• Eosinophils
• Esophageal squamous cell carcinoma
• Mutational signature
• Non-smoking female
• Tumor microenvironment

• Male
• Female
• Humans
• Esophageal Squamous Cell Carcinoma/genetics
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/pathology
• Prognosis
• Genomics
• Tumor Microenvironment

• colorectal cancer
• metabolomics
• cancer metabolism

• Humans
• Fructose-Bisphosphate Aldolase/metabolism
• Carcinoembryonic Antigen
• Drug Resistance, Neoplasm
• Cell Adhesion Molecules
• Colorectal Neoplasms/pathology
• Lactates
• Cell Line, Tumor
• Antigens, CD/genetics
• GPI-Linked Proteins

• Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
• Chang Gung Memorial Hospital, Linkou (Linkou Chang Gung Memorial Hospital)

• Energy metabolism
• Gastrointestinal neoplasms
• Glycolysis
• Hypoxia
• Mitochondria
• Oxidative phosphorylation

• Humans
• Gastrointestinal Neoplasms/drug therapy
• Carcinogenesis
• Cell Transformation, Neoplastic
• Hypoxia
• Energy Metabolism

• ATPase inhibitory factor 1
• OXPHOS
• RNA binding proteins
• Warburg effect
• cancer
• cell death
• metabolic reprogramming
• metastasis
• mitochondrial ATP synthase
• mitohormesis

• PID2019-108674RB-100 Ministry of Economy, Industry and Competitiveness
• CB06/07/0017 Instituto de Salud Carlos III

• ATP synthase
• OXPHOS
• disease
• mitochondria

• BT-474
• Breast cancer
• Proteomics
• Tamoxifen
• Trastuzumab
• Untargeted metabolomics

Mitochondria are the “gatekeeper” in a wide range of cellular functions, signaling events, cell homeostasis, proliferation, and apoptosis. Consequently, mitochondrial injury is linked to systemic effects compromising multi-organ functionality. Although mitochondrial stress is common for many pathomechanisms, individual outcomes differ significantly comprising a spectrum of associated pathologies and their severity grade. Consequently, a highly ambitious task in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM/3PM) is to distinguish between individual disease predisposition and progression under circumstances, resulting in compromised mitochondrial health followed by mitigating measures tailored to the individualized patient profile. For the successful implementation of PPPM concepts, robust parameters are essential to quantify mitochondrial health sustainability. The current article analyses added value of Mitochondrial Health Index (MHI) and Bioenergetic Health Index (BHI) as potential systems to quantify mitochondrial health relevant for the disease development and its severity grade. Based on the pathomechanisms related to the compromised mitochondrial health and in the context of primary, secondary, and tertiary care, a broad spectrum of conditions can significantly benefit from robust quantification systems using MHI/BHI as a prototype to be further improved. Following health conditions can benefit from that: planned pregnancies (improved outcomes for mother and offspring health), suboptimal health conditions with reversible health damage, suboptimal life-style patterns and metabolic syndrome(s) predisposition, multi-factorial stress conditions, genotoxic environment, ischemic stroke of unclear aetiology, phenotypic predisposition to aggressive cancer subtypes, pathologies associated with premature aging and neuro/degeneration, acute infectious diseases such as COVID-19 pandemics, among others.

• Claudin-2
• bioenergetic alteration
• colorectal cancers
• cytochrome c oxidase subunit 5b
• glycolysis
• mitochondria
• oxidative phosphorylation

• MOST 109-2314-B-182A-068- and MOST 110-2314-B-182A-095- Ministry of Science and Technology (MOST), Taiwan
• CMRPG3K2292, CMRPG3J0693 and CMRPG3J1681 Chang Gung Memorial Hospital

Reprogramming of cellular metabolism is a hallmark of cancer. Mitochondrial ATP synthase (MAS) produces most of the ATP that drives the cell. High expression of the MAS-composing proteins is found during cancer and is linked to a poor prognosis in glioblastoma, ovarian cancer, prostate cancer, breast cancer, and clear cell renal cell carcinoma. Cell surface-expressed ATP synthase, translocated from mitochondrion to cell membrane, involves the angiogenesis, tumorigenesis, and metastasis of cancer. ATP synthase has therefore been considered a therapeutic target. We review recent various ATP synthase inhibitors that suppress tumor growth and are being tested for the clinic.

