Wyniki wyszukiwania - Biblioteka Nauki

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The relationship between mitochondria function and circadian clock in peripheral oscillators

100%

Kazmierczak A. , Schmitt K. , Grimm A. , Strosznajder J. B. , Eckert A.

Acta Neurobiologiae Experimentalis

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2013

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tom 73

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nr 1

EN

Circadian rhythms govern a wide variety of physical, behavioral and metabolic changes that follow a roughly 24-hour cycle, responding primarily to light and darkness in an organism’s environment. These are controlled by the circadian clock mechanism, where rhythm-generating mechanism is encoded by a transcription-translation feedback loop. Numerous studies have pointed to a cyclic relationship wherein the rhythm impacts metabolic activity and metabolism feeds back to impinge upon the rhythm. Mitochondria play a pivotal role in regulating cellular energy and were shown to be strategically positioned at the intersection between circadian rhythm and cell metabolism. Nevertheless little is known about their function in controlling the circadian rhythm. In our study, we investigated the involvement of circadian clock in mitochondrial function as well as mitochondria-dependent regulation of circadian clock. The study was carried out in primary human fibroblasts, an already established model to investigate molecular clock mechanisms in vitro. We have found that mitochondria activity as well as network activities showed rhythmic changes within 24 hours. Circadian pattern was detected for mitochondrial ROS including superoxide anion production. A significant 24-hour oscillation was found for cellular redox state. Furthermore, mitochondrial ATP levels were rhythmic and the maximum of ATP production paralleled the peak of mitochondrial ROS level and the mitochondrial network formation. Circadian rhythm was also detected for calcium ions concentration. Increase of ATP synthesis as well as changes in calcium and ROS level activated AMP-dependent protein kinase (AMPK). We have found that in primary human fibroblasts AMPK protein level and activity fluctuate in an antiphase relationship with rhythmic ATP production. Summarizing, our data provide the evidence for circadian regulation of mitochondrial dynamics and suggest that changes of mitochondrial activity may directly influence cellular clock. Supported by grants from Sciex 10. 258 to A.K. as well as Swiss National foundation (SNF No 310030_122572) and Synapsis Foundation to A.E

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Alzheimer’s amyloid beta peptides disturb circadian oscillations of intracellular calcium concentration

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Kazmierczak A. , Schmitt K. , Grimm A. , Strosznajder J. B. , Eckert A.

Acta Neurobiologiae Experimentalis

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2013

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tom 73

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nr 1

EN

It is postulated that disturbances in calcium homeostasis play an important role in pathogenesis of Alzheimer’s disease (AD). Changes of neuronal calcium concentration are responsible for the oxidative stress as well as altered metabolism and production of amyloid-beta peptides (Aβ). Aβ may further exacerbate calcium dysregulation, causing synaptic dysfunction, neurodegeneration and cognitive impairment. Recent data indicate that AD is associated with disturbances of circadian rhythm in the patients. However, till now nothing is known about the molecular mechanisms involved in AD-related circadian clock alterations. In our study we investigated the effect of Aβ peptides on the rhythmic oscillation of cytosolic and mitochondrial calcium levels. To investigate molecular clock mechanisms, the studies we carried out in human primary skin fibroblasts, a previously established experimental model. Our data showed circadian rhythm of calcium ions concentration in cytosol and mitochondria. Moreover we observed circadian oscillation of ROS formation and redox potential. Treatment with Aβ fibrils at the concentration of 0.5 µM disturbed cytosolic calcium oscillations and mitochondrial redox state. Studying mechanisms involved in this phenomenon indicated that Aβ did not affect ER calcium stores, but induced changes of calcium influx mediated by purinergic P2X7 receptor. The specific antagonist of P2X7 receptor Brillant Blue G abolished negative impact of Aβ and restored calcium circadian rhythm. Summarizing, our results indicate that Aβ may play a significant role in disturbances of circadian calcium oscillation, suggesting the importance of this phenomenon in ADrelated changes in biological clock. Supported by grants from Sciex 10. 258 to A.K. as well as Swiss National foundation (SNF No 310030_122572) and Synapsis Foundation to A.E.

3

Memorandum

71%

Grimm A. , Kadner K.

Technika Rolnicza

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2000

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tom 49

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nr 1

3