Subclinical dose irradiation triggers human breast cancer migration via mitochondrial reactive oxygen species.

BACKGROUND: Despite technological advances in radiotherapy, cancer cells at the tumor margin and in diffusive infiltrates can receive subcytotoxic doses of photons. Even if only a minority of cancer cells are concerned, phenotypic consequences could be important considering that mitochondrial DNA (mtDNA) is a primary target of radiation and that damage to mtDNA can persist. In turn, mitochondrial dysfunction associated with enhanced mitochondrial ROS (mtROS) production could promote cancer cell migration out of the irradiation field in a natural attempt to escape therapy. In this study, using MCF7 and MDA-MB-231 human breast cancer cells as models, we aimed to elucidate the molecular mechanisms supporting a mitochondrial contribution to cancer cell migration induced by subclinical doses of irradiation (< 2 Gy). METHODS: Mitochondrial dysfunction was tested using mtDNA multiplex PCR, oximetry, and ROS-sensitive fluorescent reporters. Migration was tested in transwells 48 h after irradiation in the presence or absence of inhibitors targeting specific ROS or downstream effectors. Among tested inhibitors, we designed a mitochondria-targeted version of human catalase (mtCAT) to selectively inactivate mitochondrial H2O2. RESULTS: Photon irradiation at subclinical doses (0.5 Gy for MCF7 and 0.125 Gy for MDA-MB-231 cells) sequentially affected mtDNA levels and/or integrity, increased mtROS production, increased MAP2K1/MEK1 gene expression, activated ROS-sensitive transcription factors NF-κB and AP1 and stimulated breast cancer cell migration. Targeting mtROS pharmacologically by MitoQ or genetically by mtCAT expression mitigated migration induced by a subclinical dose of irradiation. CONCLUSION: Subclinical doses of photon irradiation promote human breast cancer migration, which can be countered by selectively targeting mtROS.

Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8+ T cell memory development.

Lactate-proton symporter monocarboxylate transporter 1 (MCT1) facilitates lactic acid export from T cells. Here, we report that MCT1 is mandatory for the development of virus-specific CD8+ T cell memory. MCT1-deficient T cells were exposed to acute pneumovirus (pneumonia virus of mice, PVM) or persistent γ-herpesvirus (Murid herpesvirus 4, MuHV-4) infection. MCT1 was required for the expansion of virus-specific CD8+ T cells and the control of virus replication in the acute phase of infection. This situation prevented the subsequent development of virus-specific T cell memory, a necessary step in containing virus reactivation during γ-herpesvirus latency. Instead, persistent active infection drove virus-specific CD8+ T cells toward functional exhaustion, a phenotype typically seen in chronic viral infections. Mechanistically, MCT1 deficiency sequentially impaired lactic acid efflux from activated CD8+ T cells, caused an intracellular acidification inhibiting glycolysis, disrupted nucleotide synthesis in the upstream pentose phosphate pathway, and halted cell proliferation which, ultimately, promoted functional CD8+ T cell exhaustion instead of memory development. Taken together, our data demonstrate that MCT1 expression is mandatory for inducing T cell memory and controlling viral infection by CD8+ T cells.

Specific HIF-2α (Hypoxia-Inducible Factor-2) Inhibitor PT2385 Mitigates Placental Dysfunction In Vitro and in a Rat Model of Preeclampsia (RUPP).

