Mitochondrial permeability transition increases reactive oxygen species production and induces DNA fragmentation in human spermatozoa

Treulén, Favián; Uribe, Pamela; Boguen, Rodrigo; Villegas, Jaime Eduardo Bernal

doi:10.1093/humrep/dev015

Cited by 67 publications

(55 citation statements)

References 59 publications

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“…This technique has been used to evaluate mPTP opening in different cells and pathological situations 25–29 but also to investigate the regulation of the pore. Different biophysical methods or pharmacological agents modulating oxidative stress or Ca 2+ fluxes have been used to induce mPTP opening 25, 30, 31 .…”

Section: Discussionmentioning

confidence: 99%

Ca2+ ionophores are not suitable for inducing mPTP opening in murine isolated adult cardiac myocytes

Panel

Ghaleh

Morin

2017

Sci Rep

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Opening of the mitochondrial permeability transition pore (mPTP) plays a major role in cell death during cardiac ischaemia-reperfusion. Adult isolated rodent cardiomyocytes are valuable cells to study the effect of drugs targeting mPTP. This study investigated whether the use of Ca2+ ionophores (A23187, ionomycin and ETH129) represent a reliable model to study inhibition of mPTP opening in cardiomyocytes. We monitored mPTP opening using the calcein/cobalt fluorescence technique in adult rat and wild type or cyclophilin D (CypD) knock-out mice cardiomyocytes. Cells were either treated with Ca2+ ionophores or subjected to hypoxia followed by reoxygenation. The ionophores induced mPTP-dependent swelling in isolated mitochondria. A23187, but not ionomycin, induced a decrease in calcein fluorescence. This loss could not be inhibited by CypD deletion and was explained by a direct interaction between A23187 and cobalt. ETH129 caused calcein loss, mitochondrial depolarization and cell death but CypD deletion did not alleviate these effects. In the hypoxia-reoxygenation model, CypD deletion delayed both mPTP opening and cell death occurring at the time of reoxygenation. Thus, Ca2+ ionophores are not suitable to induce CypD-dependent mPTP opening in adult murine cardiomyocytes. Hypoxia-reoxygenation conditions appear therefore as the most reliable model to investigate mPTP opening in these cells.

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Section: Discussionmentioning

confidence: 99%

Ca2+ ionophores are not suitable for inducing mPTP opening in murine isolated adult cardiac myocytes

Panel

Ghaleh

Morin

2017

Sci Rep

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“…Considering that damage produced by ROS can occur during germ cell development and even though mitochondria are compartmentalized organelles, an increased ROS production has been associated with sperm mitochondrial membrane permeabilization, which is accompanied by mitochondrial membrane potential dissipation, uncoupling of oxidative phosphorylation, failure to synthesize ATP and OS, culminating in oxidative DNA adduct formation, DNA strand breakage, and cell death (Oyeyipo et al, 2011;Aitken et al, 2012;Galluzzi et al, 2012;Marchetti et al, 2012;Abdul-Ghani et al, 2014;La Maestra et al, 2015;Yousefniapasha et al, 2015). Treulen et al (2015) proposed that the mitochondrial permeability transition, because of pores opening in sperm inner mitochondrial membrane, is an important mechanism of ROS overproduction and DNA fragmentation.…”

Section: (A) (B) (C) (D) (E)mentioning

confidence: 99%

Late reproductive analysis in rat male offspring exposed to nicotine during pregnancy and lactation

et al. 2016

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SUMMARYWe previously observed that nicotine, administered to rats (Wistar) during pregnancy and lactation periods, provokes, in the progeny, late morphofunctional alterations in Leydig cell, body weight increase in adulthood (90 days post partum, dpp) as well as seminiferous epithelium injury. Aiming to investigate whether the spermatogenic damage previously observed in adult progenies from pregnant and lactating nicotine-exposed rat dams are maintained or whether it is worsened in older rats, we analyzed the morphological testicular alterations after up to two complete periods of spermatogenesis (53 days each), spermatic parameters, and sperm DNA fragmentation. Pregnant and lactating rats were nicotine-exposed (2 mg/kg/day) through an osmotic minipump implanted on the first day of pregnancy and replaced after birth. Absolute Control (no minipump) and Sham Control (minipump without nicotine) groups were established. The offspring were killed at 90, 143, and 196 dpp. Significant alterations in morphometric and stereological testicular parameters, such as concentration of sperm number, daily sperm production, and plasma and intratesticular levels of cholesterol and testosterone were not observed in nicotine-exposed rats. Testicular histopathological analysis showed small intraepithelial vacuolization and an accentuated germ cell desquamation in exposed rats. However, the offspring from nicotine-exposed dams exhibited higher frequency of morphologically abnormal spermatozoa and lower sperm motility in comparison with control groups. In addition, nicotine-exposed groups showed a significant reduction in sperm mitochondrial activity and an increased sperm DNA fragmentation (Comet assay). These results indicate a late reproductive damage in the male progeny caused by maternal nicotine exposure, related to the decrease in sperm quality.

