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Glycolytic metabolism and its functional relevance in PSCs. Acetyl-CoA, acetyl-coenzyme A; ATP, adenosine triphosphate; HIF1, hypoxiainducible factor 1; HK2, hexokinase 2; LDHA, lactate dehydrogenase; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; PKM2, pyruvate kinase M2; PSC, pluripotent stem cell
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Induced pluripotent stem cells (iPSCs) were first established from differentiated somatic cells by gene introduction of key transcription factors, OCT4, SOX2, KLF4, and c-MYC, over a decade ago. Although iPSCs can be applicable for regenerative medicine, disease modeling and drug screening, several issues associated with the utilization of iPSCs su...
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Context 1
... addition, HIF1 is involved in the transcriptional regulation of several glycolytic genes that enhance the metabolic flux of glycolysis. Figure 1 shows a schematic illustration of glycolytic metabolism and the involvement of HIF1. Acetyl-CoA, acetyl-coenzyme A; ATP, adenosine triphosphate; HIF1, hypoxiainducible factor 1; HK2, hexokinase 2; LDHA, lactate dehydrogenase; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; PKM2, pyruvate kinase M2; PSC, pluripotent stem cell ...
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... the PDK1 protein is more stabilized in PSCs than in differentiated somatic cells, possibly via a HIFdependent regulation, reprogramming cells may show enhanced glycolytic activity [15] (Fig. 1). In addition, AKT activity is correlated with the upregulation of glycolytic genes and increases lactate production, resulting in improvement of the reprogramming efficiency [46,47]. TCL1, a protooncogene that phosphorylates AKT as a co-activator, is upregulated by KLF4 through direct transcriptional regulation. This increased ...
Citations
... The transcription regulatory factor HIF1 can participate in gene transcription of stem cell metabolism, and the hypoxic environment provided by HIF1 is necessary for stem cell survival, maintenance of redox homeostasis, and pluripotency ( Figure 2) [36]. Under hypoxic conditions, HIF1 upregulates Glycolysis by encoding glucose transporter protein (GLUT), phosphofructose kinase (PFK), aldolase (ALDOA), phosphoglycerate kinase-1 (PGK1), enolase (ENO), pyruvate dehydrogenase kinase 1 (PDK1), and LDHA [37]. ...
Energy metabolism regulates the proliferation of stem cells by regulating energy production and the production of substrates through biosynthetic pathways. It is an important target for cell regulation and stem cell applications, and is crucial for determining the pluripotency and cell fate of stem cells. In this context, this article focuses on reviewing the latest research progress on the association between glucose metabolism, amino acid metabolism, fatty acid metabolism, and mitophagy with stem cell function, elucidating how key energy metabolism pathways affect stem cell function by regulating signal transduction and epigenetic modifications. In this review, we discuss the key factors affecting energy metabolism and their association with stem cell function. The integration of energy metabolism and stem cell fate regulation will open up a new path for future regenerative medicine practices.
... Hypoxia profoundly impacts mitochondrial energy production, as reduced oxygen availability hinders ATP synthesis in the electron transport chain [75]. Consequently, HIF-1α suppresses aerobic oxidation and promotes glycolytic metabolism [87]. This is achieved by upregulating the expression of enzymes such as hexokinase (HK) and enolase 1 (ENO1), which accelerate pyruvate production, subsequently converted into lactate by HIF-1α-induced lactate dehydrogenase (LDHA) [88]. ...
Understanding the molecular underpinnings of neurodegeneration processes is a pressing challenge for medicine and neurobiology. Alzheimer’s disease (AD) and Parkinson’s disease (PD) represent the most prevalent forms of neurodegeneration. To date, a substantial body of experimental evidence has strongly implicated hypoxia in the pathogenesis of numerous neurological disorders, including AD, PD, and other age-related neurodegenerative conditions. Hypoxia-inducible factor (HIF) is a transcription factor that triggers a cell survival program in conditions of oxygen deprivation. The involvement of HIF-1α in neurodegenerative processes presents a complex and sometimes contradictory picture. This review aims to elucidate the current understanding of the interplay between hypoxia and the development of AD and PD, assess the involvement of HIF-1 in their pathogenesis, and summarize promising therapeutic approaches centered on modulating the activity of the HIF-1 complex.