BACKGROUND: Preeclampsia is one of the leading causes of maternal mortality worldwide and is strongly associated with long-term morbidity in mothers and newborns. Referred to as one of the deep placentation disorders, insufficient remodeling of the spiral arteries during the first trimester remains a major cause of placental dysfunction. Persisting pulsatile uterine blood flow causes abnormal ischemia/reoxygenation phenomenon in the placenta and stabilizes the HIF-2α (hypoxia-inducible factor-2α) in the cytotrophoblasts. HIF-2α signaling impairs trophoblast differentiation and increases sFLT-1 (soluble fms-like tyrosine kinase-1) secretion, which reduces fetal growth and causes maternal symptoms. This study aims to evaluate the benefits of using PT2385-an oral specific HIF-2α inhibitor-to treat severe placental dysfunction. METHODS: To evaluate its therapeutic potential, PT2385 was first studied in primary human cytotrophoblasts isolated from term placenta and exposed to 2.5% O2 to stabilize HIF-2α. Viability and luciferase assays, RNA sequencing, and immunostaining were used to analyze differentiation and angiogenic factor balance. The ability of PT2385 to mitigate maternal manifestations of preeclampsia was studied in the selective reduced uterine perfusion pressure model performed in Sprague-Dawley rats. RESULTS: In vitro, RNA sequencing analysis and conventional techniques showed that treated cytotrophoblast displayed an enhanced differentiation into syncytiotrophoblasts and normalized angiogenic factor secretion compared with vehicle-treated cells. In the selective reduced uterine perfusion pressure model, PT2385 efficiently decreased sFLT-1 production, thus preventing the onset of hypertension and proteinuria in pregnant dams. CONCLUSIONS: These results highlight HIF-2α as a new player in our understanding of placental dysfunction and support the use of PT2385 to treat severe preeclampsia in humans.

Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice.

At diagnosis, about 35% of pancreatic cancers are at the locally invasive yet premetastatic stage. Surgical resection is not a treatment option, leaving patients with a largely incurable disease that often evolves to the polymetastatic stage despite chemotherapeutic interventions. In this preclinical study, we hypothesized that pancreatic cancer metastasis can be prevented by inhibiting mitochondrial redox signaling with MitoQ, a mitochondria-targeted antioxidant. Using four different cancer cell lines, we report that, at clinically relevant concentrations (100-500 nM), MitoQ selectively repressed mesenchymal pancreatic cancer cell respiration, which involved the inhibition of the expression of PGC-1α, NRF1 and a reduced expression of electron-transfer-chain complexes I to III. MitoQ consequently decreased the mitochondrial membrane potential and mitochondrial superoxide production by these cells. Phenotypically, MitoQ further inhibited pancreatic cancer cell migration, invasion, clonogenicity and the expression of stem cell markers. It reduced by ~50% the metastatic homing of human MIA PaCa-2 cells in the lungs of mice. We further show that combination treatments with chemotherapy are conceivable. Collectively, this study indicates that the inhibition of mitochondrial redox signaling is a possible therapeutic option to inhibit the metastatic progression of pancreatic cancer.

Statins Alleviate Tumor Hypoxia in Prostate Cancer Models by Decreasing Oxygen Consumption: An Opportunity for Radiosensitization?

BACKGROUND: Because statins were found to decrease the oxygen consumption rate (OCR) of a variety of normal cells, our hypothesis was that statins may also decrease the OCR of cancer cells, alleviate tumor hypoxia and radiosensitize tumors. METHODS: OCR was assessed using the Seahorse XF96 technology and EPR respirometry in PC-3 prostate cancer cells. Mitochondrial superoxide production was measured by EPR with mitoTEMPO-H as a sensing probe. Tumor pO2 was measured in vivo using low-frequency EPR oximetry to define the optimal window of reoxygenation, the time at which tumors were irradiated with a single 6 Gy dose with a Cesium-137 irradiator. RESULTS: 24-h exposure to simvastatin and fluvastatin significantly decreased the OCR of PC-3 cancer cells. An increase in mitochondrial superoxide levels was also observed after fluvastatin exposure. The PC-3 prostate cancer model was found highly hypoxic at the basal level. When mice were treated with simvastatin or fluvastatin (daily injection of 20 mg/kg), tumor oxygenation increased 48 and 72 h after initiation of the treatment. However, despite reoxygenation, simvastatin did not sensitize the PC-3 tumor model to RT. CONCLUSIONS: exposure to statins affect tumor metabolism and tumor oxygenation, however, with limited impact on tumor growth with or without irradiation.

EPR Investigations to Study the Impact of Mito-Metformin on the Mitochondrial Function of Prostate Cancer Cells.

