• Humans
• Sulfonamides/pharmacology
• Sulfonamides/chemistry
• Sulfonamides/chemical synthesis
• Breast Neoplasms/drug therapy
• Breast Neoplasms/pathology
• Breast Neoplasms/metabolism
• Female
• Rhodium/chemistry
• Rhodium/pharmacology
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/chemical synthesis
• Cytoskeleton/drug effects
• Cytoskeleton/metabolism
• Cell Movement/drug effects
• Coordination Complexes/pharmacology
• Coordination Complexes/chemistry
• Coordination Complexes/chemical synthesis
• Cell Line, Tumor
• Mitochondrial Dynamics/drug effects
• Mitochondria/drug effects
• Mitochondria/metabolism
• Oxidative Phosphorylation/drug effects
• Cell Proliferation/drug effects

• ROS
• aging
• fertility
• gamete quality
• mitochondria
• reproductive health

• National Natural Science Foundation of China

• Glycolysis
• Iron
• Metabolism
• OXPHOS
• Oxygen
• Tumor

• Immunohistochemistry
• Intraperitoneal metastases
• Mitochondria
• Ovarian cancer
• Ovarian cancer prognosis
• Ovarian cancer xenografts

• Animals
• Mice
• Humans
• Female
• Ovarian Neoplasms
• Apoptosis
• Cell Line, Tumor
• Neoplasm Recurrence, Local
• Mitochondria
• Antibodies, Monoclonal

• Universitätsklinikum Hamburg-Eppendorf (UKE) (5411)

• cancer metabolism
• oral cancer detection
• tumour heterogeneity
• cancer imaging
• cancer microenvironment

• Humans
• Succinate Dehydrogenase/genetics
• Succinate Dehydrogenase/metabolism
• Carcinoma, Squamous Cell
• Flavin-Adenine Dinucleotide/metabolism
• Mouth Neoplasms/pathology
• Electron Transport Complex II/metabolism

• R01 CA182043 NCI NIH HHS
• U.S. Department of Health & Human Services | National Institutes of Health (NIH)

• metabolomics
• ovarian cancer
• stroma
• tumor microenvironment

• Humans
• Female
• Neoplasms/pathology
• Ovarian Neoplasms/drug therapy
• Stromal Cells/metabolism
• Cell Communication
• Tumor Microenvironment
• Cytokines/metabolism

• Autofluorescence
• flavin adenine dinucleotide (FAD)
• metabolism
• oral squamous cell carcinoma (OSCC)
• succinate dehydrogenase

• R01 CA182043 NCI NIH HHS

Epithelial ovarian cancer (EOC) is a gynecologic malignancy with a poor prognosis due to resistance to first-line chemotherapeutic agents. Some cancer cells are primarily dependent on glycolysis, but others favor mitochondrial oxidative phosphorylation (OXPHOS) over glycolysis. Changes in metabolic reprogramming have been reported to be involved in cancer cell survival. In this review, we summarize the metabolic profiles (e.g., metabolic heterogeneity, plasticity, and reprogramming) and adaptation to the dynamic tumor microenvironment and discuss potential novel therapeutic strategies. A literature search was performed between January 2000 and March 2022 in the PubMed and Google Scholar databases using a combination of specific terms. Ovarian cancer cells, including cancer stem cells, depend on glycolysis, OXPHOS, or both for survival. Several environmental stresses, such as nutrient starvation or glucose deprivation, hypoxic stress, acidification, and excessive reactive oxygen species (ROS) generation, reprogram the metabolic pathways to adapt. The interaction between tumors and adjacent stromal cells allows cancer cells to enhance mitochondrial energy metabolism. The metabolic reprogramming varies depending on genomic and epigenetic alterations of metabolism-related genes and the metabolic environment. Developing accurate and non-invasive methods for early identification of metabolic alterations could facilitate optimal cancer diagnosis and treatment. Cancer metabolism research has entered an exciting era where novel strategies targeting metabolic profiling will become more innovative.

