In a recent review published within the Cell Death Discovery Journal, researchers explored the association between ferroptosis and male reproductive failure, emphasizing the necessity for tailored therapies and preventative efforts.

Study: Emerging roles of ferroptosis in male reproductive diseases. Image Credit: Vladimir Sukhachev/Shutterstock.com

Background

Infertility is a rising concern globally, warranting research to discover novel targets that may enable the event of tailored therapy and enhance infertility care.

Research has linked ferroptosis to male reproductive disorders. Iron is required for spermatogenesis and testosterone synthesis; nonetheless, excessive amounts of iron can affect sperm quality and result in reproductive dysfunction.

In regards to the review

In the current review, researchers elucidated ferroptosis-induced male reproductive failure, the physiological role of iron regulation in male reproductive function, and its potential targets in testicular damage.

An Introduction to ferroptosis

Lipid peroxidation resulting from iron buildup results in ferroptosis, a sort of non-apoptotic cell death. It’s engaged in various disease situations, including neurodegeneration, cancerization, ulcerative colitis, and kidney and liver ischemia-reperfusion damage. Ferroptosis treatment may be a possible technique for treating individuals with reproductive problems.

Iron metabolic imbalances cause ferroptosis, which leads to elevated intracellular ferrous iron levels and iron overload. The absence of lysophosphatidylcholine acyltransferase 3 (LPCAT3) or acyl-coenzyme A indicates ferroptosis, as is lipid peroxidation.

A synthetase long-chain member of the family 4 (ACSL4) improves ferroptosis resistance and lowers ferroptosis lipid peroxidation.

The solute carrier family 7member 11 (SLC7A11 or xCT)/glutathione peroxidase 4 (GPX4) pathway prevents ferroptosis by balancing oxidative stress and antioxidant defense. A glutathione (GSH) synthesis reduction affects GPX4 activity and induces ferroptosis.

The ferroptosis suppressor protein 1 (FSP1)/coenzyme Q10 (CoQ100) axis and the guanosine triphosphate cyclohydrolase 1 (GCH1)/tetrahydrobiopterin (BH4) axis reduce ferroptosis by converting CoQ10 to ubiquitinol (CoQ10H2).

Mitochondria, semi-autonomous cell organelles, function via distinct metabolic pathways that prevent ferroptosis. Recent research has indicated that mitochondrial damage is a defining feature of ferroptosis. Proteins involved in Fe-S binding, equivalent to nuclear assembly factor 1 (NAF1), assist in iron transport within the mitochondria and suppress ferroptosis by shielding the cell organelles from lipid peroxidation in acute renal damage and tumor cells.

Through redox processes created by glucose, acetyl-CoA transports electrons to electron transport chains, creating adenine triphosphate (ATP) via oxidative phosphorylation and reactive oxygen species (ROS), which trigger ferroptosis.

Mitochondrial GPX4 helps prevent ferroptosis by collaborating with the glycerol-3-phosphate dehydrogenase 2 (GPD2)/CoQ10H2 and dihydroorotate dehydrogenase/CoQ10H2 pathways throughout the inner mitochondrial membrane.

Ferroptosis-induced biological reactions in testicular damage

Ferroptosis results in cellular death in Sertoli cells as a result of oxygen-glucose deprivation and reoxygenation damage related to several male reproductive illnesses. Thus, ferroptosis can adversely affect the male reproductive system.

Excessive autophagy could cause ferroptosis, whereas zinc could cause ferroptosis by controlling mitochondrial autophagy.

In rats, hexavalent chromium produces ferroptosis and testicular autophagy. Classic ferroptotic activators like ML-210 and inhibitors like ferrostatin-1 (Fer-1) affect autophagic flux throughout the cells, leading to testicular damage.

Testicular ferroptosis may be brought on by bad lifestyle behaviors equivalent to drinking, smoking, and never sleeping enough, which may impair the standard of spermatozoa and result in male infertility.

Nicotine disrupts the blood-testis barrier, affecting male reproductive function, and the nuclear factor erythroid 2-related factor 2 (NRF2) promotes ferroptosis induced by nicotine. Ferrostatin-1 restores testicular harm, implying that ferroptosis is brought on by smoking.

Environmental variables equivalent to 2.5-micron-sized particulate matter, bisphenol A, di-2-ethylhexyl phthalate (DEHP), and HT-2 toxins may also trigger testicular ferroptosis.

Mycotoxins enhance testicular lipid peroxidation by suppressing the expression of GPX4, SLC7A11, and NRF2. Through the buildup of ROS, HT-2 toxins reduce Leydig cell growth and testosterone release and promote ferroptosis and death, leading to lipid peroxidation. Heavy metals may also cause testicular damage.

Cadmium alters the pubertal mouse’s antioxidant signaling and iron metabolism, causes ferroptosis in spermatogonocyte cells, and inhibits spermatogenesis and testicular development.

The involvement of mammalian goal of the rapamycin (mTOR)-mediated autophagy may be explained by ferroptosis brought on by hexavalent chromium and copper.

Arsenite causes lipid peroxidation and mitochondrial dysfunction in testicular cells. Many frequently used medicines, equivalent to Busulfan, which destroys developing germ cells and inhibits the production of spermatozoa, could cause testicular damage and male infertility.

Nonetheless, the link between ferroptosis and other sorts of cell death remains to be being researched. Genetic abnormalities, environmental variables, heavy metals, and medicine usage can all impact ferroptosis.

Based on the review findings, ferroptosis, a sort of cellular death related to male reproductive failure, is a novel therapy goal.

Iron chelation treatment and antioxidants may help prevent and relieve symptoms, but further study is required to research whether specific blocking can correct testicular dysfunction and restore fertility. Predictive biomarkers for ferroptosis and male reproductive dysregulation are also required.