BACKGROUND: Mito-metformin10 (MM10), synthesized by attaching a triphenylphosphonium cationic moiety via a 10-carbon aliphatic side chain to metformin, is a mitochondria-targeted analog of metformin that was recently demonstrated to alter mitochondrial function and proliferation in pancreatic ductal adenocarcinoma. Here, we hypothesized that this compound may decrease the oxygen consumption rate (OCR) in prostate cancer cells, increase the level of mitochondrial ROS, alleviate tumor hypoxia, and radiosensitize tumors. METHODS: OCR and mitochondrial superoxide production were assessed by EPR (9 GHz) in vitro in PC-3 and DU-145 prostate cancer cells. Reduced and oxidized glutathione were assessed before and after MM10 exposure. Tumor oxygenation was measured in vivo using 1 GHz EPR oximetry in PC-3 tumor model. Tumors were irradiated at the time of maximal reoxygenation. RESULTS: 24-hours exposure to MM10 significantly decreased the OCR of PC-3 and DU-145 cancer cells. An increase in mitochondrial superoxide levels was observed in PC-3 but not in DU-145 cancer cells, an observation consistent with the differences observed in glutathione levels in both cancer cell lines. In vivo, the tumor oxygenation significantly increased in the PC-3 model (daily injection of 2 mg/kg MM10) 48 and 72 h after initiation of the treatment. Despite the significant effect on tumor hypoxia, MM10 combined to irradiation did not increase the tumor growth delay compared to the irradiation alone. CONCLUSIONS: MM10 altered the OCR in prostate cancer cells. The effect of MM10 on the superoxide level was dependent on the antioxidant capacity of cell line. In vivo, MM10 alleviated tumor hypoxia, yet without consequence in terms of response to irradiation.

Mitochondrial Protein Cox7b Is a Metabolic Sensor Driving Brain-Specific Metastasis of Human Breast Cancer Cells.

Distant metastases are detrimental for cancer patients, but the increasingly early detection of tumors offers a chance for metastasis prevention. Importantly, cancers do not metastasize randomly: depending on the type of cancer, metastatic progenitor cells have a predilection for well-defined organs. This has been theorized by Stephen Paget, who proposed the "seed-and-soil hypothesis", according to which metastatic colonization occurs only when the needs of a given metastatic progenitor cell (the seed) match with the resources provided by a given organ (the soil). Here, we propose to explore the seed-and-soil hypothesis in the context of cancer metabolism, thus hypothesizing that metastatic progenitor cells must be capable of detecting the availability of metabolic resources in order to home in a secondary organ. If true, it would imply the existence of metabolic sensors. Using human triple-negative MDA-MB-231 breast cancer cells and two independent brain-seeking variants as models, we report that cyclooxygenase 7b (Cox7b), a structural component of Complex IV of the mitochondrial electron transport chain, belongs to a probably larger family of proteins responsible for breast cancer brain tropism in mice. For metastasis prevention therapy, this proof-of-principle study opens a quest for the identification of therapeutically targetable metabolic sensors that drive cancer organotropism.

Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity.

BACKGROUND: Growing evidence supports the use of low-carbohydrate/high-fat ketogenic diets as an adjunctive cancer therapy. However, it is unclear which genetic, metabolic, or immunological factors contribute to the beneficial effect of ketogenic diets. Therefore, we investigated the effect of ketogenic diets on the progression and metabolism of genetically and metabolically heterogeneous melanoma xenografts, as well as on the development of melanoma metastases in mice with a functional immune system. METHODS: Mice bearing BRAF mutant, NRAS mutant, and wild-type melanoma xenografts as well as mice bearing highly metastatic melanoma allografts were fed with a control diet or ketogenic diets, differing in their triglyceride composition, to evaluate the effect of ketogenic diets on tumor growth and metastasis. We performed an in-depth targeted metabolomics analysis in plasma and xenografts to elucidate potential antitumor mechanisms in vivo. RESULTS: We show that ketogenic diets effectively reduced tumor growth in immunocompromised mice bearing genetically and metabolically heterogeneous human melanoma xenografts. Furthermore, the ketogenic diets exerted a metastasis-reducing effect in the immunocompetent syngeneic melanoma mouse model. Targeted analysis of plasma and tumor metabolomes revealed that ketogenic diets induced distinct changes in amino acid metabolism. Interestingly, ketogenic diets reduced the levels of alpha-amino adipic acid, a biomarker of cancer, in circulation to levels observed in tumor-free mice. Additionally, alpha-amino adipic acid was reduced in xenografts by ketogenic diets. Moreover, the ketogenic diets increased sphingomyelin levels in plasma and the hydroxylation of sphingomyelins and acylcarnitines in tumors. CONCLUSIONS: Ketogenic diets induced antitumor effects toward melanoma regardless of the tumors´ genetic background, its metabolic signature, and the host immune status. Moreover, ketogenic diets simultaneously affected multiple metabolic pathways to create an unfavorable environment for melanoma cell proliferation, supporting their potential as a complementary nutritional approach to melanoma therapy.

