Mitochondrial NAD(P)<sup>+</sup>Transhydrogenase: From Molecular Features to Physiology and Disease

Francisco, Annelise; Figueira, Tiago Rezende; Castilho, Roger F.

doi:10.1089/ars.2021.0111

Cited by 21 publications

(17 citation statements)

References 166 publications

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“…All the available biochemical, experimental, and clinical data leads us to believe that, in the present case, severe and chronic oxidative stress in the germ cells was the main factor responsible for the azoospermia [33]. We cannot, however, rule out an aggravating effect of obesity, probably by participating itself to oxidative imbalance.…”

Section: Discussionmentioning

confidence: 54%

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Testicular impairment in Primary Adrenal Insufficiency caused by Nicotinamide Nucleotide Transhydrogenase (NNT) deficiency - a case report: implication of oxidative stress and importance of fertility preservation

Ferreux

Boumerdassi

Dulioust

et al. 2023

Basic Clin. Androl.

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Introduction Nicotinamide nucleotide transhydrogenase (NNT) gene deficiency has recently been shown to be involved in Primary Adrenal Insufficiency (PAI). NNT encodes an inner mitochondrial membrane protein that produces large amounts of NADPH. NADPH is used in several biosynthesis pathways and the oxidoreduction of free radicals by the glutathione and thioredoxin systems in mitochondria. Patients with PAI due to NNT deficiency may also exhibit extra-adrenal manifestations, usually including gonadal impairment. Case report We present the case of a 35-year-old patient referred to our center for primary infertility with non-obstructive azoospermia, in a context of PAI and obesity. PAI genetic exploration carried out at the age of thirty revealed NNT deficiency due to the presence of two deleterious mutations (one on each allele) in the NNT gene. Scrotal ultrasound revealed a right Testicular Adrenal Rest Tumor (TART). Intensification of glucocorticoid therapy over the course of 8 months failed to reduce the TART volume or improve sperm production and endocrine function. No spermatozoa were found after surgical exploration of both testes, and subsequent histopathological analysis revealed bilateral Sertoli cell-only syndrome. A retrospective review of the hypothalamic-pituitary-gonadic axis hormonal assessment over 20 years showed progressive impairment of testicular function, accelerated during adulthood, leading to hypergonadotropic hypogonadism and non-obstructive azoospermia when the patient reached his thirties, while the PAI remained controlled over the same period. Conclusion This case report provides, for the first time, direct evidence of complete germ line loss in an azoospermic man with NNT deficiency. Additional data further support the hypothesis of a determinant role of oxidative cellular damage due to reactive oxygen species (ROS) imbalance in the severe gonadal impairment observed in this NNT-deficient patient. Early and regular evaluation of gonadal function should be performed in patients with PAI, especially with NNT deficiency, as soon as the patients reach puberty. Fertility preservation options should then be provided in early adulthood for these patients.

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Section: Discussionmentioning

confidence: 54%

“…This important difference may be due to the fact that distinct impairment mechanisms predominate in each of these two cell types. To date, the pathophysiology of the abnormal gonadal phenotypes profile observed in patients with NNT loss of function mutations have yet to be elucidated [33].…”

Section: Discussionmentioning

confidence: 99%

Testicular impairment in Primary Adrenal Insufficiency caused by Nicotinamide Nucleotide Transhydrogenase (NNT) deficiency - a case report: implication of oxidative stress and importance of fertility preservation

Ferreux

Boumerdassi

Dulioust

et al. 2023

Basic Clin. Androl.