Voltage dependent anion channels (VDAC) control the flux of most anionic respiratory substrates, ATP, ADP, and small cations, crossing the outer mitochondrial membrane. VDAC closure contributes to the partial suppression of mitochondrial metabolism that favors the Warburg phenotype of cancer cells. Recently, it has been shown that NADH binds to a specific pocket in the inner surface of VDAC1, also conserved in VDAC2 and 3, closing the channel. We hypothesized that binding of small molecules to the NADH pocket, maintain VDAC in an open configuration by preventing closure induced by NADH and possible other endogenous regulators. We screened in silico, the South Carolina Compound Collection SC³ (~ 100,000 proprietary molecules), using shape-based queries of the NADH binding region of VDAC. After molecular docking of selected compounds, we physically screened candidates using mitochondrial membrane potential (ΔΨm), as an overall readout of mitochondrial metabolism. We identified SC18, as the most potent compound. SC18 bound to VDAC1, as assessed by a thermal shift assay. Short-term treatment with SC18 decreased ΔΨm in SNU-449 and HepG2 human hepatocarcinoma cells. Mitochondrial depolarization was similar in wild type, VDAC1/2, 1/3, and 2/3 double KO HepG2 cells indicating that the effect of SC18 was not VDAC isoform-dependent. In addition, SC18 decreased mitochondrial NADH and cellular ATP production; and increased basal respiration. Long-term exposure to SC18, decreased cell proliferation as determined by wound-healing and cell viability assays. In summary, SC18 is a novel VDAC-targeting small molecule that induces mitochondrial dysfunction and inhibits cell proliferation.

• Cancer
• Mitochondrial dysfunction
• Mitochondrial metabolism
• NADH-binding pocket
• VDAC

Ovarian cancer is the most lethal gynecological neoplasm, and epithelial ovarian cancer (EOC) accounts for 90% of ovarian malignancies. The 5-year survival is less than 45%, and, unlike other types of cancer, the proportion of women who die from this disease has not improved in recent decades. Nerve growth factor (NGF) and tropomyosin kinase A (TRKA), its high-affinity receptor, play a crucial role in pathogenesis through cell proliferation, angiogenesis, invasion, and migration. NGF/TRKA increase their expression during the progression of EOC by upregulation of oncogenic proteins as vascular endothelial growth factor (VEGF) and c-Myc. Otherwise, the expression of most oncoproteins is regulated by microRNAs (miRs). Our laboratory group reported that the tumoral effect of NGF/TRKA depends on the regulation of miR-145 levels in EOC. Currently, mitochondria have been proposed as new therapeutic targets to activate the apoptotic pathway in the cancer cell. The mitochondria are involved in a myriad of functions as energy production, redox control, homeostasis of Ca⁺², and cell death. We demonstrated that NGF stimulation produces an augment in the Bcl-2/BAX ratio, which supports the anti-apoptotic effects of NGF in EOC cells. The review aimed to discuss the role of mitochondria in the interplay between NGF/TRKA and miR-145 and possible therapeutic strategies that may decrease mortality due to EOC.

• antitumoral complementary therapies
• chemoresistance
• epithelial ovarian cancer (EOC)
• miR-145
• miRs
• mitochondria
• nerve growth factor (NGF)
• neurotrophins (NTs)
• oxidative phosphorylation (OXPHOS)
• tropomyosin receptor kinase A (TRKA)

Ovarian cancer is one of the most common malignancies and the highest mortality among gynecological malignancy. The standard therapy options for patients with ovarian cancer are cytoreductive surgery and chemotherapy, and although most patients do better with standard treatment, it is easy to relapse and be resistant to chemotherapy. Therefore, it is important to find new therapeutic strategies. More recently, metabolic reprogramming has been recognized as a hallmark of cancer and has become a potential target for tumor therapy. Mutations of metabolic enzymes are closely related to the development of ovarian cancer. The metabolic reprogramming of ovarian cancer not only provides energy to tumor cells, but also participates in various biological processes as signaling molecules. Succinic acid (SA) is an important metabolic intermediate involved in a number of metabolic pathways, such as TCA cycle and glutamine metabolism, and is also widely present in a variety of plants and vegetables. Studies show abnormal SA metabolism in many tumors and affect tumor formation through a variety of mechanisms. But the role of SA in ovarian cancer is less studied. This paper reviews the role of SA and its abnormal metabolic pathway in ovarian cancer.

