Circular RNA circSNX6 promotes sunitinib resistance in renal cell carcinoma through the miR-1184/GPCPD1/ lysophosphatidic acid axis.

Sunitinib resistance is a major challenge in systemic therapy for renal cell carcinoma (RCC). The role of circular RNAs (circRNAs) in regulating sunitinib resistance of RCC is largely unknown. We established sunitinib-resistant RCC cell lines in vivo. Through RNA-sequencing, we identified circSNX6, whose expression is upregulated in sunitinib-resistant cells compared with their parental cells. High circSNX6 expression was correlated with sunitinib resistance and worse oncologic outcomes in a cohort of 81 RCC patients. In vitro and in vivo experiments confirmed that circSNX6 could promote sunitinib resistance in RCC. circSNX6 acts as a molecular "sponge" to relieve the suppressive effect of microRNA (miR)-1184 on its target gene, glycerophosphocholine phosphodiesterase 1 (GPCPD1), which increases intracellular lysophosphatidic acid (LPA) levels and, ultimately, promotes sunitinib resistance in RCC cells. Our findings demonstrated that the circSNX6/miR-1184/GPCPD1 axis had a critical role in regulation of intracellular LPA levels and sunitinib resistance in RCC; they also provide a novel prognostic indicator and promising therapeutic targets.

Role of protons in calcium signaling.

Thirty-six years after the publication of the important article by Busa and Nuccitelli on the variability of intracellular pH (pHi) and the interdependence of pHi and intracellular Ca2+ concentration ([Ca2+]i), little research has been carried out on pHi and calcium signaling. Moreover, the results appear to be contradictory. Some authors claim that the increase in [Ca2+]i is due to a reduction in pHi, others that it is caused by an increase in pHi. The reasons for these conflicting results have not yet been discussed and clarified in an exhaustive manner. The idea that variations in pHi are insignificant, because cellular buffers quickly stabilize the pHi, may be a limiting and fundamentally wrong concept. In fact, it has been shown that protons can move and react in the cell before they are neutralized. Variations in pHi have a remarkable impact on [Ca2+]i and hence on some of the basic biochemical mechanisms of calcium signaling. This paper focuses on the possible triggering role of protons during their short cellular cycle and it suggests a new hypothesis for an IP3 proton dependent mechanism of action.

Non-specific phospholipases C2 and C6 redundantly function in pollen tube growth via triacylglycerol production in Arabidopsis.

Non-specific phospholipase Cs (NPCs) are responsible for membrane lipid remodeling that involves hydrolysis of the polar head group of membrane phospholipids. Arabidopsis NPC2 and NPC6 are essential in gametogenesis, but their underlying role in the lipid remodeling remains elusive. Here, we show that these NPCs are required for triacylglycerol (TAG) production in pollen tube growth. NPC2 and NPC6 are highly expressed in developing pollen tubes and are localized at the endoplasmic reticulum. Mutants of NPC2 and NPC6 showed reduced rate of pollen germination, length of pollen tube and amount of lipid droplets (LDs). Overexpression of NPC2 or NPC6 induced LD accumulation, which suggests that these NPCs are involved in LD production. Furthermore, mutants defective in the biosynthesis of TAG, a major component of LDs, showed defective pollen tube growth. These results suggest that NPC2 and NPC6 are essential in gametogenesis for a role in hydrolyzing phospholipids and producing TAG required for pollen tube growth. Thus, lipid remodeling from phospholipids to TAG during pollen tube growth represents an emerging role for the NPC family in plant developmental control.

Phospholipase Cζ (PLCζ) versus postacrosomal sheath WW domain-binding protein (PAWP): Which molecule will survive as a sperm factor?

During mammalian fertilization, sperm is fused with the oocyte's membrane, triggering the resumption of meiosis from the metaphase II arrest, the extrusion of the second polar body, and the exocytosis of cortical granules; these events are collectively called 'oocyte activation.' In all species studied to date, the transient rise in the cytosolic level of calcium (in particular, the repeated calcium increases called 'calcium oscillations' in mammals) is required for these events. Researchers have focused on identifying the factor(s) that can induce calcium oscillations during fertilization. Sperm-specific phospholipase C, i.e., PLC zeta (PLCζ), is a strong candidate of the factor(s), and several research groups using different species obtained evidence that PLCζ is a sperm factor that can induce calcium oscillations during fertilization. However, postacrosomal sheath Tryptophan-Tryptophan (WW)-domain-binding protein (PAWP) was recently shown to have a pivotal role in inducing calcium oscillations in some species. In this review, we focus on PLCζ and PAWP as sperm factors, and we discuss this controversy: Which of these two molecules survives as a sperm factor?

