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.

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.

Recently, obesity has been linked to male infertility. In animal models the administration of a high-fat diet caused a reduction in sperm quality, by impairing gamete energy metabolism. The aim of this study was to investigate a possible effect of dietary fatty acids supplementation in the modulation of sperm energy metabolism and, in turn, in the improvement of sperm quality in rats fed a high-fat diet. Sexually mature male Sprague-Dawley rats were divided into four groups and fed for 4 weeks a standard diet (control group), a high-fat diet (enriched in 35% of fat and 15% sucrose), a high-fat diet supplemented with 2.5% olive oil (a source of monounsaturated fatty acids) or a high-fat diet supplemented with 2.5% krill oil (a source of n-3 polyunsaturated fatty acids). Liver and adipose tissue weight, plasma glucose, insulin and lipid concentrations were determined. Activities of enzymes involved in sperm energetic metabolism were evaluated by spectrophotometric assays. Sperm mitochondrial respiratory efficiency was also assayed. The obtained results suggest that olive oil partially counteracts the negative effects of a high-fat diet on sperm quality, by increasing gamete motility, by reducing oxidative stress and slightly improving mitochondrial respiration efficiency. On the other hand, krill oil determines an increase in sperm concentration and motility, an increase in the activities of lactate dehydrogenase, Krebs cycle enzymes and respiratory chain complexes; a parallel increase in the cellular levels of ATP and a reduction in oxidative damage were also observed. These results suggest that dietary fatty acids are able to positively influence sperm quality and function.

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.

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Obesity in men of reproductive age is increasing worldwide, impacting negatively on reproductive potential, sperm function, and assisted reproduction outcomes. Changes in modern eating behaviors are needed to invert the negative correlation between lifestyle and sperm quality. It is known from the literature that fatty acids are able to modulate lipid metabolism by complex mechanisms involving a sequence of interdependent and cross‐regulated molecular events. Although a great deal of data is currently available on the dietary modulation of lipid metabolism, little is known about the nutritional regulation of sperm energetic metabolism. In this review, major data from the literature about the role of some dietary fats as modulators of sperm function and quality are described. Moreover, biochemical mechanisms responsible for an impairment or improvement in sperm bioenergetics are critically analyzed. It is noteworthy that both quantitative and qualitative aspects of dietary fats influence sperm function. The administration of a high‐fat diet, low in polyunsaturated fatty acids, caused a significant increase in body weight hyperglycemia, hyperinsulinemia, and dyslipidemia, along with a significant reduction in sperm quality. In contrast, unsaturated fatty acids are able to positively influence sperm quality and function. The understanding of the biochemical mechanisms underlying the development of male infertility related to obesity led us to depict a possible framework for the molecular action of fatty acids on sperm quality during dysmetabolic conditions. Practical Applications: In this review major data from the literature about the spermatozoa targeting of dietary fatty acids are described and critically analyzed, because now dietary fatty acids are the current focus of research in the field of nutrition and reproduction in males. Such knowledge will eventually translate into the development of new attractive therapeutic approaches for male infertility related to alterations in lipid metabolism. Dietary fatty acids are involved in the nutritional modulation of sperm energetic metabolism. Diets rich in saturated fatty acids (SFA) and low in polyunsaturated fatty acids (PUFA) seem to correlate with defective sperm energy metabolism and reduced sperm quality. Administration of PUFA, especially n‐3 PUFA, determines an increase in sperm concentration, and motility, associated to an increase in the activities of mitochondrial enzymes involved in gamete energetic metabolism and to a reduction in oxidative damaeg

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.