A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (<i>PDP1</i>) causing pyruvate dehydrogenase complex deficiency

Bedoyan, Jirair K.; Hecht, Leah; Zhang, Shulin; Tarrant, Stacey; Bergin, Ann M.; Demirbas, Didem; Yang, Edward; Shin, Ha Kyung; Grahame, George; DeBrosse, Suzanne D.; Hoppel, Charles L.; Kerr, Douglas S.; Berry, Gerard T.

doi:10.1002/jmd2.12054

Cited by 10 publications

(9 citation statements)

References 43 publications

(71 reference statements)

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“…The mitochondrial pyruvate dehydrogenase complex is crucial for glucose homeostasis in mammalian cells, as it plays a crucial role in the fate of pyruvate, converting pyruvate to acetyl coenzyme A. The upregulation of PDP1 and PDP2 leads to hyperphosphorylation and the inhibition of pyruvate dehydrogenase complex activity and the ratio of pyruvate inversion to acetyl coenzyme A and the level of lactate catalyzed by lactate dehydrogenase (Maj et al, 2006; Bedoyan et al, 2019; Sugden & Holness, 2006). Moreover, in this study, the expression levels of LDHB and MCT4 , which participate in pyruvate conversion to lactate and transport across the plasma membrane, were downregulated by corticosterone.…”

Section: Discussionmentioning

confidence: 99%

Dysfunction in Sertoli cells participates in glucocorticoid‐induced impairment of spermatogenesis

Ren

Zhang

Xin

et al. 2021

Molecular Reproduction Devel

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The effect of stress on male fertility is a widespread public health issue, but less is known about the related signaling pathway. To investigate this, we established a hypercortisolism mouse model by supplementing the drinking water with corticosterone for four weeks. In the hypercortisolism mice, the serum corticosterone was much higher than in the control, and serum testosterone was significantly decreased. Moreover, corticosterone treatment induced decrease of sperm counts and increase of teratozoospermia. Increased numbers of multinucleated giant cells and apoptotic germ cells as well as downregulated meiotic markers suggested that corticosterone induced impaired spermatogenesis. Further, upregulation of macrophage‐specific marker antigen F4/80 as well as inflammation‐related genes suggested that corticosterone induced inflammation in the testis. Lactate content was found to be decreased in the testis and Sertoli cells after corticosterone treatment, and lactate metabolism‐related genes were downregulated. In vitro phagocytosis assays showed that the phagocytic activity in corticosterone‐treated Sertoli cells was downregulated and accompanied by decreased mitochondrial membrane potential, while pyruvate dehydrogenase kinase‐4 inhibitor supplementation restored this process. Taken together, our results demonstrated that dysfunctional phagocytosis capacity and lactate metabolism in Sertoli cells participates in corticosterone‐induced impairment of spermatogenesis.

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Section: Discussionmentioning

confidence: 99%

Dysfunction in Sertoli cells participates in glucocorticoid‐induced impairment of spermatogenesis

Ren

Zhang

Xin

et al. 2021

Molecular Reproduction Devel

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“…Активность аэробной реакции лактатдегидрогеназы определяет уровень синтеза пирувата, который может затем транспортироваться в митохондриальный компартмент, где он полностью окисляется в цикле трикарбоновых кислот в процессе аэробного дыхания клеток [2,14]. В связи с этим у пациентов с рецидивом болезни Грейвса, во-первых, может возрастать уровень лактата, что приводит к изменению функциональной активности клеток [15], и, во-вторых, снижение активности аэробного дыхания также приведет к изменению реактивности лимфоцитов [4]. При этом ингибирование Г3ФДГ также вносит отрицательный вклад в поддержание интенсивности субстратного потока по гликолизу, так как данный фермент осуществляет перенос продуктов липидного катаболизма на окислительно-восстановительные реакции гликолиза [2].…”

Section: Discussionunclassified

The activity of NAD- and NAD(P)-dependent dehydrogenases in lymphocytes of peripheral blood in Graves’ disease

Dudina

Савченко

Догадин

et al. 2020

Probl Endokrinol (Mosk)

