Figure 3.

A summary of free radical generation in mitochondria and the role of melatonin in mitigating oxidative damage and ovarian aging. Radicals are generated especially as a result of electron leakage from the electron transport chain in the inner mitochondrial membrane; the rogue electrons chemically reduce adjacent oxygen molecules to produce the superoxide anion radical (O₂^•−). This reactant is quickly dismutated by superoxide dismutase 2 (SOD2) to hydrogen peroxide (H₂O₂) or it couples with nitric oxide to produce the highly oxidizing peroxynitrite anion (ONOO⁻; not shown). H₂O₂ is converted to the hydroxyl (^•OH) radical via the Haber–Weiss reaction, which is kinetically slow, or via the Fenton reaction, both of which require a transition metal such as ferrous iron (Fe²⁺). The ^•OH, along with other oxidants, damage molecules, which initiate apoptosis. The antioxidant, melatonin, which is synthesized by a number of ovarian cells, likely in the mitochondria, as well as pineal-derived melatonin which enters these organelles, chelates iron and other redox reactive transition metals. Via the activation of sirtuin 3 (SIRT3), melatonin also upregulates SOD2 and impacts mitochondrial dynamics in favor of renewing mitochondria. Finally, melatonin directly neutralizes ^•OH and the ONOO⁻. Via these combined actions, melatonin serves as a powerful protector of mitochondrial integrity and preserves optimal cellular function which delays ovarian aging. Melatonin also functions as an anti-inflammatory which, especially when chronic, compromises mitochondrial physiology leading to ovarian cell, including oocyte deterioration. Mitochondria produced melatonin also escapes these organelles to act on melatonin receptors (MT1) in the mitochondrial membrane, which reduces the release of cytochrome C (Cyto C) thereby inhibiting programmed cell death which would otherwise advance ovarian aging. Finally, in the event of ovarian cancer, melatonin impedes the synthesis of telomeres by reducing telomerase activity thus slowing cancer cell renewal. I-IV; mitochondrial complex.