A patatin-like phospholipase functions during gametocyte induction in the malaria parasite Plasmodium falciparum.

Patatin-like phospholipases (PNPLAs) are highly conserved enzymes of prokaryotic and eukaryotic organisms with major roles in lipid homeostasis. The genome of the malaria parasite Plasmodium falciparum encodes four putative PNPLAs with predicted functions during phospholipid degradation. We here investigated the role of one of the plasmodial PNPLAs, a putative PLA2 termed PNPLA1, during blood stage replication and gametocyte development. PNPLA1 is present in the asexual and sexual blood stages and here localizes to the cytoplasm. PNPLA1-deficiency due to gene disruption or conditional gene-knockdown had no effect on intraerythrocytic growth, gametocyte development and gametogenesis. However, parasites lacking PNPLA1 were impaired in gametocyte induction, while PNPLA1 overexpression promotes gametocyte formation. The loss of PNPLA1 further leads to transcriptional down-regulation of genes related to gametocytogenesis, including the gene encoding the sexual commitment regulator AP2-G. Additionally, lipidomics of PNPLA1-deficient asexual blood stage parasites revealed overall increased levels of major phospholipids, including phosphatidylcholine (PC), which is a substrate of PLA2 . PC synthesis is known to be pivotal for erythrocytic replication, while the reduced availability of PC precursors drives the parasite into gametocytogenesis; we thus hypothesize that the higher PC levels due to PNPLA1-deficiency prevent the blood stage parasites from entering the sexual pathway.

Phospholipases in neuronal function: A role in learning and memory?

Despite the human brain being made of nearly 60% fat, the vast majority of studies on the mechanisms of neuronal communication which underpin cognition, memory and learning, primarily focus on proteins and/or (epi)genetic mechanisms. Phospholipids are the main component of all cellular membranes and function as substrates for numerous phospholipid-modifying enzymes, including phospholipases, which release free fatty acids (FFAs) and other lipid metabolites that can alter the intrinsic properties of the membranes, recruit and activate critical proteins, and act as lipid signalling molecules. Here, we will review brain specific phospholipases, their roles in membrane remodelling, neuronal function, learning and memory, as well as their disease implications. In particular, we will highlight key roles of unsaturated FFAs, particularly arachidonic acid, in neurotransmitter release, neuroinflammation and memory. In light of recent findings, we will also discuss the emerging role of phospholipase A1 and the creation of saturated FFAs in the brain.

Angiotensin-converting enzyme inhibitor-associated angioedema: from bed to bench

BACKGROUND: Angiotensin-converting enzyme inhibitor-associated angioedema (ACEI-AAE) affects 0.1%-0.7% of patients treated with ACEIs. While previous research suggests that angioedema attacks result from increased vascular permeability, the pathogenesis is not completely understood. OBJECTIVE: This study aimed to describe the clinical, genetic, and laboratory parameters of ACEI-AAE patients and to investigate the role of vascular endothelial growth factors A and C (VEGF-A and VEGF-C), angiopoietins 1 and 2 (Ang1/Ang2), and secretory phospholipase A2 (sPLA2) in the pathogenesis of ACEI-AAE. METHODS: The clinical and laboratory data of ACEI-AAE patients were collected from 2 angioedema reference centers. Healthy volunteers and ACEI-treated patients without angioedema were enrolled to compare laboratory parameters. Genetic analyses to detect mutations in the genes SERPING1, ANGPT1, PLG, and F12 were performed in a subset of patients. RESULTS: A total of 51 patients (57% male) were diagnosed with ACEI-AAE. The average time to onset of symptoms from the start of ACEI therapy was 3 years (range, 30 days-20 years). The most commonly affected sites were the lips (74.5%), tongue (51.9%), and face (41.2%). Switching from ACEIs to sartans was not associated with an increased risk of angioedema in patients with a history of ACEIAAE. VEGF-A, VEGF-C, and sPLA2 plasma levels were higher in ACEI-AAE patients than in the controls. Ang1/2 concentrations remained unchanged. No mutations were detected in the genes analyzed. CONCLUSIONS: Our data suggest that sartans are a safe therapeutic alternative in ACEI-AAE patients. Increased concentrations of VEGF-A, VEGF-C, and sPLA2 in ACEI-AAE patients suggest a possible role of these mediators in the pathogenesis of ACEI-AAE