• ATP synthase inhibitor
• cancer metabolism
• chemotherapy
• mitochondrial ATP synthase
• mitochondrial metabolism

Under dysbiosis, a gut metabolic disorder, short-chain carboxylic acids (SCCAs) are secreted to the lumen, affecting colorectal cancer (CRC) development. Butyrate and propionate act as CRC growth inhibitors, but they might also serve as carbon source. In turn, the roles of acetate as metabolic fuel and protein acetylation promoter have not been clearly elucidated. To assess whether acetate favors CRC growth through active mitochondrial catabolism, a systematic study evaluating acetate thiokinase (AcK), energy metabolism, cell proliferation, and invasiveness was performed in two CRC cell lines incubated with physiological SCCAs concentrations. In COLO 205, acetate (+glucose) increased the cell density (50%), mitochondrial protein content (3–10 times), 2-OGDH acetylation, and oxidative phosphorylation (OxPhos) flux (36%), whereas glycolysis remained unchanged vs. glucose-cultured cells; the acetate-induced OxPhos activation correlated with a high AcK activity, content, and acetylation (1.5–6-fold). In contrast, acetate showed no effect on HCT116 cell growth, OxPhos, AcK activity, protein content, and acetylation. However, a substantial increment in the HIF-1α content, HIF-1α-glycolytic protein targets (1–2.3 times), and glycolytic flux (64%) was observed. Butyrate and propionate decreased the growth of both CRC cells by impairing OxPhos flux through mitophagy and mitochondrial fragmentation activation. It is described, for the first time, the role of acetate as metabolic fuel for ATP supply in CRC COLO 205 cells to sustain proliferation, aside from its well-known role as protein epigenetic regulator. The level of AcK determined in COLO 205 cells was similar to that found in human CRC biopsies, showing its potential role as metabolic marker.

• acetate thiokinase
• acetylation
• cancer biomarker
• colon cancer
• oxidative phoshorylation

• Esophageal cancer
• Gastric cancer
• Gastroesophageal cancer
• Tumor hypoxia
• Tumour microenvironment

• Ca(2+)
• Cancer
• F-ATP synthase
• Metabolic reprogramming
• Mitochondria
• PTP
• Permeability transition
• ROS

• Cancer
• Metabolic pathways
• Metabolism
• Mitochondria
• mtDNA

• ATP synthase
• ATPase inhibitory factor 1
• RNA-binding proteins
• Ras-GTPase activating protein SH3-domain-binding protein 1
• metabolism
• mitochondria

• Warburg effect
• glycolysis
• oncogenes
• oxidative metabolism
• tumor therapy

• IG 2016, cod. rif. 19175 Associazione Italiana per la Ricerca sul Cancro
• 2019 "Finanziamento Una Tantum per la Ricerca, 2019"

• cancer therapy
• metabolic network
• metabolic rewiring
• mitochondria
• targeting mitochondria

• Animals
• Antineoplastic Agents/pharmacology
• Citric Acid Cycle/drug effects
• Heme/metabolism
• Humans
• Metabolic Networks and Pathways
• Mitochondria/drug effects
• Mitochondria/genetics
• Mitochondria/metabolism
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Oxidative Phosphorylation/drug effects

