Circadian astrocyte mitochondrial humanin regulates microglia and neuronal mitochondrial melatonergic pathway, with implications for aging and neurodegenerative conditions

There is a growing appreciation of the role of mitochondria in determining the interactions of CNS astrocytes, microglia, and neurons. The influence of circadian and systemic processes in regulating these interactions is relatively underexplored. Recent work has indicated the importance of night-time dampening and resetting in the pathoetiology of a diverse array of aging-associated medical conditions, including neurodegenerative disorders. The 10-fold decrease in pineal melatonin at night between childhood and the 9th decade of life is a major determinant of how aging associates with neurodegenerative disorders, cardiovascular disorders, and a wide range of tumors. It is proposed that the beneficial effects of pineal melatonin are mediated via its upregulation of the mitochondria-derived peptides (MDPs), including humanin. Although potentially induced in all mitochondria-containing cells, humanin is primarily produced in the CNS by astrocytes. The capacity of pineal melatonin to increase astrocyte humanin leads to the induction of the local melatonergic pathway in microglia to shift microglia from a pro-inflammatory M1-like to prophagocytic M2-like phenotype. In neurons, astrocyte-derived humanin optimizes mitochondrial function and decreases oxidant production to increase function and survival, possibly also involving mitochondrial melatonergic pathway upregulation. Concurrent effects of pineal melatonin in decreasing gut dysbiosis/permeability and stimulating oxytocin to activate the vagal nerve contribute to more optimized dampening and resetting that influences CNS interactions of glia and neurons. Overall, the conceptualizations of how astrocyte, microglial, and neuronal mitochondria interact require integration with wider circadian and systemic processes. A plethora of novel research implications are highlighted.