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Background. The regulatory effect of thyroid hormones on the metabolism of the immune system cells (activation of oxidative processes, separation of oxidative phosphorylation and increased protein synthesis) depends on their number. Changes in the activity of intracellular enzymes in Graves' disease (GD) can determine the mechanisms of maintaining autoimmune inflammation in relapse of the disease. The exact role of NAD(P)-dependent dehydrogenases in the development and maintenance of immune response in GD is still poorly investigated. Aims - to study the activity of NAD(P)-dependent dehydrogenases in lymphocytes of peripheral blood in patients with manifestation and relapse of GD. Materials and methods. A single-center, cohort, prospective, continuous, observational, open-label, controlled trial was conducted to evaluate the lymphocytes NAD(P)-dependent activity in 151 women with GD and hyperthyroidism, mean age 40,713,2, 52 (37,14%), who were on follow-up at the endocrinology center of Krasnoyarsk Regional clinical hospital from 2016 to 2019. The NAD(P)-dependent dehydrogenases activity measured using biochemiluminescence method. Results. In patients with newly diagnosed of GD, relative to the control values and levels detected in relapse group we observe the increase of G6PDH and decrease of NADH-LDH. In GD relapse group compare to the control range in blood lymphocytes decreases the activity of LDH and NADP-ICDH. In patients with newly diagnosed GD, two positive сorrelation were found: between fT3 level and MDG activity (r=0.90, p=0.037), and between fT4 level and NADP-ICDH activity (r=0.82, p=0.007). In patients with relapse of GD positive relationships between the concentration of TSH and the activity of LDH (r=0.73, p=0.039), and MDH (r=0.93, p=0.002), as well as in a pair of fT4 and NADGDH (r=0.70, p=0.036) were revealed. Conclusion. Changes in the activity of NAD(P)-dependent dehydrogenases in different clinical variants of GD can serve as a fundamentals for further immunological studies to analyze the relationship between the mechanisms of autotolerance loss with the functional and metabolic characteristics of immune cells that determine the level of immunological tension in the manifestation of thyrotoxicosis due to GD, as well as in the prognosis of the disease remission during long-term thyrostatic therapy.

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“…PDP1 localises to the mitochondrial matrix, where it catalyses the dephosphorylation of pyruvate dehydrogenase, thus activating it ( Lawson et al, 1993 ; Maj et al, 2006 ). Variants in PDP1 can cause pyruvate dehydrogenase complex deficiency, a heterogeneous mitochondrial disorder with varying phenotypes, such as fatal infantile lactic acidosis, chronic neurological dysfunction, and intermittent ataxia ( Maj et al, 2006 ; Cameron et al, 2009 ; Bedoyan et al, 2019 ). So far, three homozygous mutations that cause pyruvate dehydrogenase complex deficiency have been identified in PDP1 : a 3-bp-deletion leading to deletion of leucine 213, a G-T transversion leading to a premature stop codon at amino acid 93, and a 1-bp-duplication at base pair 575, leading to a premature stop codon at amino acid 192 ( Figure 5 ).…”

Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

The role of serine/threonine phosphatases in human development: Evidence from congenital disorders

Vaneynde

Verbinnen²,

Janssens³

2022

Front. Cell Dev. Biol.

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Reversible protein phosphorylation is a fundamental regulation mechanism in eukaryotic cell and organismal physiology, and in human health and disease. Until recently, and unlike protein kinases, mutations in serine/threonine protein phosphatases (PSP) had not been commonly associated with disorders of human development. Here, we have summarized the current knowledge on congenital diseases caused by mutations, inherited or de novo, in one of 38 human PSP genes, encoding a monomeric phosphatase or a catalytic subunit of a multimeric phosphatase. In addition, we highlight similar pathogenic mutations in genes encoding a specific regulatory subunit of a multimeric PSP. Overall, we describe 19 affected genes, and find that most pathogenic variants are loss-of-function, with just a few examples of gain-of-function alterations. Moreover, despite their widespread tissue expression, the large majority of congenital PSP disorders are characterised by brain-specific abnormalities, suggesting a generalized, major role for PSPs in brain development and function. However, even if the pathogenic mechanisms are relatively well understood for a small number of PSP disorders, this knowledge is still incomplete for most of them, and the further identification of downstream targets and effectors of the affected PSPs is eagerly awaited through studies in appropriate in vitro and in vivo disease models. Such lacking studies could elucidate the exact mechanisms through which these diseases act, and possibly open up new therapeutic avenues.

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A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency

Cited by 10 publications

References 43 publications

Dysfunction in Sertoli cells participates in glucocorticoid‐induced impairment of spermatogenesis

Dysfunction in Sertoli cells participates in glucocorticoid‐induced impairment of spermatogenesis

The activity of NAD- and NAD(P)-dependent dehydrogenases in lymphocytes of peripheral blood in Graves’ disease

The role of serine/threonine phosphatases in human development: Evidence from congenital disorders

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