Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid peroxidation due to an impaired cysteine‐glutathione‐glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as liver‐ and kidney‐related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring attention to avenues that could be followed in future research, based on the use of mitochondria‐targeted approaches as anti‐ and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.

The main pathological hallmark of diabetes is the loss of functional β‐cells. Among several types of β‐cell death in diabetes, the involvement of ferroptosis remains elusive. Therefore, we investigated the potential of diabetes‐mimicking factors: high glucose (HG), proinflammatory cytokines, hydrogen peroxide (H₂O₂), or diabetogenic agent streptozotocin (STZ) to induce ferroptosis of β‐cells in vitro. Furthermore, we tested the contribution of ferroptosis to injury of pancreatic islets in an STZ‐induced in vivo diabetic model. All in vitro treatments increased loss of Rin‐5F cells along with the accumulation of reactive oxygen species, lipid peroxides and iron, inactivation of NF‐E2‐related factor 2 (Nrf2), and decrease in glutathione peroxidase 4 expression and mitochondrial membrane potential (MMP). Ferrostatin 1 (Fer‐1), ferroptosis inhibitor, diminished the above‐stated effects and rescued cells from death in case of HG, STZ, and H₂O₂ treatments, while failed to increase MMP and to attenuate cell death after the cytokines’ treatment. Moreover, Fer‐1 protected pancreatic islets from STZ‐induced injury in diabetic in vivo model, since it decreased infiltration of macrophages and accumulation of lipid peroxides and increased the population of insulin‐positive cells. Such results revealed differences between diabetogenic stimuli in determining the destiny of β‐cells, emerging HG, H₂O₂, and STZ, but not cytokines, as contributing factors to ferroptosis and shed new light on an antidiabetic strategy based on Nrf2 activation. Thus, targeting ferroptosis in diabetes might be a promising new approach for preservation of the β‐cell population. Our results obtained from in vivo study strongly justify this approach.

Background. Semen analysis is the cornerstone in the evaluation of male (in)fertility. However, there are men with normal semen tests but with impaired fertilizing ability, as well as fertile men with poor sperm characteristics. Thus, there is rising interest to find novel parameters that will help to predict and define the functional capacity of spermatozoa.Methods. We examined whether there is a correlation between semen parameters (count, progressive motility, and morphology) and protein expression/activity of antioxidative defense enzymes in seminal plasma from 10 normospermic subjects.Results. Sperm progressive motility was in positive correlation with seminal plasma protein expression of both superoxide dismutase (SOD) isoforms (MnSOD and CuZnSOD) and catalase. Also, positive correlation was observed between sperm count and MnSOD protein expression, as well as between sperm morphology and protein expression of catalase in seminal plasma. In contrast, protein expression of glutathione peroxidase was not in correlation with any sperm parameter, while its activity negatively correlated with sperm morphology and motility.Conclusions. These data suggest that evaluation of protein expression of antioxidative defense enzymes in seminal plasma might be of importance in the evaluation of male fertility status and that could be used as an additional biomarker along with classic semen analysis in assessment of semen quality.

Introduction: Metabolic syndrome arises from abnormal adipose function accompanied by insulin resistance. As early factors reflecting/impacting lipid storage dysfunction of adipose tissues, we sought to determine adipokine levels in subcutaneous and visceral adipose tissues (SAT and VAT).Material and methods: Gene and protein expression of leptin, adiponectin, and resistin were analyzed in SAT and VAT of normal-weight and overweight/obese women, subclassified according to insulin resistance index, triglyceride, total-, LDL- and HDL-cholesterol levels into metabolically healthy and “at risk” groups.Results: Compared with normal-weight women, obese women had higher serum leptin levels (P<0.05), as well as increased leptin gene and protein expression in VAT. Conversely, expression levels of leptin were lower in SAT of obese women, and minor in the SAT of “at risk” groups of women, compared with weight-matched healthy groups. In addition, lower adiponectin levels were detected in SAT of metabolically healthy obese women (P<0.01), and lower in SAT and VAT (P<0.05) of “at risk” obese women compared to healthy, obese women. Significant differences in resistin levels were only observed in obese women; resistin gene expression was higher in VAT and SAT of obese, compared to normal-weight women. However, higher gene expression was not consistent with protein expression of resistin.Conclusions: Low adiponectin in both examined adipose tissues and inappropriate leptin expression levels in SAT appear to be important characteristics of obesity-related metabolic syndrome. Intriguingly, this adipokine dysregulation is primary seen in SAT, suggesting that endocrine dysfunction in this abdominal depot may be an early risk sign of metabolic syndrome.

Cell death plays an important role in diabetes-induced liver dysfunction. Ferroptosis is a newly defined regulated cell death caused by iron-dependent lipid peroxidation. Our previous studies have shown that high glucose and streptozotocin (STZ) cause β-cell death through ferroptosis and that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, improves β-cell viability, islet morphology, and function. This study was aimed to examine in vivo the involvement of ferroptosis in diabetes-related pathological changes in the liver. For this purpose, male C57BL/6 mice, in which diabetes was induced with STZ (40 mg/kg/5 consecutive days), were treated with Fer-1 (1 mg/kg, from day 1–21 day). It was found that in diabetic mice Fer-1 improved serum levels of ALT and triglycerides and decreased liver fibrosis, hepatocytes size, and binucleation. This improvement was due to the Fer-1-induced attenuation of ferroptotic events in the liver of diabetic mice, such as accumulation of pro-oxidative parameters (iron, lipofuscin, 4-HNE), decrease in expression level/activity of antioxidative defense-related molecules (GPX4, Nrf2, xCT, GSH, GCL, HO-1, SOD), and HMGB1 translocation from nucleus into cytosol. We concluded that ferroptosis contributes to diabetes-related pathological changes in the liver and that the targeting of ferroptosis represents a promising approach in the management of diabetes-induced liver injury.

Disorders of iron metabolism and ferroptosis play an important role in the development of diabetes and related pathologies. The involvement of ferroptosis in type 1 diabetes has mainly been investigated in animal models with chemically induced diabetes. Our aim was to examine the involvement of iron homeostasis disturbances and ferroptotic events in liver and kidney damage in non-obese diabetic (NOD) mice in the early phase of spontaneous development of diabetes (15 days of stable hyperglycemia). We found an accumulation of iron and lipid peroxides in the proximal tubule epithelial cells (PTECs) of the renal cortex and in the liver. This was accompanied by a decrease in the level of proteins involved in the sequestration (ferritin) and export (ferroportin) of iron and an increase in the level of transferrin receptor 1 in both organs. The level of activated nuclear factor erythroid 2-related factor 2 was decreased in both liver and kidney, whereas lower levels of Xc- glutamate/L-cystine antiporter and glutathione peroxidase 4 were detected only in PTECs, demonstrating the proferroptotic events in these cells. In conclusion, although iron accumulation and lipid peroxidation occur in both organs, the kidneys are more susceptible to ferroptosis in early diabetes development.