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“…Despite the hepatic glucose uptake, hepatocyte glycogen content was significantly reduced in CSF1-Fc-treated mice, with the nadir coinciding with peak liver growth (Figure 3L,M). C57BL/6J mice have a null mutation in the nicotinamide nucleotide transhydrogenase (Nnt) gene which impacts many aspects of metabolism including adiposity and glucocorticoid production (reviewed in [27]). We therefore tested whether the CSF1-Fc response was mouse strain-specific.…”

Section: Csf1-fc Treatment Alters Glucose Metabolismmentioning

confidence: 99%

Reversible expansion of tissue macrophages in response to macrophage colony-stimulating factor (CSF1) transforms systemic metabolism to fuel liver growth

Keshvari,

Masson,

Ferrari-Cestari

et al. 2023

Preprint

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Background and Aim. Macrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1. Methods and Results. Acute administration of a CSF1-Fc fusion protein led to monocytosis, increased resident tissue macrophages in the liver and all major organs, and liver growth. These effects were associated with increased hepatic glucose uptake and extensive mobilisation of body fat. The impacts of CSF1 on macrophage abundance, liver size and body composition were rapidly reversed to restore homeostasis. The effects of CSF1 on metabolism were independent of several known endocrine regulators and did not impact the physiological fasting response. Analysis using implantable telemetry in metabolic cages revealed progressively reduced body temperature and physical activity with no change in diurnal food intake. Conclusion. These results demonstrate the existence of a dynamic equilibrium between CSF1, the mononuclear phagocyte system, metabolic regulation and homeostatic control of liver:body weight ratio.

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“…There are various mitochondrial enzymatic systems for generating the antioxidant capacity needed to manage/eliminate metabolism-generated ROS. Among the most important of these is the transhydrogenase complex (NNT) [ 81 , 89 , 90 , 91 , 92 ]. The NNT complex spans the inner mitochondrial membrane and exploits energy stored in the Mitchell/Moyle proton gradient to drive the transfer of reducing potential from NADH to NADPH.…”

Section: Detailed Description Of the Steps In The Lmrs Hypothesismentioning

confidence: 99%

Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas

Bingham,

Zachar

2023

IJMS

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We review extensive progress from the cancer metabolism community in understanding the specific properties of lipid metabolism as it is redesigned in advanced carcinomas. This redesigned lipid metabolism allows affected carcinomas to make enhanced catabolic use of lipids in ways that are regulated by oxygen availability and is implicated as a primary source of resistance to diverse treatment approaches. This oxygen control permits lipid catabolism to be an effective energy/reducing potential source under the relatively hypoxic conditions of the carcinoma microenvironment and to do so without intolerable redox side effects. The resulting robust access to energy and reduced potential apparently allow carcinoma cells to better survive and recover from therapeutic trauma. We surveyed the essential features of this advanced carcinoma-specific lipid catabolism in the context of treatment resistance and explored a provisional unifying hypothesis. This hypothesis is robustly supported by substantial preclinical and clinical evidence. This approach identifies plausible routes to the clinical targeting of many or most sources of carcinoma treatment resistance, including the application of existing FDA-approved agents.

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Mitochondrial NAD(P)⁺Transhydrogenase: From Molecular Features to Physiology and Disease

Cited by 21 publications

References 166 publications

Testicular impairment in Primary Adrenal Insufficiency caused by Nicotinamide Nucleotide Transhydrogenase (NNT) deficiency - a case report: implication of oxidative stress and importance of fertility preservation

Testicular impairment in Primary Adrenal Insufficiency caused by Nicotinamide Nucleotide Transhydrogenase (NNT) deficiency - a case report: implication of oxidative stress and importance of fertility preservation

Reversible expansion of tissue macrophages in response to macrophage colony-stimulating factor (CSF1) transforms systemic metabolism to fuel liver growth

Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas

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Mitochondrial NAD(P)+Transhydrogenase: From Molecular Features to Physiology and Disease

Cited by 21 publications

References 166 publications

Testicular impairment in Primary Adrenal Insufficiency caused by Nicotinamide Nucleotide Transhydrogenase (NNT) deficiency - a case report: implication of oxidative stress and importance of fertility preservation

Testicular impairment in Primary Adrenal Insufficiency caused by Nicotinamide Nucleotide Transhydrogenase (NNT) deficiency - a case report: implication of oxidative stress and importance of fertility preservation

Reversible expansion of tissue macrophages in response to macrophage colony-stimulating factor (CSF1) transforms systemic metabolism to fuel liver growth

Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas

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Mitochondrial NAD(P)⁺Transhydrogenase: From Molecular Features to Physiology and Disease