MitoQ Prevents Human Breast Cancer Recurrence and Lung Metastasis in Mice.

In oncology, the occurrence of distant metastases often marks the transition from curative to palliative care. Such outcome is highly predictable for breast cancer patients, even if tumors are detected early, and there is no specific treatment to prevent metastasis. Previous observations indicated that cancer cell mitochondria are bioenergetic sensors of the tumor microenvironment that produce superoxide to promote evasion. Here, we tested whether mitochondria-targeted antioxidant MitoQ is capable to prevent metastasis in the MDA-MB-231 model of triple-negative human breast cancer in mice and in the MMTV-PyMT model of spontaneously metastatic mouse breast cancer. At clinically relevant doses, we report that MitoQ not only prevented metastatic take and dissemination, but also local recurrence after surgery. We further provide in vitro evidence that MitoQ does not interfere with conventional chemotherapies used to treat breast cancer patients. Since MitoQ already successfully passed Phase I safety clinical trials, our preclinical data collectively provide a strong incentive to test this drug for the prevention of cancer dissemination and relapse in clinical trials with breast cancer patients.

MitoQ Inhibits Human Breast Cancer Cell Migration, Invasion and Clonogenicity.

To successfully generate distant metastases, metastatic progenitor cells must simultaneously possess mesenchymal characteristics, resist to anoïkis, migrate and invade directionally, resist to redox and shear stresses in the systemic circulation, and possess stem cell characteristics. These cells primarily originate from metabolically hostile areas of the primary tumor, where oxygen and nutrient deprivation, together with metabolic waste accumulation, exert a strong selection pressure promoting evasion. Here, we followed the hypothesis according to which metastasis as a whole implies the existence of metabolic sensors. Among others, mitochondria are singled out as a major source of superoxide that supports the metastatic phenotype. Molecularly, stressed cancer cells increase mitochondrial superoxide production, which activates the transforming growth factor-ß pathway through src directly within mitochondria, ultimately activating focal adhesion kinase Pyk2. The existence of mitochondria-targeted antioxidants constitutes an opportunity to interfere with the metastatic process. Here, using aggressive triple-negative and HER2-positive human breast cancer cell lines as models, we report that MitoQ inhibits all the metastatic traits that we tested in vitro. Compared to other mitochondria-targeted antioxidants, MitoQ already successfully passed Phase I safety clinical trials, which provides an important incentive for future preclinical and clinical evaluations of this drug for the prevention of breast cancer metastasis.

Unconventional roles of lactate along the tumor and immune landscape.

The tumor ecosystem evolves with dynamic interactions between cancer and normal cells, and nutrients have emerged as new regulators of cancer hallmarks. Lactate has climbed the rankings as a multifunctional molecule orchestrating many aspects of the disease onset and progression. Here, we patchwork and discuss the main recent findings conferred during the EMBO workshop titled 'Lactate: Unconventional Roles of a Nutrient Along the Tumor Landscape.'

Extremely low frequency electromagnetic stimulation reduces ischemic stroke volume by improving cerebral collateral blood flow.

Extremely low frequency electromagnetic stimulation (ELF-EMS) has been considered as a neuroprotective therapy for ischemic stroke based on its capacity to induce nitric oxide (NO) signaling. Here, we examined whether ELF-EMS reduces ischemic stroke volume by stimulating cerebral collateral perfusion. Moreover, the pathway responsible for ELF-EMS-induced NO production was investigated. ELF-EMS diminished infarct growth following experimental stroke in collateral-rich C57BL/6 mice, but not in collateral-scarce BALB/c mice, suggesting that decreased lesion sizes after ELF-EMS results from improved collateral blood flow. In vitro analysis demonstrated that ELF-EMS increased endothelial NO levels by stimulating the Akt-/eNOS pathway. Furthermore, ELF-EMS augmented perfusion in the hind limb of healthy mice, which was mediated by enhanced Akt-/eNOS signaling. In healthy C57BL/6 mouse brains, ELF-EMS treatment increased cerebral blood flow in a NOS-dependent manner, whereas no improvement in cerebrovascular perfusion was observed in collateral-sparse BALB/c mice. In addition, ELF-EMS enhanced cerebral blood flow in both the contra- and ipsilateral hemispheres of C57BL/6 mice subjected to experimental ischemic stroke. In conclusion, we showed that ELF-EMS enhances (cerebro)vascular perfusion by stimulating NO production, indicating that ELF-EMS could be an attractive therapeutic strategy for acute ischemic stroke by improving cerebral collateral blood flow.