... ;https://doi.org/10.1101https://doi.org/10. /2024 production of energy with low levels of OXPHOS (Ishida, Nakao et al. 2020). Moreover, metabolic modification from OXPHOS to glycolysis in iPSCs can be explained by the Warburg effect which is essential for the maintenance of the stem cell characteristics (Prigione, Fauler et al. 2010, Varum, Rodrigues et al. 2011, Panopoulos, Yanes et al. 2012, Ishida, Nakao et al. 2020). ...
... /2024 production of energy with low levels of OXPHOS (Ishida, Nakao et al. 2020). Moreover, metabolic modification from OXPHOS to glycolysis in iPSCs can be explained by the Warburg effect which is essential for the maintenance of the stem cell characteristics (Prigione, Fauler et al. 2010, Varum, Rodrigues et al. 2011, Panopoulos, Yanes et al. 2012, Ishida, Nakao et al. 2020). ...
Aging represents the main risk factor for developing neurodegenerative disorders. One of the hallmarks of aging is mitochondrial dysfunction. Age-related mitochondrial alterations have been shown to affect mitochondrial energy metabolism and redox homeostasis as well as mitochondrial dynamics. In the present study, we addressed the question of whether or not, induced pluripotent stem cells (iPSCs) may be used as a model of “aging in a dish” to identify therapies at alleviating the aging of mitochondria. Notably, we could demonstrate that compared to human iPSCs from young donors, those from aged donors show impaired mitochondrial bioenergetics and exhibit a rise in reactive oxygen species generation. Furthermore, we demonstrate that iPSCs from aged donors present low mitochondrial mass and alterations of the morphology of the mitochondrial network. This study provides evidence that the aging phenotype is present at the mitochondrial level in iPSCs from aged donors, ranging from bioenergetics to dynamics. Thus, this model can be used for high through put screening to identify drugs that improve mitochondrial function.
Graphical abstract
... Coupled with our finding of decreased mtDNA transcript levels in Alpers' iPSCs, the reduced CI levels exhibited in the Alper's iPSCs suggests that mtDNA depletion in these Alpers' does not result in significant mitochondrial dysfunction. One possible explanation for this observation is iPSCs' higher reliance on glycolysis for iPSC energy productivity than oxidative phosphorylation [37]. ...
Alpers' syndrome is an early-onset neurodegenerative disorder usually caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG), which is essential for mitochondrial DNA (mtDNA) replication. The disease is progressive, incurable, and inevitably it leads to death from drug-resistant status epilepticus. The neurological features of Alpers' syndrome are intractable epilepsy and developmental regression, with no effective treatment; the underlying mechanisms are still elusive, partially due to lack of good experimental models. Here, we generated the patient derived induced pluripotent stem cells (iPSCs) from one Alpers' patient carrying the compound heterozygous mutations of A467T (c.1399G>A) and P589L (c.1766C>T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers' syndrome. Patient cortical organoids exhibited a phenotype that faithfully replicated the molecular changes found in patient postmortem brain tissue, as evidenced by cortical neuronal loss and depletion of mtDNA and complex I (CI). Patient NSCs showed mitochondrial dysfunction leading to ROS overproduction and downregulation of the NADH pathway. More importantly, the NAD⁺ precursor nicotinamide riboside (NR) significantly ameliorated mitochondrial defects in patient brain organoids. Our findings demonstrate that the iPSC model and brain organoids are good in vitro models of Alpers' disease; this first-in-its-kind stem cell platform for Alpers' syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers' disease and, potentially, other mitochondrial diseases with similar causes.
... The process of reprogramming adult somatic cells involves transition in cellular characteristics, genomic and epigenetic remodelling in parallel with major metabolic changes to sustain self-renewal and plasticity of iPSCs (4,5). Overall, the metabolic shift that occurs during reprogramming consists of decreasing oxidative phosphorylation (OXPHOS) while increasing glycolysis (6-8). ...
