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.
Highlights
Biological clocks govern a great range of cellular and physiological activities, and many age-linked degenerative disorders and inflammatory conditions are associated with dysregulation of clock genes [1,2,3]
We demonstrated that an increase of oxidative load in aging cells is a cause of progressive failure of nuclear factor erythroid 2-related factor 2 (Nrf2)/Peroxiredoxin 6 (Prdx6)-mediated protective response [32]
Similar to the mRNA expression pattern, protein expression of brain and muscle arnt-like protein 1 (Bmal1), Nrf2, and Prdx6 declined with advancing age, suggesting that dysregulation occurred at transcription and translation levels with aging (Figure 1J)
Summary
Biological clocks govern a great range of cellular and physiological activities, and many age-linked degenerative disorders and inflammatory conditions are associated with dysregulation of clock genes [1,2,3]. The biological rhythm produced by the molecular clock is evolutionarily conserved, allowing organisms to conform rhythms to changes in environmental conditions, such as light and stress stimuli [1,4]. To this end, biorhythms modulate cellular and molecular processes, such as gene expression [1,5]. Bmal (brain and muscle arnt-like protein 1) plays a critical role in governing the molecular clock, and its depletion leads to ablation of biological rhythm [6,7]. The major clock genes/proteins are expressed well in peripheral tissues, and perform their genetically allotted function of circadian periodicity of genes to adjust cell physiology within the cellular microenvironment [8,9]
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