ANTECEDENTES: El angioedema asociado al consumo de inhibidores de la enzima convertidora de angiotensina (IECA-AAE) ocurre en el 0,1%-0,7% de los pacientes tratados con IECA. Aunque se sugiere que los ataques de angioedema son el resultado de una mayor permeabilidad vascular, la patogénesis de este proceso no está plenamente esclarecida. OBJETIVO: En este trabajo se estudiaron los parámetros clínicos, genéticos y de laboratorio de pacientes con IECA-AAE, así como el papel de los factores de crecimiento endotelial vascular A y C (VEGF-A y VEGF-C), las angiopoyetinas 1 y 2 (Ang1/Ang2) y la fosfolipasa secretora A2 (sPLA2). MÉTODOS: Se recogieron datos clínicos y de laboratorio de pacientes con IECA-AAE procedentes de dos centros de referencia en angioedema. Se utilizaron pacientes control, que incluyeron a voluntarios sanos y a pacientes tratados con IECA sin angioedema, para comparar las concentraciones de los parámetros de laboratorio. Finalmente, se realizó un análisis genético en un subconjunto de pacientes para detectar mutaciones en los genes SERPING1, ANGPT1, PLG y F12. RESULTADOS: Se diagnosticaron a 51 pacientes (57% hombres) con IECA-AAE. El tiempo promedio para el inicio de los síntomas desde el comienzo del tratamiento con IECA fue de 3 años (rango de 30 días a 20 años). Los lugares más comúnmente afectados fueron: labios (74,5%), lengua (51,9%) y cara (41,2%). El cambio de IECA a ARA-II no se asoció con un mayor riesgo de angioedema en pacientes con antecedentes de IECA-AAE. Los niveles plasmáticos de VEGF-A, VEGF-C y sPLA2 fueron más altos en pacientes con IECA-AAE que en los controles. No se detectaron cambios en las concentraciones de Ang1/Ang2, ni se detectaron mutaciones en los genes analizados. CONCLUSIONES: Nuestros datos sugieren que los ARA-II pueden ser una alternativa terapéutica segura en pacientes con IECA-AAE. El aumento de las concentraciones de VEGF-A, VEGF-C y sPLA2 en pacientes con ACEI-AAE sugiere un posible papel de estos mediadores en la patogénesis de esta enfermedad

Patatin-like phospholipases in microbial infections with emerging roles in fatty acid metabolism and immune regulation by Apicomplexa.

Emerging lipidomic technologies have enabled researchers to dissect the complex roles of phospholipases in lipid metabolism, cellular signaling and immune regulation. Host phospholipase products are involved in stimulating and resolving the inflammatory response to pathogens. While many pathogen-derived phospholipases also manipulate the immune response, they have recently been shown to be involved in lipid remodeling and scavenging during replication. Animal and plant hosts as well as many pathogens contain a family of patatin-like phospholipases, which have been shown to have phospholipase A2 activity. Proteins containing patatin-like phospholipase domains have been identified in protozoan parasites within the Apicomplexa phylum. These parasites are the causative agents of some of the most widespread human diseases. Malaria, caused by Plasmodium spp., kills nearly half a million people worldwide each year. Toxoplasma and Cryptosporidium infect millions of people each year with lethal consequences in immunocompromised populations. Parasite-derived patatin-like phospholipases are likely effective drug targets and progress in the tools available to the Apicomplexan field will allow for a closer look at the interplay of lipid metabolism and immune regulation during host infection.

Functional Contribution of the Spastic Paraplegia-Related Triglyceride Hydrolase DDHD2 to the Formation and Content of Lipid Droplets.

