined via cell viability, cell cycle, and apoptosis assays. Colony formation assays confirmed that cinobufagin exerted potent antitumor activity in a dose-dependent manner. We found that cinobufagin could induce cell apoptosis and upregulate the expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase (PARP), and cleaved caspase-9 in vivo and in vitro. In addition, after treatment with increased concentrations of cinobufagin, the intrinsic mitochondrial apoptosis pathway was also activated, which was demonstrated by increased cell apoptosis with increased expression of Bad and Bax, decreased expression of Bcl-2 and Bcl-xl, and reduced mitochondrial membrane potential (MMP) in OCM1 cells. Taken together, the results of this preclinical study suggest that cinobufagin can both inhibit cell survival and induce cell apoptosis in a dose-dependent manner in UM cells, which provides new insights into the biochemical mechanism of cinobufagin and its potential as a future chemotherapeutic agent for UM.

Keywords:  MMP; anticancer agent; apoptosis; cinobufagin; uveal melanoma

DOI:  https://doi.org/10.3389/fonc.2020.00325
Redox Biol. 2020 Apr 05. pii: S2213-2317(19)31515-0. [Epub ahead of print]32 101520

Frataxin-deficient cardiomyocytes present an altered thiol-redox state which targets actin and pyruvate dehydrogenase.

Rosa Purroy, Marta Medina-Carbonero, Joaquim Ros, Jordi Tamarit.

Friedreich ataxia (FA) is a cardioneurodegenerative disease caused by deficient frataxin expression. This mitochondrial protein has been related to iron homeostasis, energy metabolism, and oxidative stress. Previously, we set up a cardiac cellular model of FA based on neonatal rat cardiac myocytes (NRVM) and lentivirus-mediated frataxin RNA interference. These frataxin-deficient NRVMs presented lipid droplet accumulation, mitochondrial swelling and signs of oxidative stress. Therefore, we decided to explore the presence of protein thiol modifications in this model. With this purpose, reduced glutathione (GSH) levels were measured and the presence of glutathionylated proteins was analyzed. We observed decreased GSH content and increased presence of glutahionylated actin in frataxin-deficient NRVMs. Moreover, the presence of oxidized cysteine residues was investigated using the thiol-reactive fluorescent probe iodoacetamide-Bodipy and 2D-gel electrophoresis. With this approach, we identified two proteins with altered redox status in frataxin-deficient NRVMs: electron transfer flavoprotein-ubiquinone oxidoreductase and dihydrolipoyl dehydrogenase (DLDH). As DLDH is involved in protein-bound lipoic acid redox cycling, we analyzed the redox state of this cofactor and we observed that lipoic acid from pyruvate dehydrogenase was more oxidized in frataxin-deficient cells. Also, by targeted proteomics, we observed a decreased content on the PDH A1 subunit from pyruvate dehydrogenase. Finally, we analyzed the consequences of supplementing frataxin-deficient NRVMs with the PDH cofactors thiamine and lipoic acid, the PDH activator dichloroacetate and the antioxidants N-acetyl cysteine and Tiron. Both dichloroacetate and Tiron were able to partially prevent lipid droplet accumulation in these cells. Overall, these results indicate that frataxin-deficient NRVMs present an altered thiol-redox state which could contribute to the cardiac pathology.

DOI: https://doi.org/10.1016/j.redox.2020.101520
Biochem Biophys Res Commun. 2020 Apr 13. pii: S0006-291X(20)30672-0. [Epub ahead of print]

PFKFB4 is critical for the survival of acute monocytic leukemia cells.

Gongai Wang, Shumei Li, Kewei Xue, Shasha Dong.

