Melatonin/Nrf2/NLRP3 Connection in Mouse Heart Mitochondria during Aging

Abstract

Aging is a major risk for cardiovascular diseases (CVD). Age-related disorders include oxidative stress, mitochondria dysfunction, and exacerbation of the NF-κB/NLRP3 innate immune response pathways. Some of the molecular mechanisms underlying these processes, however, remain unclear. This study tested the hypothesis that NLRP3 inflammasome plays a role in cardiac aging and melatonin is able to counteract its effects. With the aim of investigating the impact of NLRP3 inflammasome and the actions and target of melatonin in aged myocardium, we analyzed the expression of proteins implied in mitochondria dynamics, autophagy, apoptosis, Nrf2-dependent antioxidant response and mitochondria ultrastructure in heart of wild-type and NLRP3-knockout mice of 3, 12, and 24 months-old, with and without melatonin treatment. Our results showed that the absence of NLRP3 prevented age-related mitochondrial dynamic alterations in cardiac muscle with minimal effects in cardiac autophagy during aging. The deficiency of the inflammasome affected Bax/Bcl2 ratio, but not p53 or caspase 9. The Nrf2-antioxidant pathway was also unaffected by the absence of NLRP3. Furthermore, NLRP3-deficiency prevented the drop in autophagy and mice showed less mitochondrial damage than wild-type animals. Interestingly, melatonin treatment recovered mitochondrial dynamics altered by aging and had few effects on cardiac autophagy. Melatonin supplementation also had an anti-apoptotic action in addition to restoring Nrf2-antioxidant capacity and improving mitochondria ultrastructure altered by aging.

The Impact of Melatonin and NLRP3 Inflammasome on the Expression of microRNAs in Aged Muscle

“…Recent studies determined that oral melatonin supplementation preserves normal structure and muscular activity in aged mice. These studies also confirmed the NLRP3 inflammasome implication in muscular aging [ 26 , 29 ]. Although there are some miRs involved in the regulation of the inflamma-pathways and of the NLRP3 inflammasome activity, it is not known whether their expression changes in aged muscle and what effect melatonin can exert on their expression with age.…”

“…Melatonin (N-acetyl-5-methoxytryptamine, aMT) is a hormone involved in multiple functions, including antioxidative, anti-inflammatory, and immunomodulatory, and mitochondrial protective effects [ 23 , 24 , 25 , 26 ]. It is originally isolated from the pineal gland and is considered as a regulator of circadian rhythms and seasonal breeding [ 27 ]; however, it is currently known that melatonin is widely produced and distributed in all tissues and organs, including the skeletal muscle [ 28 ].…”

Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications

“…The mechanism of action of LLLT is based on photon energy absorption by cytochrome oxidase, the terminal enzyme in the mitochondrial respiratory chain. LLLT can provide neuroprotection and cognitive enhancement by facilitating mitochondrial respiration, with hormetic dose-response effects and brain region activational specificity [ 64 ].…”

Melatonin to Rescue the Aged Heart: Antiarrhythmic and Antioxidant Benefits

“…This evidence supports the crucial role of endogenous melatonin in cardiovascular pathologies [ 194 ]. Melatonin can have an antiapoptotic effect associated with restoring Nrf2 antioxidant capacity (one of the main molecules responsible for detecting oxidative stress damage), improving this way mitochondria ultrastructure altered by aging [ 195 ]. Additionally, cardioprotection by melatonin against oxidative stress and arrhythmias could be widely explained by modulation of ion channels, AP and Cx43 expression [ 196 – 198 ].…”