Discovery of small molecules interacting at lactate dehydrogenases tetrameric interface using a biophysical screening cascade.

Lactate dehydrogenases (LDHs) are tetrameric enzymes of therapeutic relevance for cancer therapy due to their important implications in cancer cell metabolism. LDH active site inhibition suffers from different drawbacks due to several features such as high cellular concentration and a shared active site among the dehydrogenase family. Conversely, targeting the LDH oligomeric state is an exciting strategy that could provide a suitable alternative to active-site inhibition. In the present study, we developed a biophysical screening cascade to probe the LDHs tetrameric interface. Using nanoscale differential fluorimetry (nanoDSF) as a primary screening method, we identified a series of hits that destabilize the tetrameric protein. From this primary screening, we validated selected hits using saturation transfer difference nuclear magnetic resonance (STD NMR) and microscale thermophoresis (MST) as a combination of orthogonal biophysical techniques. Finally, we characterized the validated hits and demonstrated that they specifically interact at the tetrameric interface of LDH-1 and LDH-5 and can inhibit the LDH tetramerization process. Overall, this work provides a convenient method for screening ligands at the LDH tetrameric interface and has identified promising hits suitable for further optimization. We believe that this biophysical screening cascade, especially the use of (nano)DSF, could be extended to other homomeric proteins.

Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells.

Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZ-induced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration.

Clinical and in Vitro Evidence against Placenta Infection at Term by Severe Acute Respiratory Syndrome Coronavirus 2.

Despite occasional reports of vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy, the question of placental infection and its consequences for the newborn remain unanswered. Herein, we analyzed the placentas of 31 coronavirus disease 2019-positive mothers by reverse transcriptase PCR, immunohistochemistry, and in situ hybridization. Only one case of placental infection was detected, which was associated with intrauterine demise of the fetus. Differentiated primary trophoblasts were then isolated from nonpathologic human placentas at term, differentiated, and exposed to SARS-CoV-2 virions. Unlike for positive control cells Vero E6, the virus inside cytotrophoblasts and syncytiotrophoblasts or in the supernatant 4 days after infection was undetectable. As a mechanism of defense, we hypothesized that trophoblasts at term do not express angiotensin-converting enzyme 2 and transmembrane protease serine 2 (TMPRSS2), the two main host membrane receptors for SARS-CoV-2 entry. The quantification of these proteins in the placenta during pregnancy confirmed the absence of TMPRSS2 at the surface of the syncytium. Surprisingly, a transiently induced experimental expression of TMPRSS2 did not allow the entry or replication of the virus in differentiated trophoblasts. Altogether, these results underline that trophoblasts are not likely to be infected by SARS-CoV-2 at term, but raise concern about preterm infection.

Mitochondrial Transfer in Cancer: A Comprehensive Review.

Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.

In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment.

To survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic end-product lactate for blood-borne glucose. This type of cooperation can be targeted therapeutically, since transmembrane lactate exchanges are facilitated by lactate-proton symporters of the monocarboxylate (MCT) family. Among new drugs, AZD3965 is a first-in-class selective MCT1 inhibitor currently tested in Phase I/II clinical trials for patients with different types of cancers. Because MCT1 can function bidirectionally, we tested here whether and how malignant and nonmalignant cells adapt their metabolism and MCT repertoire when AZD3965 inhibits either lactate import or export. Using breast-associated malignant and nonmalignant cell lines as models, we report that AZD3965 is not directly cytotoxic. In the presence of glucose and glutamine, oxidative cells can survive when lactate uptake is blocked, and proliferating cells compensate MCT1 inhibition by overexpressing MCT4, a specialized facilitator of lactate export. Phenotypic characterization of mice focusing on metabolism, muscle and brain physiology found partial and transient memory retention defect as sole consequence of MCT1 inhibition by AZD3965. We therefore conclude that AZD3965 is compatible with anticancer therapy.