  Acute myeloid leukemia (AML), which is characterized by an overproliferation of blood cells, is divided into several subtypes in adults and children. Of those subtypes, acute monocytic leukemia (M4/M5, AMoL) is reported to be associated with abnormal gene fusions that result in monocytic cell differentiation being blocked. However, few studies have shown a relationship between cellular metabolism and the initiation of AMoL. Here, we use the open-access database TCGA to analyze the expression of enzymes in the metabolic cycle and find that PFKFB4 is highly expressed in AMoL. Subsequently, knocking down PFKFB4 in THP-1 and U937 cells significantly inhibits cell growth and increases the sensitivity of cells to chemical drug-induced apoptosis. In line with the gene-editing alterations, treatment with a PFKFB4 inhibitor exhibits similar effects on THP-1 and U937 proliferation and apoptosis. In addition, we find that PFKFB4 functions as a reliable target of the epigenetic regulator MLL, which is a well-known modulator in AMoL. Mechanistically, MLL promotes PFKFB4 expression at the transcriptional level through the putative E2F6 binding site in the promoter of the pfkfb4 gene. Taken together, our results suggest PFKFB4 serves as a downstream target of MLL and functions as a potent therapeutic target in AMoL.

Keywords:  Acute monocytic leukemia; Apoptosis; MLL; PFKFB4; Transcription

DOI:  https://doi.org/10.1016/j.bbrc.2020.03.174
Sci Adv. 2020 04;6(15): eaax5150

Histone deacetylases 1 and 2 silence cryptic transcription to promote mitochondrial function during cardiogenesis.

Zachary J Milstone, Sherin Saheera, Lauren M Bourke, Tomer Shpilka, Cole M Haynes, Chinmay M Trivedi.

Cryptic transcription occurs widely across the eukaryotic genome; however, its regulation during vertebrate development is not understood. Here, we show that two class I histone deacetylases, Hdac1 and Hdac2, silence cryptic transcription to promote mitochondrial function in developing murine hearts. Mice lacking Hdac1 and Hdac2 in heart exhibit defective developmental switch from anaerobic to mitochondrial oxidative phosphorylation (OXPHOS), severe defects in mitochondrial mass, mitochondrial function, and complete embryonic lethality. Hdac1/Hdac2 promotes the transition to OXPHOS by enforcing transcriptional fidelity of metabolic gene programs. Mechanistically, Hdac1/Hdac2 deacetylates histone residues including H3K23, H3K14, and H4K16 to suppress cryptic transcriptional initiation within the coding regions of actively transcribed metabolic genes. Thus, Hdac1/2-mediated epigenetic silencing of cryptic transcription is essential for mitochondrial function during early vertebrate development.

DOI: https://doi.org/10.1126/sciadv.aax5150
Nanomaterials (Basel). 2020 Apr 13. pii: E744. [Epub ahead of print]10(4):

Alteration of the Mitochondrial Effects of Ceria Nanoparticles by Gold: An Approach for the Mitochondrial Modulation of Cells Based on Nanomedicine.

Patricia Gutiérrez-Carcedo, Sergio Navalón, Rafael Simó, Xavier Setoain, Carolina Aparicio-Gómez, Ibane Abasolo, Victor Manuel Victor, Hermenegildo García, José Raúl Herance.

  Ceria nanoparticles are cell compatible antioxidants whose activity can be enhanced by gold deposition and by surface functionalization with positive triphenylphosphonium units to selectively target the mitochondria. The antioxidant properties of these nanoparticles can serve as the basis of a new strategy for the treatment of several disorders exhibiting oxidative stress, such as cancer, diabetes or Alzheimer's disease. However, all of these pathologies require a specific antioxidant according with their mechanism to remove oxidant species excess in cells and diminish their effect on mitochondrial function. The mechanism through which ceria nanoparticles neutralize oxidative stress and their effect on mitochondrial function have not been characterized yet. In the present study, the mitochondria antioxidant effect of ceria and ceria-supported gold nanoparticles, with or without triphenylphosphonium functionalization, was assessed in HeLa cells. The effect caused by ceria nanoparticles on mitochondria function in terms of mitochondrial membrane potential (∆Ψm), adenosine triphosphate (ATP) production, nuclear respiratory factor 1 (NRF1) and nuclear factor erythroid-2-like 1 (NFE2L1) was reversed by the presence of gold. Furthermore, this effect was enhanced when nanoparticles were functionalized with triphenylphosphonium. Our study illustrates how the mitochondrial antioxidant effect induced by ceria nanoparticles can be modulated by the presence of gold.

Keywords:  antioxidant; ceria nanoparticles; gold-supported ceria nanoparticles; mitochondrial function; triphenylphosphonium gold-supported ceria nanoparticles

DOI:  https://doi.org/10.3390/nano10040744
Mol Biol Rep. 2020 Apr 11.

