Clock Protein Bmal1 and Nrf2 Cooperatively Control Aging or Oxidative Response and Redox Homeostasis by Regulating Rhythmic Expression of Prdx6

Abstract

Many disorders of aging, including blinding-diseases, are associated with deficiency of brain and muscle arnt-like protein 1 (Bmal1) and, thereby, dysregulation of antioxidant-defense pathway. However, knowledge is limited regarding the role of Bmal1 regulation of antioxidant-pathway in the eye lens/lens epithelial cells (LECs) at the molecular level. We found that, in aging human (h)LECs, a progressive decline of nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE (antioxidant response element)-mediated antioxidant genes was connected to Bmal1-deficiency, leading to accumulation of reactive oxygen species (ROS) and cell-death. Bmal1-depletion disrupted Nrf2 and expression of its target antioxidant genes, like Peroxiredoxin 6 (Prdx6). DNA binding and transcription assays showed that Bmal1 controlled expression by direct binding to E-Box in Prdx6 promoter to regulate its transcription. Mutation at E-Box or ARE reduced promoter activity, while disruption of both sites diminished the activity, suggesting that both sites were required for peak Prdx6-transcription. As in aging hLECs, ROS accumulation was increased in Bmal1-deficient cells and the cells were vulnerable to death. Intriguingly, Bmal1/Nrf2/Prdx6 and PhaseII antioxidants showed rhythmic expression in mouse lenses in vivo and were reciprocally linked to ROS levels. We propose that Bmal1 is pivotal for regulating oxidative responses. Findings also reveal a circadian control of antioxidant-pathway, which is important in combating lens/LECs damage induced by aging or oxidative stress.

Bmal1 Regulates the Redox Rhythm of HSPB1, and Homooxidized HSPB1 Attenuates the Oxidative Stress Injury of Cardiomyocytes

“…More recently, time-of-day-dependent regulation of Nrf-2 has been reported, which takes an important role for antioxidants [ 36 , 52 , 53 ]. Chhunchha et al reported that the molecular Bmal1 controls the inflammatory response through regulating Nrf-2 in innate immune cells [ 54 ]. Mahajan et al found that Bmal1 and Nrf-2 cooperatively control oxidative response and redox homeostasis by regulating the rhythmic expression of Prx [ 31 ].…”

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

“…The tryptophan-derived hormone melatonin—often viewed as a nutraceutical insomuch as it can be administered orally and is sold in capsule form over-the-counter—has phase 2 activity that appears to reflect up-regulation of nrf2 at the transcriptional level [ 86 , 87 , 88 ]. This may reflect the fact that the promoter of the nrf2 gene contains E boxes that bind the “clock” transcription factor Bmal1, in conjunction with the protein Clock, and this drives nrf2 transcription [ 89 , 90 ]. The expression of Bmal1 and other so-called clock genes varies with a diurnal rhythm in many types of cells; a nocturnal surge of melatonin produced by the pineal gland somehow functions to coordinate this diurnal variation with light/dark cycles [ 91 , 92 ].…”

A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer’s Pathogenesis—And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder

“…The neurohormone melatonin (MLT), secreted nocturnally by the pineal gland as a synchronizer of diurnal biological rhythms, is known to have this property [ 54 ]. This might reflect increased activity of the fundamental clock protein Bmal1, one of whose transcriptional targets is Nrf2 [ 55 , 56 , 57 ]. MLT administration has been found to benefit cognitive function, lessen tau phosphorylation, and decrease amyloid β levels in multiple models of AD in mice, albeit it is unclear to what extent antioxidant effects mediate these benefits [ 58 , 59 , 60 , 61 , 62 ].…”