• IDH
• SDH
• SUCNR1
• glutamine
• succinate acid

Most anionic metabolites including respiratory substrates, glycolytic adenosine triphosphate (ATP), and small cations that enter mitochondria, and mitochondrial ATP moving to the cytosol, cross the outer mitochondrial membrane (OMM) through voltage dependent anion channels (VDAC). The closed states of VDAC block the passage of anionic metabolites, and increase the flux of small cations, including calcium. Consequently, physiological or pharmacological regulation of VDAC opening, by conditioning the magnitude of both anion and cation fluxes, is a major contributor to mitochondrial metabolism. Tumor cells display a pro-proliferative Warburg phenotype characterized by enhanced aerobic glycolysis in the presence of partial suppression of mitochondrial metabolism. The heterogeneous and flexible metabolic traits of most human tumors render cells able to adapt to the constantly changing energetic and biosynthetic demands by switching between predominantly glycolytic or oxidative phenotypes. Here, we describe the biological consequences of changes in the conformational state of VDAC for cancer metabolism, the mechanisms by which VDAC-openers promote cancer cell death, and the advantages of VDAC opening as a valuable pharmacological target. Particular emphasis is given to the endogenous regulation of VDAC by free tubulin and the effects of VDAC-tubulin antagonists in cancer cells. Because of its function and location, VDAC operates as a switch to turn-off mitochondrial metabolism (closed state) and increase aerobic glycolysis (pro-Warburg), or to turn-on mitochondrial metabolism (open state) and decrease glycolysis (anti-Warburg). A better understanding of the role of VDAC regulation in tumor progression is relevant both for cancer biology and for developing novel cancer chemotherapies.

• Warburg
• cancer
• glycolysis
• metabolic flexibility
• metabolic reprogramming
• metabolism
• mitochondria
• voltage dependent anion channels

• Cancer metabolism
• Warburg effect
• amino acids
• cancer-associated fibroblasts
• lactate
• tumor microenvironment

• Actomyosin
• Cell Movement
• Collagen
• Cytoskeleton
• Extracellular Matrix

• R01 GM131178 NIGMS NIH HHS

Ovarian cancer is the fifth most common type of cancer afflicting women and frequently presents at a late stage with a poor prognosis. While paired box 2 (PAX2) expression is frequently lost in high-grade serous ovarian cancer, it is expressed in a subset of ovarian tumors and may play a role in tumorigenesis. This study investigated the expression of PAX2 in ovarian cancer. The expression of PAX2 in a murine allograft model of ovarian cancer, the RM model, led to a more rapidly growing cell line both in vitro and in vivo. This finding was in accordance with the shorter progression-free survival observed in patients with a higher PAX2 expression, as determined in this study cohort by immunohistochemistry. iTRAQ-based proteomic profiling revealed that proteins involved in fatty acid metabolism and oxidative phosphorylation were found to be upregulated in RM tumors expressing PAX2. The expression of two key fatty acid metabolic genes was also found to be upregulated in PAX2-expressing human ovarian cancer samples. The analysis of existing datasets also indicated that a high expression of key enzymes in fatty acid metabolism was associated with a shorter progression-free survival time in patients with serous ovarian cancer. Thus, on the whole, the findings of this study indicate that PAX2 may promote ovarian cancer progression, involving fatty acid metabolic reprograming.

Ovarian cancer (OC) is the most lethal gynecologic cancer characterized by an elevated apoptosis resistance that, potentially, leads to chemo-resistance in the recurrent disease. Mitochondrial oxidative phosphorylation was found altered in OC, and mitochondria were proposed as a target for therapy. Molecular evidence suggests that the deregulation of mitochondrial biogenesis, morphology, dynamics, and apoptosis is involved in carcinogenesis. However, these mitochondrial processes remain to be investigated in OC. Eighteen controls and 16 OC tissues (serous and mucinous) were collected. Enzymatic activities were performed spectrophotometrically, mitochondrial DNA (mtDNA) content was measured by real-time-PCR, protein levels were determined by Western blotting, and mitochondrial number and structure were measured by electron microscopy. Statistical analysis was performed using Student’s t-test, Mann-Whitney U test, and principal component analysis (PCA). We found, in OC, that increased mitochondrial number associated with increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and mitochondrial transcription factor A (TFAM) protein levels, as well as mtDNA content. The OC mitochondria presented an increased maximum length, as well as reduced cristae width and junction diameter, associated with increased optic atrophy 1 protein (OPA1) and prohibitin 2 (PHB2) protein levels. In addition, in OC tissues, augmented cAMP and sirtuin 3 (SIRT3) protein levels were observed. PCA of the 25 analyzed biochemical parameters classified OC patients in a distinct group from controls. We highlight a “mitochondrial signature” in OC that could result from cooperation of the cAMP pathway with the SIRT3, OPA1, and PHB2 proteins.