Deleterious mutations in the serine lipase DDHD2 are a causative basis of complex hereditary spastic paraplegia (HSP, subtype SPG54) in humans. We recently found that DDHD2 is a principal triglyceride hydrolase in the central nervous system (CNS) and that genetic deletion of this enzyme in mice leads to ectopic lipid droplet (LD) accumulation in neurons throughout the brain. Nonetheless, how HSP-related mutations in DDHD2 relate to triglyceride metabolism and LD formation remains poorly understood. Here, we have characterized a set of HSP-related mutations in DDHD2 and found that they disrupt triglyceride hydrolase activity in vitro and impair the capacity of DDHD2 to protect cells from LD accumulation following exposure to free fatty acid, an outcome that was also observed with a DDHD2-selective inhibitor. We furthermore isolated and characterized LDs from brain tissue of DDHD2-/- mice, revealing that they contain both established LD-associated proteins identified previously in other organs and CNS-enriched proteins, including several proteins with genetic links to human neurological disease. These data, taken together, indicate that the genetic inactivation of DDHD2, as caused by HSP-associated mutations, substantially perturbs lipid homeostasis and the formation and content of LDs, underscoring the importance of triglyceride metabolism for normal CNS function and the key role that DDHD2 plays in this process.

Identification mouse patatin-like phospholipase domain containing protein 1 as a skin-specific and membrane-associated protein.

Patatin-like phospholipase domain containing protein 1 (PNPLA1) mutations have been identified to be associated with autosomal recessive congenital ichthyosis (ARCI) in recent years. However, its molecular characters have not been achieved until now. In the current study, the full length coding cDNA sequence of mouse PNPLA1 (mPNPLA1) was identified firstly. There were several putative transmembrane domains (TMDs) in mPNPLA1 by bioinformation analysis. mPNPLA1 was further found to be expressed exclusively in the membrane fraction in mammalian cells. However, it did not colocalized with the endoplasmic reticulum (ER) or lipid droplets (LDs). Moreover, the mRNA levels of mPNPLA1 was detected to be highly expressed in the skin, while very weak or even less in other mouse tissues by quantitative PCR. In addition, based on experiments with inhibitors and inducer of protein degradation pathways, mPNPLA1 was demonstrated to be degraded by macroautophagy, but not by the proteasome. These results indicated PNPLA1 was a skin-specific and membrane-associated protein for the first time, suggesting that it may mainly play a role in the skin.

Specific degradation of phosphatidylglycerol is necessary for proper mitochondrial morphology and function.

In yeast, phosphatidylglycerol (PG) is a minor phospholipid under standard conditions; it can be utilized for cardiolipin (CL) biosynthesis by CL synthase, Crd1p, or alternatively degraded by the phospholipase Pgc1p. The Saccharomyces cerevisiae deletion mutants crd1Δ and pgc1Δ both accumulate PG. Based on analyses of the phospholipid content of pgc1Δ and crd1Δ yeast, we revealed that in yeast mitochondria, two separate pools of PG are present, which differ in their fatty acid composition and accessibility for Pgc1p-catalyzed degradation. In contrast to CL-deficient crd1Δ yeast, the pgc1Δ mutant contains normal levels of CL. This makes the pgc1Δ strain a suitable model to study the effect of accumulation of PG per se. Using fluorescence microscopy, we show that accumulation of PG with normal levels of CL resulted in increased fragmentation of mitochondria, while in the absence of CL, accumulation of PG led to the formation of large mitochondrial sheets. We also show that pgc1Δ mitochondria exhibited increased respiration rates due to increased activity of cytochrome c oxidase. Taken together, our results indicate that not only a lack of anionic phospholipids, but also excess PG, or unbalanced ratios of anionic phospholipids in mitochondrial membranes, have harmful consequences on mitochondrial morphology and function.

Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness.

Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photoreceptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.

Enzymatic and hemolytic activity in different Candida species.

