Inhibiting Sperm Pyruvate Dehydrogenase Complex and Its E3 Subunit, Dihydrolipoamide Dehydrogenase Affects Fertilization in Syrian Hamsters

Siva, Archana Bharadwaj; Subbarayalu, Panneerdoss; Sailasree, Purnima; Singh, Durgesh Kumar; Kameshwari, Duvurri B.; Shivaji, Sisinthy

doi:10.1371/journal.pone.0097916

Cited by 11 publications

(12 citation statements)

References 49 publications

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“…Low expression levels of Aco2 were reported in human sperm with reduced motility [111], and higher levels during mice sperm capacitation [112]. Deficiency of Dld mature protein was associated with low sperm motility in humans [113], while enzymes of this complex were also related to sperm capacitation and the acrosome reaction in the hamster and humans [114][115]. The higher expression of such proteins in might result in higher ATP production and a fitness advantage under certain ecological and environmental conditions (see section 4.3).…”

Section: Mitochondrial Proteins Linked To Energy Production and Antiomentioning

confidence: 99%

RNA-seq coupled to proteomic analysis reveals high sperm proteome variation between two closely related marine mussel species

Romero

Pérez‐Figueroa

Carrera

et al. 2019

Journal of Proteomics

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Model systems for the study of fertilization include marine invertebrates with external fertilisation, such as abalones, sea urchins and mussels, because of the ease with which large quantities of gametes released into seawater can be collected after induced spawning. Unlike abalones and sea urchins, hybridisation has been reported between mussels of different Mytilus spp., which thus makes them very appealing for the study of reproductive isolation at both pre- and postzygotic levels. There is a lack of empirical proteomic studies on sperm samples comparing different Mytilus species, which could help to advance this study. A comparative analysis of sperm proteomes across different taxa may provide important insights into the fundamental molecular processes and mechanisms involved in reproductive isolation. It might also contribute to a better understanding of sperm function and of the adaptive evolution of sperm proteins in different taxa. There is now growing evidence from genomics studies that multiple protein complexes and many individual proteins might have important functions in sperm biology and the fertilisation process. From an applied perspective, the identification of sperm-specific proteins could also contribute to the improved understanding of fertility problems and as targets for fertility control.

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Section: Mitochondrial Proteins Linked To Energy Production and Antiomentioning

confidence: 99%

RNA-seq coupled to proteomic analysis reveals high sperm proteome variation between two closely related marine mussel species

Romero

Pérez‐Figueroa

Carrera

et al. 2019

Journal of Proteomics

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“…It should be noted that MICA inhibition of the conversion of pyruvate to acetyl-CoA occurs not only just in the liver but also in many other tissues such as adipose, testis, brain, and kidney. 5 , 12 , 19 , 20 The establishment that MICA inhibits DLDH is based on the evidence that the cofactor lipoic acid instead of other cofactors such as thiamine and thiamine pyrophosphate can reverse MICA inhibition of DLDH. 14 …”

Section: -Methoxyindole-2-carboxylic Acid As a Hypoglycemic Agentmentioning

confidence: 99%

“…Since then, the property of MICA as a hypoglycemic agent has never been evaluated again, and most studies involving the use of MICA have been focused on its function as a DLDH inhibitor. 20 , 23 , 24 It should be pointed out that in this short and limited study that tested the hypoglycemic effect of MICA on diabetic Chinese hamsters, only one dosage and one means of MICA administration (via gavage) were tested. 22 It should also be noted that this single study was very limited in scope and probably also dampened any further interest in studying MICA as a therapeutic drug for diabetes.…”

Section: Mica’s Metabolic Effects and Mortality Rate In One Diabetic mentioning

confidence: 99%

“…Additionally, as MICA targets nearly all tissues in the body and has a variety of effects on protein expression and cellular pathways in numerous experimental settings or disease models, 4 , 5 , 12 , 15 , 20 , 25 – 27 its potential effect on pancreatic β-cell function and insulin secretion in the context of diabetes should also be investigated. Moreover, a comprehensive evaluation of MICA on glucose metabolism, in particular, gluconeogenesis in cultured hepatocytes should also be performed.…”

Section: Perspectivesmentioning

confidence: 99%

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Reexploring 5-methoxyindole-2-carboxylic acid (MICA) as a potential antidiabetic agent

