Dehydroepiandrosterone as an inducer of mitochondrial permeability transition

Correa, Francisco; Garcı́a, Noemı́; García, Gerardo; Chávez, Edmundo

doi:10.1016/j.jsbmb.2003.09.002

Cited by 16 publications

(11 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result indicated that the permeability of the mitochondrial membrane was significantly increased in primary Leydig cells treated with DHEA. Furthermore, this is consistent with a previous study, in which the ΔΨm declined following treatment of isolated kidney cortex mitochondria with high concentrations of DHEA ( 15 ). Shen et al ( 19 ) reported that mitochondrial membrane permeability was significantly increased in TM-3 cells following DHEA treatment.…”

Section: Discussionsupporting

confidence: 93%

“…In addition to metabolic regulation, mitochondria are also critical for modulating other cellular functions. Correa et al ( 15 ) demonstrated that DHEA inhibits malate-glutamate oxidation by blocking Site I electron transport in the respiratory chain, and induces mitochondrial swelling and transmembrane electrical gradient collapse in isolated rat kidney mitochondria. However, the mechanism of the effects of DHEA on mitochondrial function is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dehydroepiandrosterone inhibits cell proliferation and improves viability by regulating S phase and mitochondrial permeability in primary rat Leydig cells

Liu

Wang

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

Dehydroepiandrosterone (DHEA) is widely used as a nutritional supplement and exhibits putative anti-aging properties. However, the molecular basis of the actions of DHEA, particularly on the biological characteristics of target cells, remain unclear. The aim of the current study was to investigate the effects of DHEA on cell viability, cell proliferation, cell cycle and mitochondrial function in primary rat Leydig cells. Adult Leydig cells were purified by Percoll gradient centrifugation, and cell proliferation was detected using a Click-iT® EdU Assay kit and cell cycle assessment performed using flow cytometry. Mitochondrial membrane potential was detected using JC-1 staining assay. The results of the current study demonstrate that DHEA decreased cell proliferation in a dose-dependent manner, whereas it improved cell viability in a time-dependent and dose-dependent manner. Flow cytometry analysis demonstrated that DHEA treatment increased the S phase cell population and decreased the G2/M cell population. Cyclin A and CDK2 mRNA levels were decreased in primary rat Leydig cells following DHEA treatment. DHEA treatment decreased the transmembrane electrical gradient in primary Leydig cells, whereas treatment significantly increased succinate dehydrogenase activity. These results indicated that DHEA inhibits primary rat Leydig cell proliferation by decreasing cyclin mRNA level, whereas it improves cells viability by modulating the permeability of the mitochondrial membrane and succinate dehydrogenase activity. These findings may demonstrate an important molecular mechanism by which DHEA activity is mediated.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Dehydroepiandrosterone inhibits cell proliferation and improves viability by regulating S phase and mitochondrial permeability in primary rat Leydig cells

Liu

Wang

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…The increased permeability of the inner membrane to protons and other ions is the most common mechanism for mitochondrial toxicity [5]. Examples of agents initiating the 3 rd mechanism include dehydroepiandrosterone [39], Naproxen [40], oxygen radicals, intramitochondrial calcium [7], salicylic acid [41], and the neurotoxin MPP + [42]. Other drugs such as cyclosporine and Ro 68-3400 have the opposite effect by inhibiting MTP and preventing apoptosis [43], providing valuable tools for experimental studies of the MTP function and its control.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Drug-Associated Mitochondrial Toxicity and its Detection