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“…When mitochondria are damaged, a major outcome is the overproduction of mitochondrial reactive oxygen species (mROS), which then elevates the level of total cellular ROS. Excessive ROS can cause severe oxidative damages to spermatozoa membranes and DNA [14,16], leading to lowered integrity of these subcellular components, impaired spermatozoa motility, and subsequent infertility [8,16,17]. Spermatozoa motility is considered the earliest and most sensitive indicator of spermatozoa oxidative damage [17].…”

Section: Introductionmentioning

confidence: 99%

UCP2 Mitigates the Loss of Human Spermatozoa Motility by Promoting mROS Elimination

Wang

Hua

Huang

et al. 2018

Cell Physiol Biochem

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Background/Aims: To demonstrate the function of uncoupling protein 2 (UCP2) in the regulation of human spermatozoa motility. Methods: Semen samples were collected from donors with either normal spermatozoa motility (normospermia [NS]) or poor spermatozoa motility (asthenospermia [AS]). UCP2 protein in spermatozoawas quantified by Western blotting. The level of mitochondrial reactive oxygen species (mROS) was evaluated by MitoSOX Red. The activity of mitochondrial membrane potential (MMP) in spermatozoa was evaluated by a JC-1 assay and the ATP level was monitored by a luciferin-luciferase assay. Results: UCP2 was expressed in both NS and AS groups, with the former exhibiting a higher level than the latter. Immunofluorescence analysis shows that UCP2 is mainly located at the mid-region of human spermatozoa. The inhibition of UCP2 by a highly selective inhibitor, Genipin, results in not only impaired spermatozoa mobility (P<.05) but also an elevated level of mROS (P<.05), suggesting that UCP2 is involved in the maintenance of the spermatozoa mobility, which probably is achieved by promoting mROS elimination. Furthermore, H₂O₂ treatment of spermatozoa increases the mROS level coupled with the loss of spermatozoa mobility. Unexpectedly, this treatment also has a positive impact on the expression of UCP2 within a certain range of supplemental H₂O₂, indicating the moderate mROS level possibly serves as a feedback signal to stimulate the expression of UCP2. Finally, the treatment of spermatozoa by an ROS scavenger, N-acetyl-l-cysteine (NAC),decreases the level of mROS and increases the curvilinear velocity (VCL) of spermatozoa, but the UCP2 level is not affected. Conclusion: These results suggest an UCP2–mROS–motility regulatory system exists for maintaining spermatozoa mobility in humans. In such a system, UCP2 fulfills its function by promoting mROS elimination, and slightly over-produced mROS in turn serves as a signal to stimulates the expression of UCP2. This regulatory system represents a new potential target for the discovery of novel pharmaceuticals for the treatment of patients with low spermatozoa motility.

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Mitochondrial permeability transition increases reactive oxygen species production and induces DNA fragmentation in human spermatozoa

Abstract: This study was funded by grant DI12-0102 from the Universidad de La Frontera (J.V.V.) and a doctoral scholarship from CONICYT Chile (F.T.). The authors disclose no potential conflicts of interest.

Cited by 67 publications

References 59 publications

Ca2+ ionophores are not suitable for inducing mPTP opening in murine isolated adult cardiac myocytes

Ca2+ ionophores are not suitable for inducing mPTP opening in murine isolated adult cardiac myocytes

Late reproductive analysis in rat male offspring exposed to nicotine during pregnancy and lactation

UCP2 Mitigates the Loss of Human Spermatozoa Motility by Promoting mROS Elimination

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