Effects of MOTS-c on the mitochondrial function of cells harboring 3243 A to G mutant mitochondrial DNA.

Chang Ho Ahn, Eun Hye Choi, Byung Soo Kong, Young Min Cho.

  Mitochondrial derived peptides (MDPs) are a class of peptide encoded in small open reading frames of mitochondrial DNA (mtDNA). MOTS-c, a recently discovered MDP, participates in retrograde signaling from the mitochondria to the nucleus to control cellular metabolism. Humanin, another MDP, has cytoprotective properties and enhances mitochondrial function. However, it has not yet been tested whether MOTS-c can affect mitochondrial function. We investigated the effect of exogenous and endogenous MOTS-c on mitochondrial function in a cybrid cell harboring 3243 A to G mutant mtDNA, which causes significant mitochondrial dysfunction. To test the effects of endogenous MOTS-c, the cybrid cell was transfected with a MOTS-c EGFP expression vector. Exogenous (synthetic) MOTS-c did not show a significant effect on the ATP content or the mRNA and protein levels of the mitochondrial complex in the mutant cybrid cells. Basal and stimulated mitochondrial respiration were also not affected by exogenous MOTS-c. The mutant cybrid cells transfected with the MOTS-c EGFP expression vector stably expressed MOTS-c, but ATP production and mRNA and protein levels of the mitochondrial complex were not affected. In contrast to other MDPs, MOTS-c does not improve mitochondrial dysfunction in cybrid cells with mutant mtDNA, which suggests the heterogeneous nature of MDPs.

Keywords:  Cybrid cell; MOTS-c; Mitochondrial DNA 3243 mutation; Mitochondrial derived peptide

DOI:  https://doi.org/10.1007/s11033-020-05429-z
Aging Cell. 2020 Apr 15. e13140

miR-181a regulates p62/SQSTM1, parkin, and protein DJ-1 promoting mitochondrial dynamics in skeletal muscle aging.

Katarzyna Goljanek-Whysall, Ana Soriano-Arroquia, Rachel McCormick, Caroline Chinda, Brian McDonagh.

  One of the key mechanisms underlying skeletal muscle functional deterioration during aging is disrupted mitochondrial dynamics. Regulation of mitochondrial dynamics is essential to maintain a healthy mitochondrial population and prevent the accumulation of damaged mitochondria; however, the regulatory mechanisms are poorly understood. We demonstrated loss of mitochondrial content and disrupted mitochondrial dynamics in muscle during aging concomitant with dysregulation of miR-181a target interactions. Using functional approaches and mito-QC assay, we have established that miR-181a is an endogenous regulator of mitochondrial dynamics through concerted regulation of Park2, p62/SQSTM1, and DJ-1 in vitro. Downregulation of miR-181a with age was associated with an accumulation of autophagy-related proteins and abnormal mitochondria. Restoring miR-181a levels in old mice prevented accumulation of p62, DJ-1, and PARK2, and improved mitochondrial quality and muscle function. These results provide physiological evidence for the potential of microRNA-based interventions for age-related muscle atrophy and of wider significance for diseases with disrupted mitochondrial dynamics.

Keywords:  aging; miR-181a; mitophagy; p62; parkin; protein DJ-1; skeletal muscle

DOI:  https://doi.org/10.1111/acel.13140
Sci Rep. 2020 Apr 14. 10(1): 6289

Evaluation of cell metabolic adaptation in wound and tumour by Fluorescence Lifetime Imaging Microscopy.

Diego Morone, Francesca D' Autilia, Tilo Schorn, Marco Erreni, Andrea Doni.