• OPA1
• SIRT3
• cAMP
• mitochondria
• mitochondrial biogenesis
• ovarian cancer
• oxidative phosphorylation system (OXPHOS)
• prohibitins

• Cancer metabolism
• Lactate
• Metabolic flexibility
• PEPCK
• TCA cycle

Ovarian cancer is the leading cause of death from gynecologic malignancy in the Western world. This is due, in part, to the fact that despite standard treatment of surgery and platinum/paclitaxel most patients recur with ultimately chemoresistant disease. Ovarian cancer is a unique form of solid tumor that develops, metastasizes and recurs in the same space, the abdominal cavity, which becomes a unique microenvironment characterized by ascites, hypoxia and low glucose levels. It is under these conditions that cancer cells adapt and switch to mitochondrial respiration, which becomes crucial to their survival, and therefore an ideal metabolic target for chemoresistant ovarian cancer. Importantly, independent of microenvironmental factors, mitochondria spatial redistribution has been associated to both tumor metastasis and chemoresistance in ovarian cancer while specific sets of genetic mutations have been shown to cause aberrant dependence on mitochondrial pathways in the most aggressive ovarian cancer subtypes. In this review we summarize on targeting mitochondria for treatment of chemoresistant ovarian cancer and current state of understanding of the role of mitochondria respiration in ovarian cancer. We feel this is an important and timely topic given that ovarian cancer remains the deadliest of the gynecological diseases, and that the mitochondrial pathway has recently emerged as critical in sustaining solid tumor progression.

• OXPHOS
• SWI/SNF complex
• ascites
• chemoresistant ovarian cancer
• mitochondrial inhibitor

• OXPHOS
• analyse du contrôle métabolique
• cancer colorectal
• colorectal cancer
• metabolic control analysis
• mitochondrial metabolism
• métabolisme mitochondrial

• Energy metabolism
• Lung adenocarcinoma
• SCO2
• TIGAR
• p53

Most cancer cells perform glycolysis despite having sufficient oxygen. The specific metabolic pathways of cancer cells have become the focus of cancer treatment. Recently, accumulating evidence indicates oxidative phosphorylation (OXPHOS) and glycolysis can be regulated with each other. Thus, we suggest that the glycolysis of cancer cells is inhibited by restoring or improving OXPHOS in cancer cells. In our study, we found that oxaloacetate (OA) induced apoptosis in HepG2 cells in vivo and in vitro. Meanwhile, we found that OA induced a decrease in the energy metabolism of HepG2 cells. Further results showed that the expression and activity of glycolytic enzymes were decreased with OA treatment. Conversely, the expression and activity of enzymes involved in the TCA cycle and OXPHOS were increased with OA treatment. The results indicate that OA can inhibit glycolysis through enhancement of OXPHOS. In addition, OA‐mediated suppression of HIF1α, p‐Akt, and c‐myc led to a decrease in glycolysis level. Therefore, OA has the potential to be a novel anticancer drug.