... Mitochondria play a crucial role in cellular energy production through oxidative phosphorylation (OXPHOS), generating ATP in all nucleated cells (4). They consist of the electron transport respiratory chain (ETC) complexes I-IV and the ATP synthase complex V (10). ...
... High amounts of ROS generated from OXPHOS results in HIF1a induction which serve as a signal to modify cysteine residues on Kelch like ECA associated protein 1 (Keap1). Keap1 is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase and directly regulates the activity of Nrf2 to acts as a sensor for oxidative and electrophilic stresses, KEAP1, the repressor of Nrf2, resulting in Nrf2 activation, and the subsequent interaction with HIF1a to induce the metabolic shift towards glycolysis as well as PPP and increase in nucleic acid synthesis (4). Furthermore, Nrff2 is a pivotal regulator of selfrenewal, proliferation, and differentiation where High levels of ROS will modify KEAP1 and NRF2 activity to allow them freely to interact with bind Oct4 and Nanog promoters for self-renewal induction while maintaining pluripotency (77). ...
Mexico
Mitochondria are the powerhouse of the cell and dynamically control fundamental biological processes including cell reprogramming, pluripotency, and lineage specification. Although remarkable progress in induced pluripotent stem cell (iPSC)-derived cell therapies has been made, very little is known about the role of mitochondria and the mechanisms involved in somatic cell reprogramming into iPSC and directed reprogramming of iPSCs in terminally differentiated cells. Reprogramming requires changes in cellular characteristics, genomic and epigenetic regulation, as well as major mitochondrial metabolic changes to sustain iPSC self-renewal, pluripotency, and proliferation. Differentiation of autologous iPSC into terminally differentiated β-like cells requires further metabolic adaptation. Many studies have characterized these alterations in signaling pathways required for the generation and differentiation of iPSC; however, very little is known regarding the metabolic shifts that govern pluripotency transition to tissue-specific lineage differentiation. Understanding such metabolic transitions and how to modulate them is essential for the optimization of differentiation processes to ensure safe iPSC-derived cell therapies. In this review, we summarize the current understanding of mitochondrial metabolism during somatic cell reprogramming to iPSCs and the metabolic shift that occurs during directed differentiation into pancreatic β-like cells.
... Для МСК, як і для інших клітин з ознаками "стовбуровості", характерним є активізація гліколізу замість окиснення субстратів у циклі Кребса Хоча гліколіз менш енергетично вигідний шлях, він супроводжується активізацією пентозо-фосфатного шунту і синтезу макромолекул, необхідних для швидко проліферуючих клітин. Аналогічну функцію у стовбурових клітинах виконує активізація процесу окиснення жирних кислот (Ishida et al., 2020). ...
The content of fatty acids in the lipids of mesenchymal stem cells of dog adipose tissue culture was studied. Mesenchymal stem cells of dog adipose tissue culture were obtained by culturing the primary material in a CO2 incubator with a content of 5 % CO2, at a temperature of 37 °C in DMEM medium with the addition of 10–15 % fetal bovine serum and 1 % antibiotic-antimycotic. When the confluency of the monolayer reached 70–80 %, the cells were transferred to a suspension and subcultivated in order to reduce the heterogeneity of the culture and obtain a sufficient amount of biological material. The lipids of the obtained stem cells were analyzed for the content of fatty acids by the method of thin-layer gas-liquid chromatography. Determination of the content of lipids of fatty acids in FSK of a cat was carried out by the Folch method. A mixture of fatty acid methyl esters was analyzed on a Trace GC Ultra gas chromatograph with a flame ionization detector on a capillary column SPTM –2560, 100 m x 0.25 mm ID, 0.20 μm film (Supelco). Identification of fatty acids was carried out using a standard sample of Supelco 37 Сomponent FAME Mix. Quantitative assessment of the LC spectrum was carried out by the method of normalization of the peak planes of methylated LC derivatives and their content was determined as