Acidic pH occurs in acute wounds progressing to healing as consequence of a cell metabolic adaptation in response to injury-induced tissue hypoperfusion. In tumours, high metabolic rate leads to acidosis affecting cancer progression. Acidic pH affects activities of remodelling cells in vitro. The pH measurement predicts healing in pathological wounds and success of surgical treatment of burns and chronic ulcers. However, current methods are limited to skin surface or based on detection of fluorescence intensity of specific sensitive probes that suffer of microenvironment factors. Herein, we ascertained relevance in vivo of cell metabolic adaptation in skin repair by interfering with anaerobic glycolysis. Moreover, a custom-designed skin imaging chamber, 2-Photon microscopy (2PM), fluorescence lifetime imaging (FLIM) and data mapping analyses were used to correlate maps of glycolytic activity in vivo as measurement of NADH intrinsic lifetime with areas of hypoxia and acidification in models of skin injury and cancer. The method was challenged by measuring the NADH profile by interfering with anaerobic glycolysis and oxidative phosphorylation in the mitochondrial respiratory chain. Therefore, intravital NADH FLIM represents a tool for investigating cell metabolic adaptation occurring in wounds, as well as the relationship between cell metabolism and cancer.

DOI: https://doi.org/10.1038/s41598-020-63203-4
J Clin Med. 2020 Apr 12. pii: E1095. [Epub ahead of print]9(4):

Decreased Triacylglycerol Content and Elevated Contents of Cell Membrane Lipids in Colorectal Cancer Tissue: A Lipidomic Study.

Adriana Mika, Alicja Pakiet, Aleksandra Czumaj, Zbigniew Kaczynski, Ivan Liakh, Jarek Kobiela, Adrian Perdyan, Krystian Adrych, Wojciech Makarewicz, Tomasz Sledzinski.

  Recent evidence suggests that lipid composition in cancer tissues may undergo multiple alterations. However, no comprehensive analysis of various lipid groups in colorectal cancer (CRC) tissue has been conducted thus far. To address the problem in question, we determined the contents of triacylglycerols (TG), an energetic substrate, various lipids necessary for cell membrane formation, among them phospholipids (phosphatidylcholine, phosphatidylethanolamine), sphingolipids (sphingomyelin) and cholesterol (free, esterified and total), and fatty acids included in complex lipids. 1H-nuclear magnetic resonance (1H-NMR) and gas chromatography-mass spectrometry (GC-MS) were used to analyze the lipid composition of colon cancer tissue and normal large intestinal mucosa from 25 patients. Compared with normal tissue, cancer tissues had significantly lower TG content, along with elevated levels of phospholipids, sphingomyelin, and cholesterol. Moreover, the content of oleic acid, the main component of TG, was decreased in cancer tissues, whereas the levels of saturated fatty acids and polyunsaturated fatty acids (PUFAs), which are principal components of polar lipids, were elevated. These lipidome rearrangements were associated with the overexpression of genes associated with fatty acid oxidation, and the synthesis of phospholipids and cholesterol. These findings suggest that reprogramming of lipid metabolism might occur in CRC tissue, with a shift towards increased utilization of TG for energy production and enhanced synthesis of membrane lipids, necessary for the rapid proliferation of cancer cells.

Keywords:  cancer cell proliferation; cell membrane; colorectal cancer; lipid oxidation; lipids; nuclear magnetic resonance; polyunsaturated fatty acids

DOI:  https://doi.org/10.3390/jcm9041095
Biochem J. 2020 Apr 16. pii: BCJ20190754. [Epub ahead of print]

Leucine and branched chain amino acid metabolism contribute to the growth of bone sarcomas by regulating AMPK and mTORC1 signaling.

Shailer B Martin, William S Reiche, Nicholas A Fifelski, Alexander J Schultz, Spencer J Stanford, Alexander A Martin, Danielle L Nack, Bernard Radlwimmer, Michael P Boyer, Elitsa Ananieva.

  Osteosarcoma and chondrosarcoma are sarcomas of the bone and the cartilage that are primarily treated by surgical intervention combined with high toxicity chemotherapy. In search of alternative metabolic approaches to address the challenges in treating bone sarcomas, we assessed the growth dependence of these cancers on leucine, one of the branched chain amino acids (BCAAs), and BCAA metabolism. Tumor biopsies from bone sarcoma patients revealed differential expression of BCAA metabolic enzymes. The cytosolic branched chain aminotransferase (BCATc) that is commonly overexpressed in cancer cells, was downregulated in chondrosarcoma (SW1353) in contrast to osteosarcoma (143B) cells that expressed both BCATc and its mitochondrial isoform BCATm. Treating SW1353cells with gabapentin, a selective inhibitor of BCATc, further revealed that these cells failed to respond to gabapentin. Application of the structural analog of leucine, N-acetyl-leucine amide (NALA) to disrupt leucine uptake, indicated that all bone sarcoma cells used leucine to support their energy metabolism and biosynthetic demands. This was evident from the increased activity of the energy sensor AMP-activated protein kinase (AMPK), downregulation of complex 1 of the mammalian target of rapamycin (mTORC1), and reduced cell viability in response to NALA. The observed changes were most profound in the 143B cells, which appeared highly dependent on cytosolic and mitochondrial BCAA metabolism. This study thus demonstrates that bone sarcomas rely on leucine and BCAA metabolism for energy and growth; however, the differential expression of BCAA enzymes and the presence of other carbon sources may dictate how efficiently these cancer cells take advantage of BCAA metabolism.