2018

DMSO

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5-Methoxyindole-2-carboxylic acid (MICA) is a potent hypoglycemic agent that inhibits gluconeogenesis in the liver. It is also a well-known inhibitor of mitochondrial dihydrolipoamide dehydrogenase. MICA was extensively studied in the 1960s and 1970s and was once tested for its antidiabetic effect in diabetic Chinese hamsters, whereby MICA was shown to exhibit pronounced glucose-lowering ability while also leading to increased rate of death of the diabetic animals. Since then, MICA’s potential ability in lowering blood glucose in diabetes has never been revisited. In my opinion, MICA should be comprehensively reexplored for its antidiabetic properties in a variety of rodent diabetes models. For a given animal model, its dose-dependent effect and the effects of different routes of administrations as well as its synergistic effects with other glucose-lowering drugs should also be investigated. More studies in the future on this chemical may provide novel insights into its role as an antidiabetic agent.

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“…In this study we used a chemical inhibitor of DLD known as 5-methoxyindole-2-carboxylic acid (MICA) [479] to determine whether it also could alleviate Aβ toxicity in C. elegans that express human Aβ.…”

Section: Introductionmentioning

confidence: 99%

Metabolic study of Alzheimer’s disease using mutant C. elegans

Ahmad¹

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Alzheimer's disease (AD) is associated with chronic neurodegeneration and is the cause of the most common form of dementia. The main hallmarks of AD are aggregates of amyloid beta (Aβ) and formation of hyperphosphorylated tau neurofibrillary tangles (NFTs). Unfortunately, after more than 100 years of research the exact cause(s) and mechanisms involved in AD progression remain unclarified. Evidence indicates that impaired mitochondrial bioenergetics may precede by decades, the neurodegeneration and cognitive decline associated with AD. Moreover, a genetic association of the core metabolic enzyme dihydrolipoamide dehydrogenase (DLD) with late-onset AD and reduced activity of DLD-containing enzymes suggests glucose hypo-metabolism as a possible cause of AD. Contrary to this, improvements of AD symptoms under caloric restriction or other means of reducing-glucose dependent energy metabolism supports an alternative hypothesis that a decrease in glucose metabolism may be protective. In the present study, we used mutant Caenorhabditis elegans (C. elegans) to investigate the effect of glucose metabolism on AD progression. We initially looked at the role of suppressed DLD-1, and then we focused on the effect of high glucose in AD pathogenesis.Transgenic expression of Aβ in C. elegans causes both phenotypic and behavioral defects and results in accumulation of toxic Aβ oligomers, culminating in protein aggregation as is normally associated with AD pathophysiology. Aβ expression in worm muscle causes agedependent progressive paralysis and impaired acetylcholine neurotransmission while neuronal Aβ expression results in defective chemotaxis and impaired serotonin sensitivity as well as reduced fecundity and egg hatching. Suppression of the dld-1 gene alleviated paralysis, improved acetylcholine neurotransmission, enhanced chemotaxis and restored normal sensitivity to serotonin.dld-1 gene suppression also protects vitality as indicated by improved fecundity and egg hatching.Interestingly, protective effects of dld-1 suppression could be reversed using the calcium ionophore (CaI), indicating that the protective mechanism involves calcium signaling. Each of these beneficial effects of dld-1 gene suppression could be mimicked using a specific, small molecule inhibitor of the DLD-1 enzyme, 5-methoxyindole-2-carboxylic acid (MICA).High glucose levels are associated with the metabolic disorder, diabetes, which is a major risk factor for AD. In fact, it has been suggested that AD is a neural form of diabetes, type 3 diabetes. If true, drugs used to treat diabetes could act as possible treatments for AD. In this study, I investigated the effect of elevated glucose, the glucose metabolism inhibitor, 2-deoxy-d-glucose ii (2DOG) as well as the anti-diabetes drugs, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on AD progression. Elevated glucose in the growth medium induced hyperactivity, which interfered with the paralysis assays, but it was seen to impair cholinergic neurotransmission, egg laying and hatc...

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Inhibiting Sperm Pyruvate Dehydrogenase Complex and Its E3 Subunit, Dihydrolipoamide Dehydrogenase Affects Fertilization in Syrian Hamsters

Cited by 11 publications

References 49 publications

RNA-seq coupled to proteomic analysis reveals high sperm proteome variation between two closely related marine mussel species

RNA-seq coupled to proteomic analysis reveals high sperm proteome variation between two closely related marine mussel species

Reexploring 5-methoxyindole-2-carboxylic acid (MICA) as a potential antidiabetic agent

Metabolic study of Alzheimer’s disease using mutant C. elegans

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