BACKGROUND: Candida species, in conditions of microbiota imbalance or decreased immune defenses, may be one of the main human fungal pathogens. Virulence factors constitute the mechanisms used by the fungus to avoid host defenses. AIMS: This study aimed to investigate the in vitro production of virulence factors, such as hemolytic activity, and deoxyribonuclease (DNase), proteinase, and phospholipase activities in Candida spp. METHODS: Fifty clinical isolates were analyzed for virulence factors: Candida albicans (15), Candida tropicalis (15), Candida parapsilosis (10), Candida glabrata (5), and Candida krusei (5). Hemolytic activity was determined in Sabouraud dextrose agar plates containing 3% glucose and 7% sheep red cells. Culture media containing, respectively, agar-base DNA, egg yolk, and bovine albumin were used to determine DNase, phospholipase and proteinase activities, respectively. RESULTS: Forty-eight (96%) of 50 isolates showed hemolytic activity, with 10 (20%) positive for DNase, 19 (38%) for proteinase, and 16 (32%) for phospholipase. Statistically significant differences were observed between species for phospholipase (p<0.0001) and proteinase (p<0.05) production. CONCLUSIONS: It is concluded that all species had hemolytic activity. DNase activity was detected in all species except in C. glabrata; proteinase activity was detected in C. albicans, C. tropicalis, and C. parapsilosis; and phospholipase activity was observed in C. albicans and C. tropicalis.

Competition between Grb2 and Plcγ1 for FGFR2 regulates basal phospholipase activity and invasion.

FGFR2-expressing human cancer cells with low concentrations of the adaptor protein Grb2 show high prevalence for metastatic outcome. In nonstimulated cells, the SH3 domain (and not the SH2 domains) of Plcγ1 directly competes for a binding site at the very C terminus of FGFR2 with the C-terminal SH3 domain of Grb2. Reduction of Grb2 concentration permits Plcγ1 access to the receptor. Recruitment of Plcγ1 in this way is sufficient to upregulate phospholipase activity. This results in elevated phosphatidylinositol 4,5-bisphosphate turnover and intracellular calcium levels, thus leading to increased cell motility and promotion of cell-invasive behavior in the absence of extracellular receptor stimulation. Therefore, metastatic outcome can be dictated by the constitutive competition between Grb2 and Plcγ1 for the phosphorylation-independent binding site on FGFR2.

Amyloplast displacement is necessary for gravisensing in Arabidopsis shoots as revealed by a centrifuge microscope.

The starch-statolith hypothesis proposes that starch-filled amyloplasts act as statoliths in plant gravisensing, moving in response to the gravity vector and signaling its direction. However, recent studies suggest that amyloplasts show continuous, complex movements in Arabidopsis shoots, contradicting the idea of a so-called 'static' or 'settled' statolith. Here, we show that amyloplast movement underlies shoot gravisensing by using a custom-designed centrifuge microscope in combination with analysis of gravitropic mutants. The centrifuge microscope revealed that sedimentary movements of amyloplasts under hypergravity conditions are linearly correlated with gravitropic curvature in wild-type stems. We next analyzed the hypergravity response in the shoot gravitropism 2 (sgr2) mutant, which exhibits neither a shoot gravitropic response nor amyloplast sedimentation at 1 g. sgr2 mutants were able to sense and respond to gravity under 30 g conditions, during which the amyloplasts sedimented. These findings are consistent with amyloplast redistribution resulting from gravity-driven movements triggering shoot gravisensing. To further support this idea, we examined two additional gravitropic mutants, phosphoglucomutase (pgm) and sgr9, which show abnormal amyloplast distribution and reduced gravitropism at 1 g. We found that the correlation between hypergravity-induced amyloplast sedimentation and gravitropic curvature of these mutants was identical to that of wild-type plants. These observations suggest that Arabidopsis shoots have a gravisensing mechanism that linearly converts the number of amyloplasts that settle to the 'bottom' of the cell into gravitropic signals. Further, the restoration of the gravitropic response by hypergravity in the gravitropic mutants that we tested indicates that these lines probably have a functional gravisensing mechanism that is not triggered at 1 g.

Legionella phospholipases implicated in virulence.

Phospholipases are diverse enzymes produced in eukaryotic hosts and their bacterial pathogens. Several pathogen phospholipases have been identified as major virulence factors acting mainly in two different modes: on the one hand, they have the capability to destroy host membranes and on the other hand they are able to manipulate host signaling pathways. Reaction products of bacterial phospholipases may act as secondary messengers within the host and therefore influence inflammatory cascades and cellular processes, such as proliferation, migration, cytoskeletal changes as well as membrane traffic. The lung pathogen and intracellularly replicating bacterium Legionella pneumophila expresses a variety of phospholipases potentially involved in disease-promoting processes. So far, genes encoding 15 phospholipases A, three phospholipases C, and one phospholipase D have been identified. These cell-associated or secreted phospholipases may contribute to intracellular establishment, to egress of the pathogen from the host cell, and to the observed lung pathology. Due to the importance of phospholipase activities for host cell processes, it is conceivable that the pathogen enzymes may mimic or substitute host cell phospholipases to drive processes for the pathogen's benefit. The following chapter summarizes the current knowledge on the L. pneumophila phospholipases, especially their substrate specificity, localization, mode of secretion, and impact on host cells.