• Akt/HIF pathway
• apoptosis
• glycolysis
• oxaloacetate
• oxidative phosphorylation

• Cancer metabolism
• Erastin
• Glycolysis
• Mitochondria
• Oxidative stress
• Tubulin
• Voltage-dependent anion channel
• Warburg effect

Arsenic and benzo[β]pyrene (B[a]P) are common contaminants in developing countries. Many studies have investigated the consequences of arsenic and/or B[a]P-induced cellular transformation, including altered metabolism. In the present study, we show that, in addition to elevated glycolysis, B[a]P/arsenic-induced transformation also stimulates oxidative phosphorylation (OXPHOS). Proteomic data and immunoblot studies demonstrated that enzymatic activities, involved in both glycolysis and OXPHOS, are upregulated in the primary transformed rat lung epithelial cell (TLEC) culture, as well as in subcloned TLEC cell lines (TMCs), indicating that OXPHOS was active and still contributed to energy production. LEC expression, of the glycolytic enzyme phosphoglycerate mutase (PGAM) and the TCA cycle enzyme alpha-ketoglutarate dehydrogenase (OGDH), revealed an alternating cyclic pattern of glycolysis and OXPHOS during cell transformation. We also found that the expression levels of hypoxia-inducible factor-1β were consistent with the pattern of glycolysis during the course of transformation. Low doses of an ATP synthase inhibitor depleted endogenous ATP levels to a greater extent in TLECs, compared to parental LECs, indicating greater sensitivity of B[a]P/arsenic-transformed cells to ATP depletion. However, TLEC cells exhibited better survival under hypoxia, possibly due to further induction of anaerobic glycolysis. Collectively, our data indicate that B[a]P/arsenic-transformed cells can maintain energy production through upregulation of both glycolysis and OXPHOS. Selective inhibition of metabolic pathways may serve as a therapeutic option for cancer therapy.

• Warburg effect
• arsenic
• benzo[α]pyrene
• hypoxia
• oxidative phosphorylation

Focus on the Warburg effect, initially descriptive of increased glycolysis in cancer cells, has served to illuminate mitochondrial function in many other pathologies. This review explores our current understanding of the Warburg effect’s role in cancer, diabetes and ageing. We highlight how it can be regulated through a chain of oncogenic events, as a chosen response to impaired glucose metabolism or by chance acquisition of genetic changes associated with ageing. Such chain, choice or chance perspectives can be extended to help understand neurodegeneration, such as Alzheimer’s disease, providing clues with scope for therapeutic intervention. It is anticipated that exploration of Warburg effect pathways in extreme conditions, such as deep space, will provide further insights crucial for comprehending complex metabolic diseases, a frontier for medicine that remains equally significant for humanity in space and on earth.

• Warburg effect
• metabolism
• mitochondria
• neurodegenerative diseases
• radiation
• space biology

We conducted quantitative cellular respiration analysis on samples taken from human breast cancer (HBC) and human colorectal cancer (HCC) patients. Respiratory capacity is not lost as a result of tumor formation and even though, functionally, complex I in HCC was found to be suppressed, it was not evident on the protein level. Additionally, metabolic control analysis was used to quantify the role of components of mitochondrial interactosome. The main rate-controlling steps in HBC are complex IV and adenine nucleotide transporter, but in HCC, complexes I and III. Our kinetic measurements confirmed previous studies that respiratory chain complexes I and III in HBC and HCC can be assembled into supercomplexes with a possible partial addition from the complex IV pool. Therefore, the kinetic method can be a useful addition in studying supercomplexes in cell lines or human samples. In addition, when results from culture cells were compared to those from clinical samples, clear differences were present, but we also detected two different types of mitochondria within clinical HBC samples, possibly linked to two-compartment metabolism. Taken together, our data show that mitochondrial respiration and regulation of mitochondrial membrane permeability have substantial differences between these two cancer types when compared to each other to their adjacent healthy tissue or to respective cell cultures.