Keywords:  BCAAs; BCATc; BCATm; Leucine; chondrosarcoma; osteosarcoma

DOI:  https://doi.org/10.1042/BCJ20190754
Proc Natl Acad Sci U S A. 2020 Apr 14. pii: 202001572. [Epub ahead of print]

A common coupling mechanism for A-type heme-copper oxidases from bacteria to mitochondria.

Amandine Maréchal, Jing-Yang Xu, Naho Genko, Andrew M Hartley, Francis Haraux, Brigitte Meunier, Peter R Rich.

  Mitochondria metabolize almost all the oxygen that we consume, reducing it to water by cytochrome c oxidase (CcO). CcO maximizes energy capture into the protonmotive force by pumping protons across the mitochondrial inner membrane. Forty years after the H+/e- stoichiometry was established, a consensus has yet to be reached on the route taken by pumped protons to traverse CcO's hydrophobic core and on whether bacterial and mitochondrial CcOs operate via the same coupling mechanism. To resolve this, we exploited the unique amenability to mitochondrial DNA mutagenesis of the yeast Saccharomyces cerevisiae to introduce single point mutations in the hydrophilic pathways of CcO to test function. From adenosine diphosphate to oxygen ratio measurements on preparations of intact mitochondria, we definitely established that the D-channel, and not the H-channel, is the proton pump of the yeast mitochondrial enzyme, supporting an identical coupling mechanism in all forms of the enzyme.

Keywords:  ADP/O ratio; H/e stoichiometry; cytochrome c oxidase; mitochondria; proton pumping

DOI:  https://doi.org/10.1073/pnas.2001572117
Cancer Res. 2020 Apr 17. pii: canres.2660.2019. [Epub ahead of print]

Tumor cell-derived Angiopoietin-2 promotes metastasis in melanoma.

Ashik Ahmed Abdul Pari, Mahak Singhal, Corinne Hübers, Carolin Mogler, Benjamin Schieb, Anja Gampp, Nicolas Gengenbacher, Louise E Reynolds, Dorothee Terhardt, Cyrill Géraud, Jochen Utikal, Markus Thomas, Sergij Goerdt, Kairbaan M Hodivala-Dilke, Hellmut G Augustin, Moritz Felcht.

The Angiopoietin (Angpt)-TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1-TIE2 signaling to destabilize the microvasculature during pathological disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing in situ hybridization-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of melanoma patients. Comparative analysis of biopsies revealed a higher fraction of ANGPT2-expressing tumor cells in metastatic versus primary sites. Tumor cell-expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress. Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2-silenced tumor cells, thereby resulting in enhanced ROS production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell-expressed ANGPT2 as an autocrine positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of melanoma patients.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-2660
J Cancer. 2020 ;11(12): 3454-3466

Niclosamide inhibits ovarian carcinoma growth by interrupting cellular bioenergetics.

Fugen Shangguan, Yan Liu, Li Ma, Guiwu Qu, Qing Lv, Jing An, Shude Yang, Bin Lu, Qizhi Cao.