Discovery of a novel lactate dehydrogenase tetramerization domain using epitope mapping and peptides.

Despite being initially regarded as a metabolic waste product, lactate is now considered to serve as a primary fuel for the tricarboxylic acid cycle in cancer cells. At the core of lactate metabolism, lactate dehydrogenases (LDHs) catalyze the interconversion of lactate to pyruvate and as such represent promising targets in cancer therapy. However, direct inhibition of the LDH active site is challenging from physicochemical and selectivity standpoints. However, LDHs are obligate tetramers. Thus, targeting the LDH tetrameric interface has emerged as an appealing strategy. In this work, we examine a dimeric construct of truncated human LDH to search for new druggable sites. We report the identification and characterization of a new cluster of interactions in the LDH tetrameric interface. Using nanoscale differential scanning fluorimetry, chemical denaturation, and mass photometry, we identified several residues (E62, D65, L71, and F72) essential for LDH tetrameric stability. Moreover, we report a family of peptide ligands based on this cluster of interactions. We next demonstrated these ligands to destabilize tetrameric LDHs through binding to this new tetrameric interface using nanoscale differential scanning fluorimetry, NMR water-ligand observed via gradient spectroscopy, and microscale thermophoresis. Altogether, this work provides new insights on the LDH tetrameric interface as well as valuable pharmacological tools for the development of LDH tetramer disruptors.

Adaptations of the human placenta to hypoxia: opportunities for interventions in fetal growth restriction.

BACKGROUND: The placenta is the functional interface between the mother and the fetus during pregnancy, and a critical determinant of fetal growth and life-long health. In the first trimester, it develops under a low-oxygen environment, which is essential for the conceptus who has little defense against reactive oxygen species produced during oxidative metabolism. However, failure of invasive trophoblasts to sufficiently remodel uterine arteries toward dilated vessels by the end of the first trimester can lead to reduced/intermittent blood flow, persistent hypoxia and oxidative stress in the placenta with consequences for fetal growth. Fetal growth restriction (FGR) is observed in ∼10% of pregnancies and is frequently seen in association with other pregnancy complications, such as preeclampsia (PE). FGR is one of the main challenges for obstetricians and pediatricians, as smaller fetuses have greater perinatal risks of morbidity and mortality and postnatal risks of neurodevelopmental and cardio-metabolic disorders. OBJECTIVE AND RATIONALE: The aim of this review was to examine the importance of placental responses to changing oxygen environments during abnormal pregnancy in terms of cellular, molecular and functional changes in order to highlight new therapeutic pathways, and to pinpoint approaches aimed at enhancing oxygen supply and/or mitigating oxidative stress in the placenta as a mean of optimizing fetal growth. SEARCH METHODS: An extensive online search of peer-reviewed articles using PubMed was performed with combinations of search terms including pregnancy, placenta, trophoblast, oxygen, hypoxia, high altitude, FGR and PE (last updated in May 2020). OUTCOMES: Trophoblast differentiation and placental establishment are governed by oxygen availability/hypoxia in early pregnancy. The placental response to late gestational hypoxia includes changes in syncytialization, mitochondrial functions, endoplasmic reticulum stress, hormone production, nutrient handling and angiogenic factor secretion. The nature of these changes depends on the extent of hypoxia, with some responses appearing adaptive and others appearing detrimental to the placental support of fetal growth. Emerging approaches that aim to increase placental oxygen supply and/or reduce the impacts of excessive oxidative stress are promising for their potential to prevent/treat FGR. WIDER IMPLICATIONS: There are many risks and challenges of intervening during pregnancy that must be considered. The establishment of human trophoblast stem cell lines and organoids will allow further mechanistic studies of the effects of hypoxia and may lead to advanced screening of drugs for use in pregnancies complicated by placental insufficiency/hypoxia. Since no treatments are currently available, a better understanding of placental adaptations to hypoxia would help to develop therapies or repurpose drugs to optimize placental function and fetal growth, with life-long benefits to human health.