• gelsolin
• marker
• ovarian cancer
• secretome
• target

Aerobic enhanced glycolysis characterizes the Warburg phenotype. In cancer cells, suppression of mitochondrial metabolism contributes to maintain a low ATP/ADP ratio that favors glycolysis. We propose that the voltage-dependent anion channel (VDAC) located in the mitochondrial outer membrane is a metabolic link between glycolysis and oxidative phosphorylation in the Warburg phenotype. Most metabolites including respiratory substrates, ADP, and Pi enter mitochondria only through VDAC. Oxidation of respiratory substrates in the Krebs cycle generates NADH that enters the electron transport chain (ETC) to generate a proton motive force utilized to generate ATP and to maintain mitochondrial membrane potential (ΔΨ). The ETC is also the major source of mitochondrial reactive oxygen species (ROS) formation. Dimeric α-β tubulin decreases conductance of VDAC inserted in lipid bilayers, and high free tubulin in cancer cells by closing VDAC, limits the ingress of respiratory substrates and ATP decreasing mitochondrial ΔΨ. VDAC opening regulated by free tubulin operates as a “master key” that “seal–unseal” mitochondria to modulate mitochondrial metabolism, ROS formation, and the intracellular flow of energy. Erastin, a small molecule that binds to VDAC and kills cancer cells, and erastin-like compounds antagonize the inhibitory effect of tubulin on VDAC. Blockage of the VDAC–tubulin switch increases mitochondrial metabolism leading to decreased glycolysis and oxidative stress that promotes mitochondrial dysfunction, bioenergetic failure, and cell death. In summary, VDAC opening-dependent cell death follows a “metabolic double-hit model” characterized by oxidative stress and reversion of the pro-proliferative Warburg phenotype.

• Warburg effect
• cancer metabolism
• erastin
• glycolysis
• mitochondria
• oxidative stress
• tubulin
• voltage-dependent anion channel

• Cancer progression
• Carbonyl content
• Colorectal tumors
• Gene expression
• Mitochondria

• Aged
• Colorectal Neoplasms/etiology
• Colorectal Neoplasms/metabolism
• Cytochromes b/genetics
• Electron Transport Complex IV/genetics
• Female
• Humans
• Male
• Mitochondrial Proton-Translocating ATPases/genetics
• NADH Dehydrogenase/genetics
• RNA, Ribosomal/genetics
• Reactive Oxygen Species/metabolism

• G12 MD007602 NIMHD NIH HHS
• S21 MD000101 NIMHD NIH HHS
• SC3 GM099663 NIGMS NIH HHS
• SC3 GM122669 NIGMS NIH HHS

The increasing body of evidence suggest that nanomaterials toxicity is associated with generation of oxidative stress. In this paper we investigated the role of respiration in silver nanoparticles (AgNPs) generated oxidative stress and toxicity. Since cancer cells rely on glucose as the main source of energy supply, glucose availability might be an important determinant of NPs toxicity.

AgNPs of 20 nm nominal diameter were used as a model NPs. HepG2 cells were cultured in the media with high (25 mM) or low (5.5 mM) glucose content and treated with 20 nm AgNPs. AgNPs-induced toxicity was tested by neutral red assay. Generation of H₂O₂ in mitochondria was evaluated by use of mitochondria specific protein indicator HyPer-Mito. Expression of a 77 oxidative stress related genes was assessed by qPCR. The activity of antioxidant enzymes was estimated colorimetrically by dedicated methods in cell homogenates.

AgNPs-induced dose-dependent generation of H₂O₂ and toxicity was observed. Toxicity of AgNPs towards cells maintained in the low glucose medium was significantly lower than the toxicity towards cells growing in the high glucose concentration. Scarceness of glucose supply resulted in upregulation of the endogenous antioxidant defence mechanisms that in turn alleviated AgNPs dependent ROS generation and toxicity.

Glucose availability can modify toxicity of AgNPs via elevation of antioxidant defence triggered by oxidative stress resulted from enhanced oxidative phosphorylation in mitochondria and associated generation of ROS. Presented results strengthen the idea of strong linkage between NPs toxicity and intracellular respiration and possibly other mitochondria dependent processes.

The online version of this article (doi:10.1186/s12951-015-0132-2) contains supplementary material, which is available to authorized users.

