The Mammalian Circadian Clock Gene Per2 Modulates Cell Death in Response to Oxidative Stress

Magnone, Maria Chiara; Langmesser, Sonja; Bezdek, April Candice; Tallone, Tiziano; Rusconi, Sandro; Albrecht, Urs

doi:10.3389/fneur.2014.00289

Cited by 47 publications

(44 citation statements)

References 49 publications

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“…A fragmented mitochondrial network was detected in DS HF (Figure 1d, insets) as illustrated by a lower MDV compared to control diploid human fibroblasts (NL) (Figure 1d), and also in Dp16 MEF (Figure 1e; Supporting Information Figure S4D), albeit to a lesser extent. Wild‐type (WT) MEF treated with 200 μM paraquat (PQ) (Lang et al, 2010; Magnone et al, 2014) for 48 hr were included in the analysis as a positive control of network fragmentation. Consistent with the alterations described above, the MMP was decreased in DS cells (Figure 1f).…”

Section: Resultsmentioning

confidence: 99%

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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SummaryMounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2‐mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria‐targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2‐mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial‐specific interventions as a key aspect of antioxidant and antiaging therapies.

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Section: Resultsmentioning

confidence: 99%

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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“…Mitochondria in macrophages exhibit daily morphological changes in vitro as well (29). By contrast, the overall number of mitochondria, assessed by mitochondrial genome copy number, appears to be constant throughout the day and is independent of clock genes (16, 17, 20, 30). Collectively, these studies point to circadian regulation of mitochondrial dynamics, such as changes in mitochondrial mass and morphology, with major implications on mitochondrial function.…”

Section: Circadian Rhythms In Mitochondrial Morphologymentioning

confidence: 92%

The Circadian Nature of Mitochondrial Biology

Manella

Asher

2016

Front. Endocrinol.

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Circadian clocks orchestrate the daily changes in physiology and behavior of light-sensitive organisms. These clocks measure about 24 h and tick in a self-sustained and cell-autonomous manner. Mounting evidence points toward a tight intertwining between circadian clocks and metabolism. Although various aspects of circadian control of metabolic functions have been extensively studied, our knowledge regarding circadian mitochondrial function is rudimentary. In this review, we will survey the current literature related to the circadian nature of mitochondrial biology: from mitochondrial omics studies (e.g., proteome, acetylome, and lipidome), through dissection of mitochondrial morphology, to analyses of mitochondrial processes such as nutrient utilization and respiration. We will describe potential mechanisms that are implicated in circadian regulation of mitochondrial functions in mammals and discuss the possibility of a mitochondrial-autonomous oscillator.

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“…Additionally, oxidative stress causes alterations in the oxidation of DNA, which further affect gene expression and cell cycle leading to dysfunctional circadian clock. Evolution has probably made the cellular machinery in such a way that it uses circadian clock to meet its time‐dependant oxidative stress and immune function . Deregulation in circadian clock or any of its components will therefore alter its cellular response to oxidative stress at least, if not directly leading to stress generation.…”

Section: Discussionmentioning

confidence: 99%

Lithium acts to modulate abnormalities at behavioral, cellular, and molecular levels in sleep deprivation‐induced mania‐like behavior

Andrabi

Kunjunni

et al. 2019

Bipolar Disorders

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Background: Ample amount of data suggests role of rapid eye movement (REM) sleep deprivation as the cause and effect of mania. Studies have also suggested disrupted circadian rhythms contributing to the pathophysiology of mood disorders, including bipolar disorder. However, studies pertaining to circadian genes and effect of lithium treatment on clock genes are scant. Thus, we wanted to determine the effects of REM sleep deprivation on expression of core clock genes and determine whether epigenetics is involved. Next, we wanted to explore ultrastructural abnormalities in the hippocampus. Moreover, we were interested to determine oxidative stress, tumor necrosis factor-α (TNF-α), and brain-derived neurotrophic factor levels in the central and peripheral systems.Methods: Rats were sleep deprived by the flower pot method and were then analyzed for various behaviors and biochemical tests. Lithium was supplemented in diet. Results:We found that REM sleep deprivation resulted in hyperactivity, reduction in anxiety-like behavior, and abnormal dyadic social interaction. Some of these behaviors were sensitive to lithium. REM sleep deprivation also altered circadian gene expression and caused significant imbalance between histone acetyl transferase/ histone deacetylase (HAT/HDAC) activity. Ultrastructural analysis revealed various cellular abnormalities. Lipid peroxidation and increased TNF-α levels suggested oxidative stress and ongoing inflammation. Circadian clock genes were differentially modulated with lithium treatment and HAT/HDAC imbalance was partially prevented.Moreover, lithium treatment prevented myelin fragmentation, disrupted vasculature, necrosis, inflammation, and lipid peroxidation, and partially prevented mitochondrial damage and apoptosis. Conclusions:Taken together, these results suggest plethora of abnormalities in the brain following REM sleep deprivation, many of these changes in the brain may be target of lithium's mechanism of action. K E Y W O R D SBDNF, circadian clock, HAT/HDAC, mania, oxidative stress, REM sleep deprivation | 267 ANDRABI et Al

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The Mammalian Circadian Clock Gene Per2 Modulates Cell Death in Response to Oxidative Stress

Cited by 47 publications

References 49 publications

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

The Circadian Nature of Mitochondrial Biology

Lithium acts to modulate abnormalities at behavioral, cellular, and molecular levels in sleep deprivation‐induced mania‐like behavior

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