Amacher¹

2005

CMC

View full text Add to dashboard Cite

Mitochondrial dysfunction is a fundamental mechanism in the pathogenesis of several significant toxicities in mammals, especially those associated with the liver, skeletal and cardiac muscle, and the central nervous system. These changes can also occur as part of the natural aging process and have been linked to cellular mechanisms in several human disease states including Parkinson's and Alzheimer's, as well as ischemic perfusion injury and the effects of hyperglycemia in diabetes mellitus. Our knowledge of the effects of xenobiotics on mitochondrial function has expanded to the point that chemical structure and properties can guide the pharmaceutical scientist in anticipating mitochondrial toxicity. Recognition that maintenance of the mitochondrial membrane potential is essential for normal mitochondrial function has resulted in the development of predictive cell-based or isolated mitochondrial assay systems for detecting these effects with new chemical entities. The homeostatic role of some uncoupling proteins, differences in mitochondrial sensitivity to toxicity, and the pivotal role of mitochondrial permeability transition (MPT) as the determinant of apoptotic cell death are factors that underlie the adverse effects of some drugs in mammalian systems. In order to preserve mitochondrial integrity in potential target organs during therapeutic regimens, a basic understanding of mitochondrial function and its monitoring in the drug development program are essential. Toward this end, this review focuses on two topics, (1) the specific effects of xenobiotics on mitochondrial structure and function and (2) a summarization of current methods for quantifying these changes in a preclinical toxicology laboratory.

show abstract

“…In the present study, the occurrence of MPT may be triggered by the oxidation of ROS generating from the mitochondria themselves. Furthermore, it has been suggested that mitochondrial membrane lipid peroxidation is also a regulator mediating the induction of MPT (Kristal et al 1996;Santos et al 1998;Correa et al 2003). Reactive products of lipid peroxidation such as malondialdehyde and 4-hydroxynonenal may form adducts with cystine or other residues in membrane protein sulfhydryls, thereby altering the conformation of MPTP (Esterbauer et al 1991).…”

Section: Discussionmentioning

confidence: 99%

Effects ofFusariumMycotoxin Butenolide on Myocardial Mitochondria In Vitro

Wang

Liu

Peng

2009

Toxicology Mechanisms and Methods

View full text Add to dashboard Cite

Fusarium mycotoxin toxicosis has been implicated in the etiology of Keshan disease, an endemic mitochondrial cardiomyopathy prevailing in certain areas of China. Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone) is one of the Fusarium mycotoxins which are frequently detected from cereal grains in endemic areas. A recent study indicates that this mycotoxin induces rat cardiotoxicity, but its effect on the myocardial mitochondria remains unclear. The present study is therefore undertaken to explore the toxic effect potential of butenolide on the myocardial mitochondria. Exposure of cultured cardiac myocytes to 50 microg/ml of butenolide provoked dissipation of mitochondrial membrane potential. Incubation of isolated rat myocardial mitochondria with butenolide of 100 microg/ml for 60 min resulted in mitochondrial swelling, indicating the occurrence of mitochondrial permeability transition. Furthermore, marked oxidative damage in myocardial mitochondria was observed after incubation of isolated myocardial mitochondria with butenolide ranging from 0 to 50 microg/ml for 60 min, as manifested by concentration-dependent increases in the production of thiobarbituric acid reactive substances, the indicator of lipid peroxidation. Contrarily, a representative antioxidant glutathione significantly alleviated this oxidative mitochondrial damage induced by butenolide. In conclusion, these observations clearly show that butenolide can induce dysfunction of myocardial mitochondria, and oxidative damage appears to play a crucial role in these deleterious effects. The present study supports the hypothesis that mycotoxin toxicosis is a probable etiological factor of Keshan disease, the mitochondrial cardiomyopathy.

show abstract

Dehydroepiandrosterone as an inducer of mitochondrial permeability transition

Cited by 16 publications

References 29 publications

Dehydroepiandrosterone inhibits cell proliferation and improves viability by regulating S phase and mitochondrial permeability in primary rat Leydig cells

Dehydroepiandrosterone inhibits cell proliferation and improves viability by regulating S phase and mitochondrial permeability in primary rat Leydig cells

Drug-Associated Mitochondrial Toxicity and its Detection

Effects ofFusariumMycotoxin Butenolide on Myocardial Mitochondria In Vitro

Contact Info

Product

Resources

About