a percentage of the total content of all LC. The conducted study of the content of fatty acids in lipids made it possible to reveal certain features of the lipid metabolism of mesenchymal stem cells cultured in dog adipose tissue. A high content of oleic acid, characteristic of cells resistant to apoptosis and with high proliferative potential, was determined; a high ratio of unsaturated linoleic to saturated stearic acid (С18:1/С18.0), which reflects the high activity of the stearoyl-coenzyme-desaturase enzyme and, indirectly, the active state of the Wnt/β-catenin signaling pathway; inability to lengthen the chain of saturated fatty acids; lack or low activity of de novo synthesis of omega-6 polyunsaturated fatty acids. 18 fatty acids were found in the composition of lipids of fetal stem cells of a cat, of the saturated ones - the most palmitic acid (33.70 ± 0.02 %), of the monounsaturated ones – oleic acid (21.63 ± 0.03 %), of the polyunsaturated ones – linoleic acid (6.45 ± 0.07 %). The least amount of cis-,11,14-eicosadienoic acid (0.04 ± 0.01 %) was found in the composition of cell lipids. The total amount of saturated fatty acids in dog mesenchymal stem cell lipids was 65.65 ± 0.02 %), unsaturated fatty acids – 34.35 ± 0.02 %. Monoene fatty acids were determined in the amount of 24.46 ± 0.02 %, and polyene – 9.89 ± 0.02 %. The ratio index of polyunsaturated fatty acids ω 3 to ω 6 is 0.40. Lipids of mesenchymal stem cells of adipose tissue culture were characterized by a lower content of monoene unsaturated fatty acids 24.46 ± 0.02; (P < 0.05), with a higher content of ω3 fatty acids 3.04 ± 0.02 %; (P < 0.05), with a lower content of ω6 fatty acids 6.86 ± 0.02 %; (P < 0.05) in contrast to lipids of red bone marrow stem cells.
... Coupled with our finding of decreased mtDNA transcript levels in Alpers' iPSCs, the reduced CI levels exhibited in the Alper's iPSCs suggests that mtDNA depletion in these Alpers' does not result in significant mitochondrial dysfunction. One possible explanation for this observation is iPSCs' higher reliance on glycolysis for iPSC energy productivity than oxidative phosphorylation [37]. ...
Alpers' syndrome is an early-onset neurodegenerative disorder usually caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG), which is essential for mitochondrial DNA (mtDNA) replication. The disease is progressive, incurable, and inevitably it leads to death from drug-resistant status epilepticus. The neurological features of Alpers' syndrome are intractable epilepsy and developmental regression, with no effective treatment; the underlying mechanisms are still elusive, partially due to lack of good experimental models. Here, we generated the patient-derived induced pluripotent stem cells from one Alpers' patient carrying the compound heterozygous mutations of A467T (c.1399G>A) and P589L (c.1766C>T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers' syndrome. Patient cortical organoids exhibited a phenotype that faithfully replicated the molecular changes found in patient postmortem brain tissue, as evidenced by cortical neuronal loss and depletion of mtDNA and complex I (CI). Patient NSCs showed mitochondrial dysfunction leading to ROS overproduction and downregulation of the NADH pathway. More importantly, the NAD+ precursor nicotinamide riboside (NR) significantly ameliorated mitochondrial defects in patient brain organoids. Our findings demonstrate that the iPSC model and brain organoids are good in vitro models of Alpers' disease; this first-in-its-kind stem cell platform for Alpers' syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers' disease and, potentially, other mitochondrial diseases with similar causes.
... Over the past years, human-induced pluripotent stem cells (iPSCs) have emerged as powerful resources for the development of improved human neuronal models to study the pathogenic mechanisms underlying neurodegenerative diseases [12]. Moreover, they provide an enormous potential for application in regenerative medicine and patient-specific cell and drug therapy [13]. Given that human iPSCs feature the ability to self-renew unlimitedly and possess the capacity to differentiate into any neuronal cell type [14], the resulting neuronal cultures have the advantage of endogenously expressing mutant genes of interest [15]. ...
