Melatonin, clock genes and mitochondria in sepsis

Abstract

After the characterization of the central pacemaker in the suprachiasmatic nucleus, the expression of clock genes was identified in several peripheral tissues including the immune system. The hierarchical control from the central clock to peripheral clocks extends to other functions including endocrine, metabolic, immune, and mitochondrial responses. Increasing evidence links the disruption of the clock genes expression with multiple diseases and aging. Chronodisruption is associated with alterations of the immune system, immunosenescence, impairment of energy metabolism, and reduction of pineal and extrapineal melatonin production. Regarding sepsis, a condition coursing with an exaggerated response of innate immunity, experimental and clinical data showed an alteration of circadian rhythms that reflects the loss of the normal oscillation of the clock. Moreover, recent data point to that some mediators of the immune system affects the normal function of the clock. Under specific conditions, this control disappears reactivating the immune response. So, it seems that clock gene disruption favors the innate immune response, which in turn induces the expression of proinflammatory mediators, causing a further alteration of the clock. Here, the clock control of the mitochondrial function turns off, leading to a bioenergetic decay and formation of reactive oxygen species that, in turn, activate the inflammasome. This arm of the innate immunity is responsible for the huge increase of interleukin-1β and entrance into a vicious cycle that could lead to the death of the patient. The broken clock is recovered by melatonin administration, that is accompanied by the normalization of the innate immunity and mitochondrial homeostasis. Thus, this review emphasizes the connection between clock genes, innate immunity and mitochondria in health and sepsis, and the role of melatonin to maintain clock homeostasis.

Melatonin and inflammation—Story of a double‐edged blade

“…In the latter category, antioxidative protection and preservation of mitochondrial function have to be foremost mentioned, as they counteract consequences of inflammation and reduce inflammation itself via promoting antioxidative processes, decreasing free radical formation, and excessive NO formation. As these details exceed the immunological topic of this article, most of them should be followed via the references provided here . However, it should be emphasized that an important nexus exists between mitochondrial dysfunction and inflammation that concerns elevated levels of NO.…”

“…This effect that has been interpreted as a means for enhancing the rhythm amplitude, but may also influence the phase position of a rhythm. The role of SIRT1‐mediated effects on core oscillator expression in inflammation and inflammasome expression has been discussed in the context of aging and sepsis and recently reviewed in relation to mitochondrial function . In NLRP3 −/− knockout mice, the Bmal1 gene repressor, Rev‐Erbα, was not upregulated.…”

Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3

“…Since bacteria contain melatonin, presumably a result of its synthesis in these prokaryotes [174], and mitochondria derived from bacteria that were initially phagocytized as food by early eukaryotes, we surmised that the melatonin-synthesizing machinery of bacteria was retained by the evolved mitochondria. This idea stimulated investigations that have led to compelling evidence that mitochondria of every cell fabricates melatonin for its own use [145,182]; this explains the very wide distribution of melatonin in multicellular organisms [230,231]. That mitochondria produce melatonin has only been shown in a small number of cells, i.e., brain and oocyte.…”

“…Additionally, SIRT3 affects mitochondrial dynamics [233,234,235,236,237]. Melatonin shares many of these same actions [231,238,239,240,241,242,243]. Whether melatonin’s effects on mitophagy, mitochondrial bioenergetics, fusion or fission are a consequence of its epigenetic actions may be a fruitful area of investigation.…”

Pharmacological plasticity—How do you hit a moving target?

“…There is growing evidence that in patients with severe sepsis, kept in an intensive care unit for days, the circadian rhythm is disturbed. Modification of the light and dark cycle by intensifying the contrast and minimizing light‐dark disruption or treating with melatonin can exert beneficial effects on the outcome of the condition . At least in immuno‐inflammatory disorders, it is worth pointing out that the cyclical circulating concentrations of melatonin, itself a potent antioxidant and anti‐inflammatory agent, may exert a direct effect on immunopathology .…”