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Abstract Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, which is characterized by high heterogeneity and metabolic dysregulation. Inositol monophosphatase 1(IMPA1) is critical for the metabolism of inositol, which has profound effects on gene expression and other biological processes. Here, we report for the first time that IMPA1 was upregulated in TNBC cell lines and tissues, and enhanced cell colony formation and proliferation in vitro and tumorigenicity in vivo. Additionally, IMPA1 promoted cell motility in vitro and metastatic lung colonization in vivo. Mechanistic investigations by transcriptome sequencing revealed that 4782 genes were differentially expressed between cells with IMPA1 knockdown and control cells. Among the differentially expressed genes after IMPA1 knockdown, five significantly altered genes were verified via qRT‐PCR assays. Morerover, we found that the expression profile of those five targets as a gene set was significantly associated with IMPA1 status in TNBC cells. As this gene set was associated with mTOR pathway and epithelial‐mesenchymal transition (EMT) process, we further confirmed that IMPA1 induced mTOR activity and EMT process, which at least in part contributed to IMPA1‐induced TNBC progression. Collectively, our findings reveal a previously unrecognized role of IMPA1 in TNBC progression and identify IMPA1 as a potential target for TNBC therapy.

Biallelic loss of function of IMPA1 causes autosomal recessive intellectual developmental disorder 59 (MRT59, OMIM #617323). MRT59 has been reported to present with significant intellectual disability and disruptive behavior, but little is known about the neurocognitive pattern of those patients. Thus, the aims of this study were: (1) to assess the cognitive profile of these patients, and (2) to evaluate their functional dependence levels. Eighteen adults, aged 37 to 89 years, participated in this study: nine MRT59 patients, five heterozygous carriers and four non-carrier family members. All of them were from a consanguineous family living in Northeast Brazil. All IMPA1 patients had the (c.489_493dupGGGCT) pathogenic variant in homozygosis. For cognitive assessment, the WASI battery was applied in nine MRT59 patients and compared to heterozygous carriers and non-carrier family members. Functional dependence was evaluated using the functional independence measure (FIM). Patients showed moderate to severe intellectual disability and severe functional disabilities. Heterozygous carriers did not differ from non-carriers. MRT59 patients should be followed up by health professionals in an interdisciplinary way to understand their cognitive disabilities and functional needs properly. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, which is characterized by high heterogeneity and metabolic dysregulation. Inositol monophosphatase 1(IMPA1) is critical for the metabolism of inositol, which has profound effects on gene expression and other biological processes. Here, we report for the first time that IMPA1 was upregulated in TNBC cell lines and tissues, and enhanced cell colony formation and proliferation in vitro and tumorigenicity in vivo. Additionally, IMPA1 promoted cell motility in vitro and metastatic lung colonization in vivo. Mechanistic investigations by transcriptome sequencing revealed that 4782 genes were differentially expressed between cells with IMPA1 knockdown and control cells. Among the differentially expressed genes after IMPA1 knockdown, five significantly altered genes were verified via qRT‐PCR assays. Morerover, we found that the expression profile of those five targets as a gene set was significantly associated with IMPA1 status in TNBC cells. As this gene set was associated with mTOR pathway and epithelial‐mesenchymal transition (EMT) process, we further confirmed that IMPA1 induced mTOR activity and EMT process, which at least in part contributed to IMPA1‐induced TNBC progression. Collectively, our findings reveal a previously unrecognized role of IMPA1 in TNBC progression and identify IMPA1 as a potential target for TNBC therapy. [ABSTRACT FROM AUTHOR]

Lithium is known to be efficient in treatment for mental disorders in people with bipolar disorder. The aim of the study was to identify bipolar disorder-specific MicroRNAs (miRNAs) that are associated with genes targeted by lithium treatment and lead to variance in the clinical response. miRNAs which are experimentally validated and shown to have differential expression pattern in bipolar disorder were selected from online public databases miRTarbase and HMDD v3.2. Target prediction was carried out for each miRNA, and experimentally validated miRNA-target mRNA pairs were obtained and analyzed by miRTarbase, HMDD v3.2, TargetScan, and DIANA databases. miRNA-target genes that are associated with lithium was determined by the use of DrugBank. According to the in silico analysis, it has been found that IMPA1 gene was targeted by hsa-mir-34a and GRIA3 gene was targeted by hsa-mir-124. The present study demonstrated that IMPA1, GRIA3, hsa-mir-34a, hsa-mir-124 may have the potential to be used as molecular biomarkers for estimating and monitoring the response to lithium treatment in bipolar disorder.