... In contrast, triple taumutant iPSCs exhibited deficits in glycolysis, and thus, no attempt to metabolically switch on glycolysis occurred to maintain ATP production. Nevertheless, this is hardly surprising as stem cells primarily rely on aerobic glycolysis to generate ATP and intermediates, which in turn are essential for maintaining stem cell properties such as rapid cell proliferation and pluripotency [13]. Regardless of the relatively low contribution of OXPHOS for ATP production, several studies proved that although stem cell mitochondria possess the capacity to promote ATP generation via OXPHOS, it rather seems that they are actively repressed through several mechanisms to do so [20]. ...
Pathological abnormalities in the tau protein give rise to a variety of neurodegenerative diseases, conjointly termed tauopathies. Several tau mutations have been identified in the tau-encoding gene MAPT, affecting either the physical properties of tau or resulting in altered tau splicing. At early disease stages, mitochondrial dysfunction was highlighted with mutant tau compromising almost every aspect of mitochondrial function. Additionally, mitochondria have emerged as fundamental regulators of stem cell function. Here, we show that compared to the isogenic wild-type triple MAPT-mutant human-induced pluripotent stem cells, bearing the pathogenic N279K, P301L, and E10+16 mutations, exhibit deficits in mitochondrial bioenergetics and present altered parameters linked to the metabolic regulation of mitochondria. Moreover, we demonstrate that the triple tau mutations disturb the cellular redox homeostasis and modify the mitochondrial network morphology and distribution. This study provides the first characterization of disease-associated tau-mediated mitochondrial impairments in an advanced human cellular tau pathology model at early disease stages, ranging from mitochondrial bioenergetics to dynamics. Consequently, comprehending better the influence of dysfunctional mitochondria on the development and differentiation of stem cells and their contribution to disease progression may thus assist in the potential prevention and treatment of tau-related neurodegeneration.
... Importantly, the expression of glycolysis-related genes and lactate production in Embryonic Stem Cells (ESCs) and adult multipotent stem cells is higher compared to terminally differentiated cells, which rely preferentially on mitochondrial oxidative phosphorylation (OXPHOS) to fulfill their energy needs [48]. Oxidative phosphorylation is used by somatic cells for energy production, but during cell reprogramming, the transition to pluripotency is accompanied by a shift to glycolytic metabolism, and in fact, the efficiency of cell reprogramming is significantly enhanced by raising glucose concentrations in the culture medium [49,50]. It should also be noted that many components of the core pluripotency factor network crucially regulate cellular metabolism [46,51]. ...
The Dental Pulp of permanent human teeth is home to stem cells with remarkable multi-lineage differentiation ability: human Dental Pulp Stem Cells (DPSCs). These cells display a very notorious expression of pluripotency core factors, and the ability to give rise to mature cell lineages belonging to the three embryonic layers. For these reasons, several researchers in the field have long considered human DPSCs as pluripotent-like cells. Notably, some signaling pathways such as Notch and Wnt contribute to maintaining the stemness of these cells through a complex network involving metabolic and epigenetic regulatory mechanisms. The use of recombinant proteins and selective pharmacological modulators of Notch and Wnt pathways, together with serum-free media and appropriate scaffolds that allow the maintenance of the non-differentiated state of hDPSC cultures could be an interesting approach to optimize the potency of these stem cells, without a need for genetic modification. In this review, we describe and integrate findings that shed light on the mechanisms responsible for stemness maintenance of hDPSCs, and how these are regulated by Notch/Wnt activation , drawing some interesting parallelisms with pluripotent stem cells. We summarize previous work on the stem cell field that includes interactions between epigenetics, metabolic regulations, and pluripotency core factor expression in hDPSCs and other stem cell types.
... The dependence of cellular reprogramming on metabolic reprogramming and linkage to epithelial mesenchymal transition (EMT) has also been reviewed here in brief. Cell growth and proliferation is dependent on metabolism [19,20]. The entire process of metabolic reprogramming is dependent upon many factors and processes, or pathways, referred to as 'stages' in the present manuscript, affected by dietary components. ...