  Background: Ovarian carcinoma is a common malignant tumor of the female reproductive organs with an incidence rate second only to cervical and endometrial cancers. In the past 10 years, anticancer therapy has focused on Niclosamide, an anthelmintic teniacide that is commonly used against tapeworms and has been approved for use in humans for nearly 50 years. Importantly, Niclosamide has been confirmed to target the Wnt/β-catenin, mTOR, STAT3, NF-κB, and Notch pathways has been widely investigated in multiple cancer types. However, the potential benefits of Niclosamide therapy for treatment of ovarian carcinoma have not been established. Methods: CCK-8 colony formation assays were performed to evaluate cell viability and tumor growth. Cell apoptosis was measured by flow cytometry. A Seahorse XF96 analyzer was used to measure cellular bioenergetics. Mito-tracker stained mitochondria were visualized by confocal microscopy. Western blotting was used to detect expressed proteins. A nude mouse transplanted-tumor model was used to evaluate the antitumor activity of Niclosamide in ovarian carcinoma. Result: Niclosamide treatment significantly suppressed ovarian carcinoma growth and induced cell apoptosis by inactivating MEK1/2-ERK1/2 mediated signal transduction. Overall, mitochondrial respiration and aerobic glycolysis were both decreased by Niclosamide treatment. Niclosamide dramatically enhanced ROS-activated and JNK-mediated apoptosis in cells subjected to glucose deprivation. Niclosamide also showed in vivo antitumor activity in the nude mouse transplanted-tumor model. Conclusion: Collectively, these data highlight a novel anti-tumor mechanism of Niclosamide that involves an interruption of cell metabolism. The finding also indicates a potential for the application of Niclosamide in ovarian carcinoma therapy.

Keywords:  MEK1/2-ERK1/2 signal; Niclosamide; cellular bioenergetics; ovarian carcinoma

DOI:  https://doi.org/10.7150/jca.41418
Aging (Albany NY). 2020 Apr 14. 12

Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence.

Yongtao Wang, Tao Yu, Yanying Zhou, Shike Wang, Xunian Zhou, Limin Wang, Tianmiao Ou, Yixin Chen, Yawen Zhou, Huizhen Zhang, Ying Wang, Xiaomei Fan, Pan Chen, Frank J Gonzalez, Aiming Yu, Peng Huang, Min Huang, Huichang Bi.

  Stable transfection manipulation with antibiotic selection and passaging induces progressive cellular senescence phenotypes. However, the underlying mechanisms remain poorly understood. This study demonstrated that stable transfection of the empty vector induced PANC-1 cells into cellular senescence. Metabolomics revealed several acylcarnitines and their upstream regulatory gene, carnitine palmitoyltransferase 1C (CPT1C) involved in fatty acid β-oxidation in mitochondria, were strikingly decreased in senescent PANC-1 cells. Low CPT1C expression triggered mitochondrial dysfunction, inhibited telomere elongation, impaired cell survival under metabolic stress, and hindered the malignance and tumorigenesis of senescent cells. On the contrary, mitochondrial activity was restored by CPT1C gain-of-function in senescent vector PANC-1 cells. PPARα and TP53/CDKN1A, crucial signaling components in cellular senescence, were downregulated in senescent PANC-1 cells. This study identifies CPT1C as a key regulator of stable transfection-induced progressive PANC-1 cell senescence that inhibits mitochondrial function-associated metabolic reprogramming. These findings confirm the need to identify cell culture alterations after stable transfection, particularly when cells are used for metabolomics and mitochondria-associated studies, and suggest inhibition of CPT1C could be a promising target to intervene pancreatic tumorigenesis.

Keywords:  carnitine palmitoyltransferase 1C; metabolic reprogramming; mitochondria; senescence; stable transfection

DOI:  https://doi.org/10.18632/aging.103033
Aging (Albany NY). 2020 Apr 14. 12

FAM84B, amplified in pancreatic ductal adenocarcinoma, promotes tumorigenesis through the Wnt/β-catenin pathway.

Xin Zhang, Jiapeng Xu, Ronglin Yan, Yu Zhang, Zunqi Hu, Hongbing Fu, Qing You, Qingping Cai, Dejun Yang.