• DIA
• biomarkers
• gastric cancer
• metabolic network

• Cancer
• Genetic variation
• Mitochondrial DNA

Circulating tumor cells (CTCs) are cancer cells that detach from the primary site and travel in the blood stream. A higher number of CTCs increases the risk of breast cancer metastasis, and it is inversely associated with the survival rates of patients with breast cancer. Although the numbers of CTCs are generally low and the majority of CTCs die in circulation, the survival of a few CTCs can seed the development of a tumor at a secondary location. An increasing number of studies demonstrate that CTCs undergo modification in response to the dynamic biophysical environment in the blood due in part to fluid shear stress. Fluid shear stress generates reactive oxygen species (ROS), triggers redox-sensitive cell signaling, and alters the function of intracellular organelles. In particular, the mitochondrion is an important target organelle in determining the metastatic phenotype of CTCs. In healthy cells, mitochondria produce adenosine triphosphate (ATP) via oxidative phosphorylation in the electron transport chain, and during oxidative phosphorylation, they produce physiological levels of ROS. Mitochondria also govern death mechanisms such as apoptosis and mitochondrial permeability transition pore opening to, in order eliminate unwanted or damaged cells. However, in cancer cells, mitochondria are dysregulated, causing aberrant energy metabolism, redox homeostasis, and cell death pathways that may favor cancer invasiveness. In this review, we discuss the influence of fluid shear stress on CTCs with an emphasis on breast cancer pathology, then discuss alterations of cellular mechanisms that may increase the metastatic potentials of CTCs.

• breast cancer
• circulating tumor cells
• fluid shear stress
• mitochondria
• oxidative stress

• Metronidazole resistance
• Proteome
• Trichomonas vaginalis

• fermentation
• glutaminolysis
• glycolysis
• inflammation
• metastasis
• non-toxic
• survival

• ATP synthase
• ATPase inhibitory factor 1
• Enzyme biomarkers
• Metabolism
• Mitochondria
• Reverse phase protein arrays
• patients' survival

Cancer immunotherapy, in the form of vaccination, adoptive cellular transfer, or immune checkpoint inhibitors, has emerged as a promising practice within the field of oncology. However, despite the developing field's potential to revolutionize cancer treatment, the presence of immunotherapeutic-resistant tumor cells in many patients present a challenge and limitation to these immunotherapies. These cells not only indicate immunotherapeutic resistance, but also show multi-modal resistance to conventional therapies, abnormal metabolism, stemness, and metastasis. How can immunotherapeutic-resistant tumor cells render multi-malignant phenotypes? We reasoned that the immune-refractory phenotype could be associated with multi-malignant phenotypes and that these phenotypes are linked together by a factor that acts as the master regulator. In this review, we discussed the role of the embryonic transcription factor NANOG as a crucial master regulator we named “common factor” in multi-malignant phenotypes and presented strategies to overcome multi-malignancy in immunotherapeutic-resistant cancer by restraining the NANOG-mediated multi-malignant signaling axis. Strategies that blunt the NANOG axis could improve the clinical management of therapy-refractory cancer.

• Common factor
• Immunotherapy
• Multi-malignant phenotypes
• NANOG
• Therapy-refractory cancer

• genotoxicity
• glycolysis
• hepatocarcinogenesis
• liver
• oxidative phosphorylation
• rat

Metastasis remains the major cause of death from colon cancer. We intend to identify differentially expressed genes that are associated with the metastatic process and prognosis in colon cancer. ATP synthase epsilon subunit (ATP5E) gene was found to encode the mitochondrial F₀F₁ ATP synthase subunit epsilon that was overexpressed in tumor cells compared to their normal counterparts, while other genes encoding the ATP synthase subunit were repressed in public microarray datasets. CRC cells in which ATP5E was silenced showed markedly reduced invasive and migratory abilities. ATP5E inhibition significantly reduced the incidence of distant metastasis in a mouse xenograft model. Mechanistically, increased ATP5E expression resulted in a prominent reduction in E-cadherin and an increase in Snail expression. Our data also showed that an elevated ATP5E level in metastatic colon cancer samples was significantly associated with the AMPK-AKT-hypoxia-inducible factor-1α (HIF1α) signaling axis; silencing ATP5E led to the degradation of HIF1α under hypoxia through AMPK-AKT signaling. Our findings suggest that elevated ATP5E expression could serve as a marker of distant metastasis and a poor prognosis in colon cancer, and ATP5E functions via modulating AMPK-AKT-HIF1α signaling.

