Crosstalk between mitochondrial metabolism and oxidoreductive homeostasis: a new perspective for understanding the effects of bioactive dietary compounds.

Mitochondria play an important role in a number of fundamental cellular processes, including energy production, biosynthetic pathways and cellular oxidoreductive homeostasis (redox status), and their dysfunction can lead to numerous pathophysiological consequences. As the biochemical mechanisms orchestrating mitochondrial metabolism and redox homeostasis are functionally linked, mitochondria have been identified as a potential therapeutic target. Consequently, considerable effort has been made to evaluate the efficacy of natural compounds that modulate mitochondrial function. Molecules produced by plants (for example, polyphenols and isothiocyanates) have been shown to modulate mitochondrial metabolism/biogenesis and redox status; however, despite the existence of a functional link, few studies have considered the combined efficacy of these mitochondrial functions. The present review provides a complete overview of the molecular pathways involved in modulating mitochondrial metabolism/biogenesis and redox status. Crosstalk between these critical mechanisms is also discussed, whilst major data from the literature regarding their antioxidant abilities are described and critically analysed. We also provide a summary of recent evidence regarding the ability of several plant-derived compounds to target these mitochondrial functions. An in-depth understanding of the functional link between mitochondrial metabolism/biogenesis and redox status could facilitate the analysis of the biological effects of natural compounds as well as the development of new therapeutic approaches.

Herbicides glyphosate and glufosinate ammonium negatively affect human sperm mitochondria respiration efficiency.

The widespread cultivation of genetically modified organisms (GMOs) led to a widespread use of selective herbicides to which GMOs are resistant, thus increasing the concern about human exposure to them. Glyphosate (GLY) and glufosinate ammonium (GA), the active principles of the main formulations, have been investigated for their effects on human health, mainly cancer and reproductive toxicity. However, little is known about their effects on the molecular mechanisms related to sperm quality. To investigate the effects of GLY and GA on mitochondrial respiration efficiency, we took advantage of our already established ex vivo human sperm mitochondria assay. Since spermatozoa are highly regulated by sex steroids, we tested at first testosterone (T), di-hydroxytestosterone (DHT), 17ß-estradiol (E2) and progesterone (P4). Then, we tested the effects of GLY and GA and of the hormone-like flavonoid quercetin (QRC) in a dose-dependent manner. The 0.1-1000 nM concentration range has been considered because it covers both the sexual hormones physiologically relevant concentrations (10 nM), triggering endogenously hormone-dependent signaling pathways, and the estimated (nM range) QRC dietary intake. Subsequently, co-incubation experiments were carried out with the two herbicides in the presence of 10 nM of each sex steroid and QRC. We found that: i) DHT and QRC are able to significantly reduce mitochondrial functionality at concentrations ≥ 10 nM; ii) GLY and GA negatively affect mitochondrial respiration efficiency; iii) in the presence of 10 nM DHT, the negative effect of GLY was increased; iiii) DHT, QRC and GA target mitochondria by using a mechanism different from GLY.

Modulation of Human Sperm Mitochondrial Respiration Efficiency by Plant Polyphenols.

Plant bioactives, such as polyphenols, can differentially affect (positively or negatively) sperm quality, depending on their concentration. These molecules have been proposed as natural scavengers of reactive oxygen species (ROS) for male infertility treatment. However, few data are available about their effects on the molecular mechanisms related to sperm quality and, in particular, to sperm mitochondrial function. We investigated the effects of quercetin, naringenin, genistein, apigenin, luteolin, and resveratrol at the concentration of 0.1-1000 nM on mitochondrial respiration efficiency. Upon chemical exposure, spermatozoa were swollen in a hypotonic solution and used for polarographic assays of mitochondrial respiration. All tested compounds, except for apigenin, caused a significant increase in the mitochondrial respiration efficiency at the concentration of 0.1 nM, and a significant decrease starting from concentrations of 10 nM. The analysis of oxygen consumption rate in the active and in the resting state of mitochondrial respiration suggested different mechanisms by which the tested compounds modulate mitochondrial function. Therefore, by virtue of their ability to stimulate the respiration active state, quercetin, genistein, and luteolin were found to improve mitochondrial function in asthenozoospermic samples. Our results are relevant to the debate on the promises and perils of natural antioxidants in nutraceutical supplementation.