  Altered expression of family with sequence similarity 84, member B (FAM84B) has been found in various human cancers. However, the expression and function of FAM84B in pancreatic ductal adenocarcinoma (PDAC) has not been studied. Here, by analyzing The Cancer Genome Atlas cohort, we found that FAM84B amplification was observed in 11% of 141 PDAC patients, and FAM84B amplification was correlated with higher mRNA expression of FAM84B. FAM84B amplification and overexpression was significantly correlated with poor overall survival. Moreover, knockdown of FAM84B in PDAC cell lines suppressed cell proliferation and induced apoptosis. FAM84B knockdown also suppressed mitochondrial function and glycolysis of PDAC cells. Interestingly, knockdown of FAM84B decreased the nuclear accumulation of β-catenin, and the expression of c-Myc and lactate dehydrogenase A, but enhanced the expression of Survivin. On the contrary, FAM84B overexpression displayed reversed effects in cell proliferation, apoptosis, mitochondrial function, and glycolysis, which was blocked by the Wnt/β-catenin pathway inhibitor (XAV939). In addition, PDAC cells with lower expression of FAM84B were more sensitive to gemcitabine-induced cell proliferation inhibition both in vitro and in vivo. In conclusion, FAM84B plays an important role in aerobic glycolysis and tumorigenesis in PDAC and Wnt/β-catenin may be involved in this process.

Keywords:  Wnt/β-catenin; apoptosis; gemcitabine; glycolysis; proliferation

DOI:  https://doi.org/10.18632/aging.103044
Onco Targets Ther. 2020 ;13 2613-2627

PCK1 Regulates Glycolysis and Tumor Progression in Clear Cell Renal Cell Carcinoma Through LDHA.

Liang Shi, Shuxian An, Ying Liu, Jianjun Liu, Feng Wang.

   Background: Suppressed gluconeogenesis and increased glycolysis are common in clear cell renal cell carcinoma (ccRCC). Phosphoenolpyruvate carboxykinase 1 (PCK1) is a rate-limiting gluconeogenesis enzyme. However, the role of PCK1 in tumor metabolism and progression remains unclear.
Methods: Artificial modulation of PCK1 (down- and upregulation) in two ccRCC cell lines was performed to explore the role of PCK1 in the glycolytic phenotype and in tumor growth and metastasis in vitro and in vivo. Sixty-two patients with ccRCC underwent 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography. The levels of PCK1 and lactate dehydrogenase A (LDHA) in ccRCC tissues and peritumor tissues were investigated with immunohistochemistry. The relationships between 18F-FDG accumulation and the expression of PCK1 and LDHA were analyzed. The mechanisms underlying the regulation of LDHA by PCK1 were analyzed using in vitro molecular techniques.
Results: PCK1 suppressed ccRCC cell growth and metastasis in vitro and inhibited tumorigenesis in nude mice by blocking the aerobic glycolysis pathway. Clinically, low levels of PCK1 expression were associated with poor prognosis in patients with ccRCC. The expression level of PCK1 was negatively correlated with tumor progression, the LDHA expression level and 18F-FDG accumulation in primary ccRCC tissue. We also demonstrated that PCK1 reduces the stability of LDHA through posttranslational regulation. Finally, we showed that the effects of PCK1 on glucose metabolism, cell proliferation and metastasis are mediated via the inhibition of LDHA.
Conclusion: Our study identified a novel molecular mechanism underlying the Warburg effect. PCK1 may serve as a candidate prognostic biomarker, and targeting the PCK1/LDHA pathway might be a new strategy to selectively inhibit tumor metabolism in human ccRCC.

Keywords:  LDHA; PCK1; clear cell renal cell carcinoma; glycolysis

DOI:  https://doi.org/10.2147/OTT.S241717
Cell. 2020 Apr 16. pii: S0092-8674(20)30346-9. [Epub ahead of print]181(2): 236-249

The Human Tumor Atlas Network: Charting Tumor Transitions across Space and Time at Single-Cell Resolution.

Human Tumor Atlas Network

  Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

Keywords:  AI; Cancer Moonshot; Human Tumor Atlas; cancer transitions; data integration; data visualization; metastasis; pre-cancer; resistance; single-cell genomics; spatial genomics; spatial imaging; tumor

DOI:  https://doi.org/10.1016/j.cell.2020.03.053
J Exp Med. 2020 Jun 01. pii: e20200310. [Epub ahead of print]217(6):

NNT in NSCLC: No need to worry?

Marcus Conrad.