• AMPK
• ATP5E
• Colorectal Cancer
• EMT
• Metastasis

• Apoptosis
• Autophagy
• Mitochondrial biogenesis
• Mitochondrial dysfunction
• Mitophagy
• Ochratoxin A

• Cytochrome b
• Gene expression
• Head and neck squamous cell carcinoma
• Mitochondrial genes
• NADH

• Adult
• Aged
• Aged, 80 and over
• Cytochromes b/genetics
• Cytochromes b/metabolism
• DNA, Mitochondrial
• Down-Regulation
• Electron Transport Complex IV/genetics
• Female
• Gene Expression Regulation, Neoplastic
• Genome, Mitochondrial/genetics
• Humans
• Male
• Middle Aged
• Mitochondria/genetics
• Mitochondria/metabolism
• Mitochondrial Proton-Translocating ATPases/genetics
• NAD/genetics
• NAD/metabolism
• Neoplasm Staging
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• RNA, Mitochondrial/genetics
• RNA, Mitochondrial/metabolism
• Squamous Cell Carcinoma of Head and Neck/genetics

Switching of cellular energy production from oxidative phosphorylation (OXPHOS) to aerobic glycolysis occurs in many types of tumors. However, the significance of energy metabolism for the development of prostate carcinoma is poorly understood. We investigated the expression of OXPHOS complexes in 94 human prostate carcinomas and paired benign tissue using immunohistochemistry. Overall mitochondrial mass was upregulated in carcinomas compared to benign prostate tissue in all Gleason grades. A significant direct correlation between the expression of OXPHOS complexes I, II, and V and the Gleason score was observed. However, 17% of prostate carcinomas and 18% of benign prostate tissues showed isolated or combined deficiency of OXPHOS complexes (one deficiency in 12% of the tumors, combined deficiencies in 5%). Complex I was absent in 9% of the samples, with only parts of the tumor affected. ATP5F1A, a complex V protein, was the most frequently affected subunit, in 10% of tumors and 11% of benign prostate tissues (but not both tissues in any single patient). A possible role of complex V in prostate cancer development is suggested by the significant positive correlation of ATP5F1A levels with earlier-onset prostate cancer (age at diagnosis and at prostatectomy) and free PSA percentage. The relatively high percentage (17%) of prostate carcinomas with regional foci of partial OXPHOS complex deficiencies could have important therapeutic implications.

• Cancer
• Immunology
• Oncology

• Animals
• Antioxidants/administration & dosage
• Cell Line, Tumor
• Combined Modality Therapy
• Drug Resistance, Neoplasm
• Epigenesis, Genetic
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Immunotherapy
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Mitochondria/metabolism
• Mitochondrial ADP, ATP Translocases/deficiency
• Mitochondrial ADP, ATP Translocases/genetics
• Mitochondrial Proton-Translocating ATPases/deficiency
• Mitochondrial Proton-Translocating ATPases/genetics
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/therapy
• Radiation Tolerance
• Tumor Escape

• P50 CA096784 NCI NIH HHS
• P50 CA098252 NCI NIH HHS
• R01 CA114425 NCI NIH HHS
• T32 GM007309 NIGMS NIH HHS
• National Research Foundation of Korea
• National Cancer Institute

Cancer cells reprogram energy metabolism by boosting aerobic glycolysis as a main pathway for the provision of metabolic energy and of precursors for anabolic purposes. Accordingly, the relative expression of the catalytic subunit of the mitochondrial H⁺-ATP synthase—the core hub of oxidative phosphorylation—is downregulated in human carcinomas when compared with its expression in normal tissues. Moreover, some prevalent carcinomas also upregulate the ATPase inhibitory factor 1 (IF1), which is the physiological inhibitor of the H⁺-ATP synthase. IF1 overexpression, both in cells in culture and in tissue-specific mouse models, is sufficient to reprogram energy metabolism to an enhanced glycolysis by limiting ATP production by the H⁺-ATP synthase. Furthermore, the IF1-mediated inhibition of the H⁺-ATP synthase promotes the production of mitochondrial ROS (mtROS). mtROS modulate signaling pathways favoring cellular proliferation and invasion, the activation of antioxidant defenses, resistance to cell death, and modulation of the tissue immune response, favoring the acquisition of several cancer traits. Consistently, IF1 expression is an independent marker of cancer prognosis. By contrast, inhibition of the H⁺-ATP synthase by α-ketoglutarate and the oncometabolite 2-hydroxyglutarate, reduces mTOR signaling, suppresses cancer cell growth, and contributes to lifespan extension in several model organisms. Hence, the H⁺-ATP synthase appears as a conserved hub in mitochondria-to-nucleus signaling controlling cell fate. Unraveling the molecular mechanisms responsible for IF1 upregulation in cancer and the signaling cascades that are modulated by the H⁺-ATP synthase are of utmost interest to decipher the metabolic and redox circuits contributing to cancer origin and progression.