This review summarizes the literature data on the role of lithium compounds in modern pharmacotherapy of various diseases of the central nervous system. Attention is also paid to other therapeutic properties of lithium in atherosclerosis, cardiovascular diseases, diabetes, hematopoietic disorders, inflammation, and diseases of the urinary system. Possible ways of delivering lithium into the body have been charted, in particular, when lithium salt is combined with a sorbent (solid porous carrier). Such compounds have additional therapeutic properties. Data on the significance of lithium compounds in studies on models of diseases of the nervous system in animals are analyzed. Among these models, models of neonatal ischemia/hypoxia of the brain in vivo, neurodegenerative diseases, psychopathological states (aggressiveness, depression) and craniocerebral injury are discussed. There are researches in which the results of the lithium preparations use in clinical practice are investigated. It emphasizes the influence of genetic factors on the lithium effects. Particular attention is paid to the possibility of preventing the toxicity of lithium compounds for the body. The currently known molecular mechanisms of lithium action are discussed: inhibition of glycogen synthase kinase 3β (GSK-3β) and inositol monophosphatase 1 (IMPA1), which have key value for autophagy, oxidative stress, inflammation, mitochondrial function, induction of neurotrophic factors, apoptosis. It was concluded that the study of the molecular pathways of the functioning of lithium compounds empowers understanding both the reasons for its effectiveness in the nervous system diseases and the mechanisms of action on other body systems.

Abstract Background Dysregulation of the inositol cycle is implicated in a wide variety of human diseases, including developmental defects and neurological diseases. A homozygous frameshift mutation in IMPA1, coding for the enzyme inositol monophosphatase 1 (IMPase), has recently been associated with severe intellectual disability (ID) in a geographically isolated consanguineous family in Northeastern Brazil (Figueredo et al., 2016). However, the neurophysiologic mechanisms that mediate the IMPA1 mutation and associated ID phenotype have not been characterized. To this end, resting EEG (eyes-open and eyes-closed) was collected from the Figueredo et al. pedigree. Quantitative EEG measures, including mean power, dominant frequency and dominant frequency variability, were investigated for allelic associations using multivariate family-based association test using generalized estimating equations. Results We found that the IMPA1 mutation was associated with relative decreases in frontal theta band power as well as altered alpha-band variability with no regional specificity during the eyes-open condition. For the eyes-closed condition, there was altered dominant theta frequency variability in the central and parietal regions. Conclusions These findings represent the first human in vivo phenotypic assessment of brain function disturbances associated with a loss-of-function IMPA1 mutation, and thus an important first step towards an understanding the pathophysiologic mechanisms of intellectual disability associated with the mutation that affects this critical metabolic pathway.

Inositol monophosphatase (IMPase) is an enzyme with two homologs—IMPA1 and IMPA2—that is responsible for dephosphorylating myo-inositol monophosphate to generate myo-inositol. IMPase has been extensively studied in neuropsychiatric diseases and is regarded as a susceptibility gene. Recently, emerging evidence has implied that IMPase is linked to cancer development and progression and correlates with patient survival outcomes. Interestingly, whether it acts as a tumor-promoter or tumor-suppressor is inconsistent among different research studies. In this review, we summarize the latest findings on IMPase in cancer, focusing on exploring the underlying mechanisms for its pro- and anticancer roles. In addition, we discuss the potential methods of IMPase regulation in cancer cells and the possible approaches for IMPase intervention in clinical practice. [Display omitted] • The role of IMPase in cancer has not been revealed until recently. • IMPase can act as both a tumor-promoter and tumor-inhibitor. • IMPase is associated with a number of crucial biological processes in cancer cells. • Cancer cell can modify IMPase at the levels of gene expression and enzyme-activity. • Intervening IMPase with chemical compounds is a potential cancer treatment strategy. [ABSTRACT FROM AUTHOR]