In this study, Ward et al. (https://doi.org/10.1084/jem.20191689) provide exciting evidence that nucleotide nicotinamide transhydrogenase (NNT), a mitochondrial matrix-located enzyme harnessing the proton gradient to generate NADPH using NADH, markedly contributes to non-small cell lung carcinoma (NSCLC), which is abrogated in the murine C57BL/6J background, a strain known to be deficient in NNT.

DOI: https://doi.org/10.1084/jem.20200310
Trends Cell Biol. 2020 Apr 14. pii: S0962-8924(20)30058-1. [Epub ahead of print]

The Complex Interplay between Antioxidants and ROS in Cancer.

Isaac S Harris, Gina M DeNicola.

  Reactive oxygen species (ROS) play important roles in tissue homeostasis, cellular signaling, differentiation, and survival. In this review, we discuss the types of ROS, their impact on cellular processes, and their pro- and antitumorigenic effects. Further, we discuss recent advances in our understanding of both endogenous and exogenous antioxidants in tumorigenic processes. Finally, we discuss how aberrant activation of antioxidant programs by the transcription factor NFE2-related factor 2 (NRF2) influences tumorigenesis and metastasis, and where the current gaps in our knowledge remain.

Keywords:  NRF2; ROS; antioxidant; cancer; glutathione

DOI:  https://doi.org/10.1016/j.tcb.2020.03.002
Nat Commun. 2020 Apr 14. 11(1): 1779

Sex-associated molecular differences for cancer immunotherapy.

Youqiong Ye, Ying Jing, Liang Li, Gordon B Mills, Lixia Diao, Hong Liu, Leng Han.

Immune checkpoint blockade therapies have extended patient survival across multiple cancer lineages, but there is a heated debate on whether cancer immunotherapy efficacy is different between male and female patients. We summarize the existing meta-analysis to show inconsistent conclusions for whether gender is associated with the immunotherapy response. We analyze molecular profiling from ICB-treated patients to identify molecular differences for immunotherapy responsiveness. We perform comprehensive analyses for patients from The Cancer Genome Atlas (TCGA) and reveal divergent patterns for sex bias in immune features across multiple cancer types. We further validate our observations in multiple independent data sets. Considering that the majority of clinical trials are in melanoma and lung cancer, meta-analyses that pool multiple cancer types have limitations to discern whether cancer immunotherapy efficacy is different between male and female patients. Future studies should include omics profiling to investigate sex-associated molecular differences in immunotherapy.

DOI: https://doi.org/10.1038/s41467-020-15679-x
Hepatology. 2020 Apr 16.

PGC1α suppresses metastasis of HCC by inhibiting Warburg effect via PPARγ-dependent WNT/β-catenin/PDK1 axis.

Qiaozhu Zuo, Jia He, Shu Zhang, Hui Wang, Guangzhi Jin, Haojie Jin, Zhuoan Cheng, Xuemei Tao, Chengtao Yu, Botai Li, Chen Yang, Siying Wang, Yuanyuan Lv, Fangyu Zhao, Ming Yao, Wenming Cong, Cun Wang, Wenxin Qin.

  Peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1α (PGC1α) is a key regulator of mitochondrial biogenesis and respiration. PGC1α is involved in the carcinogenesis, progression, and metabolic state of cancer. However, its role in progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we observed that PGC1α was downregulated in human HCC. A clinical study showed that the low levels of PGC1α expression were correlated with poor survival, vascular invasion, and larger tumor size. PGC1α inhibited the migration and invasion of HCC cells both in vitro experiment and in vivo mouse model. Mechanistically, PGC1α suppressed Warburg effect through the downregulation of pyruvate dehydrogenase kinase isozyme 1 (PDK1) mediated by WNT/β-catenin pathway, and the inhibition of WNT/β-catenin pathway was induced by the activation of PPARγ. Conclusion: Low levels of PGC1α expression indicate a poor prognosis for HCC patients. PGC1α suppresses HCC metastasis by inhibiting aerobic glycolysis through regulating WNT/β-catenin/PDK1 axis, which depends on PPARγ. PGC1α is a potential factor for predicting prognosis and therapeutic target for HCC patients.

Keywords:  PDK1; Transcription coactivator; aerobic glycolysis; tumor progression; β-catenin

DOI:  https://doi.org/10.1002/hep.31280