• ATPase inhibitory factor 1
• hepatocarcinogenesis
• inflammation
• metabolic reprogramming
• mitohormesis
• oxidative phosphorylation

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the growth of fluid-filled cysts in the kidneys. Several studies reported that the serine-threonine kinase Lkb1 is dysregulated in PKD. Here we show that genetic ablation of Lkb1 in the embryonic ureteric bud has no effects on tubule formation, maintenance, or growth. However, co-ablation of Lkb1 and Tsc1, an mTOR repressor, results in an early developing, aggressive form of PKD. We find that both loss of Lkb1 and loss of Pkd1 render cells dependent on glutamine for growth. Metabolomics analysis suggests that Lkb1 mutant kidneys require glutamine for non-essential amino acid and glutathione metabolism. Inhibition of glutamine metabolism in both Lkb1/Tsc1 and Pkd1 mutant mice significantly reduces cyst progression. Thus, we identify a role for Lkb1 in glutamine metabolism within the kidney epithelia and suggest that drugs targeting glutamine metabolism may help reduce cyst number and/or size in PKD.

Polycystic kidney disease (PKD) is characterized by the formation of large fluid-filled cysts. Here Flowers and colleagues show that loss of Lkb1, downregulated in PKD, renders kidney cells dependent on glutamine for growth, and suggest that inhibition of glutamine metabolism may prevent cyst development in PKD.

• Cancer
• Drosophila
• Drp-1
• Mitochondria
• Parkin
• scribble

• Animals
• Carcinogenesis
• Cytoskeletal Proteins/metabolism
• Drosophila
• Drosophila Proteins/genetics
• Drosophila Proteins/metabolism
• Epistasis, Genetic
• GTP-Binding Proteins/metabolism
• Gene Knockdown Techniques
• Gene Regulatory Networks
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Mitochondrial Dynamics
• Ubiquitin-Protein Ligases/metabolism

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. In this study, we had analysed the copy number variations and heteroplasmic mutations of mitochondria (MT) in 88 HCC individuals. The average copy number of MT genome in normal samples was significantly greater than that in tumor samples. Overall, the number of heteroplasmic mutations in 88 tumor and their matched normal samples were 241 and 173, respectively. There was higher positive ratio of heteroplasmic mutations in tumor samples (86%) than normal samples (73%). Worthwhile mention, ND1 gene harbored greater mutation frequency and more nonsynonymous mutations in tumor samples. Interestingly, 202 tumor-specific heteroplasmic mutations were detected. Moreover, ND1, ND3, ND4, ND5 and ND6 genes had higher ratio of nonsynonymous versus synonymous mutations in tumor-specific heteroplasmic mutations. It might suggest that the disorder of NADH dehydrogenase (complex I) resulted by heteroplasmic mutations may have close relation with tumorigenesis of hepatocellular carcinoma. This study provided theoretical basis for further understanding mechanism of tumorigenesis from the perspective of mitochondrial heteroplasmic mutations.

• Copy Number
• Hepatocellular carcinoma.
• Heteroplasmy
• Mitochondrial Genome

• CTGF
• Metabolism
• Mitochondrion
• OSCC
• mtTFA

• AMPK
• ATP
• Cancer
• Energy production
• Mitochondria
• OXPHOS

• HEMA
• RAFT polymerization
• amphiphilic polymers
• anticancer nanoparticles
• terpolymers
• α-tocopheryl succinate