Previous microarray studies in our laboratory identified a number of genes that were differentially expressed in “silver” eels after transfer from freshwater (FW) to seawater (SW). A group of genes, which are related to the synthesis, processing, and transport of certain known osmolytes in mammalian cells, have been identified. One gene implicated with osmolyte production is myo-inositol monophosphatase (IMPA1). The aim of this study was to compare the expression of IMPA1 in the major osmoregulatory tissues (intestine, gill, and kidney) as fish move between FW and SW environments. No difference in IMPA1 gene expression was observed in any tissues 6 h after eel transfer to SW; however, after 2 days acclimation, a 1.9- and a 2.5-fold increase in mRNA expression was found in kidney and gill, respectively. These elevated levels were maintained for up to 5 months (4.9- and 3.4-fold, respectively) after SW transfer. No IMPA1 mRNA expression was detected in the intestine. Western blot analysis confirmed the IMPA1 protein was upregulated in the gill, but no changes in protein abundance were detected in the kidney 5 months after SW transfer. Our studies have revealed a potential role for IMPA1 in salinity adaptation in the European eel. [ABSTRACT FROM AUTHOR]

Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1−/−) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1−/− mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1−/− mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1−/− mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1−/− mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.Neuropsychopharmacology (2008) 33, 674–684; doi:10.1038/sj.npp.1301431; published online 25 April 2007 [ABSTRACT FROM AUTHOR]

Myo-inositol monophosphatase 1 (IMPase 1) is one of the targets for the mood-stabilizing action of lithium. Inhibition of IMPase is the basis for the “inositol depletion hypothesis” for the molecular action of lithium. To better understand the precise action of chronic (up to 4 weeks) lithium treatment on IMPase 1 activity, we measured IMPase 1 activity using both a colorimetric and a radiometric assay in rats (53–58 days old) fed a diet containing 0.2% lithium carbonate. Our results show that IMPase 1 activity increases substantially in the various brain regions analyzed, even doubling in some regions in the following order, after chronic treatment: hippocampus>cerebellum>striatum>cerebral cortex>brain stem. Both the qualitative and quantitative increases of IMPase 1 activity by chronic lithium treatment were substantiated by Western blot analysis of hippocampal and cerebral cortex regions. We conclude that the increased IMPase 1 activity is an adaptational response to chronic lithium treatment, and may involve direct or indirect stimulation of IMPA1 (which encodes IMPase 1) and/or turnover of the enzyme. The increased enzyme activity may alter critical neurochemical processes involving either free myo-inositol, the precursor of inositol based signaling system or other metabolic pathways, since IMPase 1 also utilizes selective sugar phosphates, such as galactose-1-phosphate, as substrates. One or more of these signal and metabolic pathways may be associated with lithium''s psychotherapeutic mood-stabilizing action. [Copyright &y& Elsevier]

Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission. [Display omitted] • IMPA-derived inositol modulates mitochondrial fission • Inositol restricts aberrant AMPK activation and mitochondrial fission • Inositol decline leads to AMPK-dependent mitochondrial fission upon energy stress • Inositol binds directly to AMPKγ and competes with AMP for AMPKγ binding Hsu et al. demonstrate that inositol serves as an endogenous suppressor to limit AMPK activation and mitochondrial fission through its direct binding to the AMPKγ subunit. AMP/inositol and AMP/ATP ratios serve as critical determinants for AMPK activation and mitochondrial fission. AMPK is therefore an inositol sensor orchestrating mitochondrial fission by detecting the inositol gradient in cells. [ABSTRACT FROM AUTHOR]

Background: Dysregulation of the inositol cycle is implicated in a wide variety of human diseases, including developmental defects and neurological diseases. A homozygous frameshift mutation in IMPA1, coding for the enzyme inositol monophosphatase 1 (IMPase), has recently been associated with severe intellectual disability (ID) in a geographically isolated consanguineous family in Northeastern Brazil (Figueredo et al., 2016). However, the neurophysiologic mechanisms that mediate the IMPA1 mutation and associated ID phenotype have not been characterized. To this end, resting EEG (eyes-open and eyes-closed) was collected from the Figueredo et al. pedigree. Quantitative EEG measures, including mean power, dominant frequency and dominant frequency variability, were investigated for allelic associations using multivariate family-based association test using generalized estimating equations.Results: We found that the IMPA1 mutation was associated with relative decreases in frontal theta band power as well as altered alpha-band variability with no regional specificity during the eyes-open condition. For the eyes-closed condition, there was altered dominant theta frequency variability in the central and parietal regions.Conclusions: These findings represent the first human in vivo phenotypic assessment of brain function disturbances associated with a loss-of-function IMPA1 mutation, and thus an important first step towards an understanding the pathophysiologic mechanisms of intellectual disability associated with the mutation that affects this critical metabolic pathway. [ABSTRACT FROM AUTHOR]