Centrifugation Force and Time Alter CASA Parameters and Oxidative Status of Cryopreserved Stallion Sperm.

Conventional sperm selection techniques used in ARTs rely on centrifugation steps. To date, the different studies reported on the effects of centrifugation on stallion sperm motility provided contrasting results and do not include effects on mitochondrial functionality and different oxidative parameters. The effects of different centrifugation protocols (300 ×g for 5', 300 ×g for 10', 1500 ×g for 5' and 1500 ×g for 10' vs no centrifugation) on motility and oxidative status in cryopreserved stallion sperm, were analyzed. After centrifugation, almost all motility parameters were significantly altered, as observed by computer-assisted sperm analysis. A polarographic assay of oxygen consumption showed a progressive decrease in mitochondria respiration from the gentlest to the strongest protocol. By laser scanning confocal microscopy, significant reduction of mitochondrial membrane potential, at any tested protocol, and time-dependent effects, at the same centrifugal force, were found. Increased DNA fragmentation index at any tested protocol and time-dependent effects at the same centrifugal force were found, whereas increased protein carbonylation was observed only at the strongest centrifugal force. These results provide more comprehensive understandings on centrifugation-induced effects on cryopreserved stallion sperm and suggest that, even at a weak force for a short time, centrifugation impairs different aspects of equine sperm metabolism and functionality.

Metabolic reprogramming in breast cancer results in distinct mitochondrial bioenergetics between luminal and basal subtypes.

Mitochondrial dysfunction is a key feature of cancer and is frequently associated with increased aggressiveness and metastatic potential. Recent evidence has brought to light a metabolic rewiring that takes place during the epithelial-to-mesenchymal transition (EMT), a process that drives the invasive capability of malignant tumors, and highlights a mechanistic link between mitochondrial dysfunction and EMT that has been only partially investigated. In this study, we characterized mitochondrial function and bioenergetic status of cultured human breast cancer cell lines, including luminal-like and basal-like subtypes. Through a combination of biochemical and functional studies, we demonstrated that basal-like cell lines exhibit impaired, but not completely inactive, mitochondrial function, and rely on a consequent metabolic switch to glycolysis to support their ATP demand. These altered metabolic activities are linked to modifications of key electron transport chain proteins and a significant increase in levels of reactive oxygen species compared to luminal cells. Furthermore, we observed that the stable knockdown of EMT markers caused functional changes in mitochondria that result in acquisition of a hybrid glycolysis/OXPHOS phenotype in cancer cells as a means to sustain their metabolic demand.

Prunus Mahaleb Fruit Extract Prevents Chemically Induced Colitis and Enhances Mitochondrial Oxidative Metabolism via the Activation of the Nrf2 Pathway.

SCOPE: Polyphenols exhibit their antioxidant activity downstream the activation of the nuclear factor erythroid 2-related factor 2 pathway (Nrf2), but the connection between lipid metabolism and the Nrf2 pathway is still unknown. Flavonoid-rich concentrated extract from Prunus mahaleb (mahaleb concentrated fruit extract; MCFE) may act on oxido-reductive homeostasis and hepatic lipid metabolism via Nrf2. METHODS & RESULTS: MCFE ability to enhance the activity of Nrf2-mediated antioxidant/detoxifying enzymes is investigated in liver and colon of BALB/c mice. After a 4-week supplementation, macroscopic, histological, and biochemical signs of colitis are examined in mouse colon pulsed with 5% (w/v) dextran sodium sulfate (DSS). Untreated or DSS-supplemented mice are used as negative or positive control. MCFE effect on liver lipid metabolism and its possible link with the Nrf2 pathway is investigated. MCFE intake increases antioxidant defenses in mice colon and its pretreatment blunts pathological signs of colitis, as compared to positive control. In the liver, the increase in antioxidant defenses is associated with enhanced oxidative metabolism and with higher levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and of hemeoxygenase-1 (HO-1), in comparison with negative controls. CONCLUSION: Cytoprotective and hypolipidemic effect produced by MCFE intake results, at least in part, by the activation of the Nrf2 pathway.

Antioxidant dietary approach in treatment of fatty liver: New insights and updates.

Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols (i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids (i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates (i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.