• Aerobic glycolysis
• Hepatocellular carcinoma
• Lactate
• Metabolic interventions
• Oxidative stress

• Clear cell renal cell carcinoma (ccRCC)
• Mitochondrial membrane potential (MMP)
• Oxidative phosphorylation (OXPHOS)
• Uncoupling protein 2 (UCP2)
• Uncoupling protein 3 (UCP3)
• Warburg effect

• Bioenergetics
• Cardiomyocyte
• Development
• Intracellular architecture
• Mitochondria
• Tubulin

• Adenosine Triphosphate/biosynthesis
• Amino Acids/metabolism
• Anoikis/physiology
• Cell Line, Tumor
• Cell Movement/physiology
• Cell Survival/physiology
• Citric Acid Cycle/physiology
• Culture Media
• Energy Metabolism/physiology
• Female
• Humans
• Indicators and Reagents
• Kinetics
• Mitochondria/physiology
• Neoplasm Invasiveness/pathology
• Neovascularization, Pathologic/metabolism
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Oxidative Phosphorylation
• Oxygen Consumption/physiology
• Protein Footprinting
• Pyruvic Acid/metabolism
• Wound Healing/physiology

Akt, a serine/threonine kinase has been shown to stimulate glycolysis in cancer cells but its role in mitochondrial respiration is unknown. Using PTEN-knockout mouse embryonic fibroblasts (MEF^PTEN−/−) with hyper-activated Akt as a cell model, we observed a higher respiratory capacity in MEF^PTEN−/− compared to the wildtype (MEF^WT). The respiratory phenotype observed in MEF^PTEN−/− was reproduced in MEF^WT by gene silencing of PTEN which substantiated its role in regulating mitochondrial function. The increased activities of the respiratory complexes (RCs) I, III and IV were retained in the same relative proportions as those present in MEF^WT, alluding to a possible co-ordinated regulation by PTEN/Akt. Using LY294002 (a PI3K inhibitor) and Akt inhibitor IV, we showed that the regulation of enzyme activities and protein expressions of the RCs was dependent on PI3K/Akt. There was insignificant difference in the protein expressions of mitochondrial transcription factor: peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and its downstream targets, the nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (mtTFA) between MEF^PTEN−/− and MEF^WT. Similarly, mRNA levels of the same subunits of the RCs detected in Western blots were not significantly different between MEF^PTEN−/− and MEF^WT suggesting that the regulation by Akt on mitochondrial function was probably not via gene transcription. On the other hand, a decrease of total 4E-BP1 with a higher expression of its phosphorylated form relative to total 4E-BP1 was found in MEF^PTEN−/−, which inferred that the regulation of mitochondrial respiratory activities by Akt was in part through this protein translation pathway. Notably, gene silencing of 4E-BP1 up-regulated the protein expressions of all RCs and the action of 4E-BP1 appeared to be specific to these mitochondrial proteins. In conclusion, PTEN inactivation bestowed a bioenergetic advantage to the cells by up-regulating mitochondrial respiratory capacity through the 4E-BP1-mediated protein translation pathway.

• Adaptor Proteins, Signal Transducing/metabolism
• Adenosine Triphosphate/metabolism
• Animals
• Cell Cycle Proteins
• Cells, Cultured
• Chromones/pharmacology
• Electron Transport Complex IV/metabolism
• Enzyme Inhibitors/pharmacology
• Fibroblasts/metabolism
• Gene Silencing
• Membrane Potentials
• Mice
• Mice, Transgenic
• Mitochondria/metabolism
• Morpholines/pharmacology
• PTEN Phosphohydrolase/metabolism
• Phosphoproteins/metabolism
• Protein Biosynthesis
• Proto-Oncogene Proteins c-akt/metabolism
• Tricarboxylic Acids/metabolism

Aerobic glycolysis is an important metabolic adaptation of cancer cells. There is growing evidence that oxidative phosphorylation is also an active metabolic pathway in many tumors, including in high grade serous ovarian cancer. Metastasized ovarian tumors use fatty acids for their energy needs. There is also evidence of ovarian cancer stem cells privileging oxidative phosphorylation (OXPHOS) for their metabolic needs. Metformin and thiazolidinediones such as rosiglitazone restrict tumor growth by inhibiting specific steps in the mitochondrial electron transport chain. These observations suggest that strategies to interfere with oxidative phosphorylation should be considered for the treatment of ovarian tumors. Here, we review the literature that supports this hypothesis and describe potential agents and critical control points in the oxidative phosphorylation pathway that can be targeted using small molecule agents. In this review, we also discuss potential barriers that can reduce the efficacy of the inhibitors of oxidative phosphorylation.

• P30 CA014520 NCI NIH HHS