• Antioxidants/chemistry
• Antioxidants/pharmacology
• Biocompatible Materials/chemistry
• Breast Neoplasms/drug therapy
• Breast Neoplasms/pathology
• Coumarins/chemistry
• Coumarins/metabolism
• Drug Delivery Systems
• Female
• Humans
• Hydrophobic and Hydrophilic Interactions
• Methacrylates/chemistry
• Nanoparticles/administration & dosage
• Nanoparticles/chemistry
• Polyethylene Glycols/chemistry
• Polymerization
• Polymers/administration & dosage
• Polymers/chemistry
• Thiazoles/chemistry
• Thiazoles/metabolism
• Tumor Cells, Cultured
• alpha-Tocopherol/chemistry
• alpha-Tocopherol/pharmacology

• T32 GM008433 NIGMS NIH HHS

• bioenergetics
• mitochondria
• mitochondrial oncobioenergetic index
• oncobioenergetics
• prostate cancer

The heterogeneous and dynamic tumor microenvironment has significant impact on cancer cell proliferation, invasion, drug response, and is probably associated with entering dormancy and recurrence. However, these complex settings are hard to recapitulate in vitro.

In this study, we mimic different restriction forces that tumor cells are exposed to using a physiologically relevant 3D model with tunable mechanical stiffness.

Breast cancer MDA-MB-231, colon cancer HCT-116 and pancreatic cancer CFPAC cells embedded in the stiffer gels exhibit a changed morphology and cluster formation, prolonged doubling time, and a slower metabolism rate, recapitulating the pathway from competency to dormancy. Altering environmental restriction allows them to re-enter and exit dormant conditions and change their sensitivities to drugs such as paclitaxol and gemcitabine. Cells surviving drug treatments can still regain competent growth and form tumors in vivo.

We have successfully developed an in vitro 3D model to mimic the effects of matrix restriction on tumor cells and this high throughput model can be used to study tumor cellular functions and their drug responses in their different states. This all in one platform may aid effective drug development.

• Glioblastoma/metabolism
• Glioblastoma/pathology
• Gluconeogenesis
• Glutamine/metabolism
• Glutathione/metabolism
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Ketone Oxidoreductases/metabolism
• Neoplasms/metabolism
• Neoplasms/pathology
• Reactive Oxygen Species/metabolism

Numerous studies have demonstrated that functional mitochondria are required for tumorigenesis, suggesting that mitochondrial oxidative phosphorylation (OXPHOS) might be a potential target for cancer therapy. In this study, we investigated the effects of BAY 87-2243, a small molecule that inhibits the first OXPHOS enzyme (complex I), in melanoma in vitro and in vivo.

BAY 87-2243 decreased mitochondrial oxygen consumption and induced partial depolarization of the mitochondrial membrane potential. This was associated with increased reactive oxygen species (ROS) levels, lowering of total cellular ATP levels, activation of AMP-activated protein kinase (AMPK), and reduced cell viability. The latter was rescued by the antioxidant vitamin E and high extracellular glucose levels (25 mM), indicating the involvement of ROS-induced cell death and a dependence on glycolysis for cell survival upon BAY 87-2243 treatment. BAY 87-2243 significantly reduced tumor growth in various BRAF mutant melanoma mouse xenografts and patient-derived melanoma mouse models. Furthermore, we provide evidence that inhibition of mutated BRAF using the specific small molecule inhibitor vemurafenib increased the OXPHOS dependency of BRAF mutant melanoma cells. As a consequence, the combination of both inhibitors augmented the anti-tumor effect of BAY 87-2243 in a BRAF mutant melanoma mouse xenograft model.

Taken together, our results suggest that complex I inhibition has potential clinical applications as a single agent in melanoma and also might be efficacious in combination with BRAF inhibitors in the treatment of patients with BRAF mutant melanoma.

The online version of this article (doi:10.1186/s40170-015-0138-0) contains supplementary material, which is available to authorized users.

• Anti-tumor efficacy
• BRAF mutant melanoma
• Cancer metabolism
• Mitochondrial complex I
• Oxidative phosphorylation (OXPHOS)
• Reactive oxygen species (ROS)
• Small molecule inhibitor

• Cell surface ATP synthase
• mouse pheochromocytoma cells
• paraganglioma
• pheochromocytoma
• resveratrol