[Phospholipase and proteinase production by Malassezia pachydermatis isolated in dogs with and without otitis]. / Producción de fosfolipasa y proteinasa en cepas de Malassezia pachydermatis aisladas de perros con otitis y sin otitis.

BACKGROUND: Malassezia pachydermatis is part of the skin microbiota of dogs and cats. M. pachydermatis has been associated with external otitis and seborrhoeic dermatitis, reported more often in dogs than in cats. When the physical, chemical or immunological mechanisms of the skin are altered, M. pachydermatis could act as a pathogen. Thus, several virulence factors, such as the ability to produce esterase, lipase, lipoxygenase, protease, chondroitin sulphatase, and hyaluronidase, have been studied. AIMS: In the present study, we aim to identify the phospholipase activity measured at pH 6.3, and the proteinase activity measured at pH 6.3 and pH 6.8 (pH from ears of dogs with external otitis) of M. pachydermatis strains isolated from dogs with and without external otitis. METHODS: The phospholipase activity was measured using a semi-quantitative method with egg yolk, and the proteinase activity with a semi-quantitative method using bovine serum albumin agar. The study was performed on 96 isolates of M. pachydermatis, 43 isolated from dogs without clinical symptoms of otitis, and 52 isolated from dogs with otitis. RESULTS: In our study, 75.8% of the isolates showed phospholipase activity at pH 6.3, and 81 and 97.9% of them showed proteinase activity measured at pH 6.3 and 6.8, respectively. A higher phospholipase activity was detected in strains isolated from dogs with otitis. The proteinase activity was increased at a pH of 6.8 (97.9%) in comparison to a pH of 6.3 (81%). CONCLUSIONS: Our results suggest that the phospholipase activity may play an important role in the invasion of host tissues in chronic canine otitis cases. The proteinase activity results obtained in this study suggest that a reduction in the pH of the treatment may improve its efficacy in the resolution of M. pachydermatis otitis.

Phospholipase signalling networks in cancer.

Phospholipases (PLC, PLD and PLA) are essential mediators of intracellular and intercellular signalling. They can function as phospholipid-hydrolysing enzymes that can generate many bioactive lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid and arachidonic acid. Lipid mediators generated by phospholipases regulate multiple cellular processes that can promote tumorigenesis, including proliferation, migration, invasion and angiogenesis. Although many individual phospholipases have been extensively studied, how phospholipases regulate diverse cancer-associated cellular processes and the interplay between different phospholipases have yet to be fully elucidated. A thorough understanding of the cancer-associated signalling networks of phospholipases is necessary to determine whether these enzymes can be targeted therapeutically.

[Do phospholipases, key enzymes in sperm physiology, represent therapeutic challenges?]. / Les phospholipases, enzymes clés de la physiologie spermatique: quels enjeux thérapeutiques ?

The spermatozoon is one of the most differentiated cells in mammals and its production requires an extremely complex machinery. Subtle but critical molecular changes take place during capacitation, which comprises the last series of maturation steps that naturally occur between the cauda epididymidis where spermatozoa are stored and their ultimate destination inside the oocyte. Phospholipases, by hydrolyzing various phospholipids, have been found to be critical in sperm processes such as 1) the control of flagellum beats, 2) capacitation - the molecular transformations preparing the sperm for fertilization, 3) acrosome reaction and 4) oocyte activation by eliciting calcium oscillations. The emerging important role of phospholipases is also emphasized by the fact that alterations of sperm lipids can lead to infertility. Phospholipases may represent valuable targets to develop anti- and pro-fertility drugs. Results obtained in mice are encouraging, since treatment of sperm with recombinant sPLA(2) of group X, known to be involved in capacitation, improves fertilization in vitro, while co-injection of PLCζ RNA with infertile sperm restores oocyte activation.