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The mamalian circadian clock regulates the abundance and expression of mitochondrial DNA in the nuclear compartment

Authors
  • Boyer, Hélène
Publication Date
Jun 08, 2020
Source
HAL
Keywords
Language
English
License
Unknown
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Abstract

The mitochondrial genome is minimal and most of the mitochondrial proteins are encoded in the nuclear genome. Thus, although mitochondrial and nuclear genomes are physically separated in the cell, anterograde (nuclear to mitochondrial) and retrograde (mitochondrial to nuclear) signals are essential for mitochondrial biogenesis to be coordinated with the cellular energetic demands. Those demands are cyclical in nature, and the circadian clock regulates numerous aspects of mitochondrial biology, including the dynamics of fusion and fission that shape the architecture of the mitochondrial network. In murine livers, the network oscillates between fused (during the day) and fragmented structures (during the night). A fused network is associated with a more efficient ATP production whereas fragmentation is associated with elevated mitochondrial ROS levels and mitophagy. In other words, if mtDNA was to ever escape mitochondria, fission would help. Complementation experiments in yeast have shown that mitochondrial DNA (mtDNA) is able to escape from the mitochondria and enter the nucleus. In human cells (HeLa), the intact and full-length mitochondrial genome has been detected in the nucleus. Evolutionary analyses of nuclear inserted mitochondrial sequences (numts) suggest an ongoing process of integration of mitochondrial sequences into the nuclear genome. Also, abundant somatically acquired mitochondrial- nuclear genome fusion events (simts) have been shown to occur in human cancer cells - an extreme context of genomic instability and disrupted circadian rhythms. The availability of mtDNA in the cytoplasm, protected by vesicles, to be taken up by the nucleus is thought to result from mitophagy. As mitophagy and mitochondrial dynamics are regulated by the circadian clock, we investigated whether mtDNA would accumulate in the nuclear compartment as a function of circadian time. We addressed this question in the mouse liver, a differentiate mammalian tissue. This work demonstrates that the nuclear abundance of mtDNA in murine livers is regulated by the circadian clock – with a zenith at the end of the circadian night. Nuclear mtDNA is differentially hydroxymethylated relative to the total mtDNA extracted from the same tissue. Also, circadian clock disruption altered the phase and abundance of nuclear mtDNA. Additionally, we observed that concurrent accumulation of nuclear mtRNA was sensitive to nutritional challenges. Probably, these dynamics are driven by mitochondrial network remodeling dynamics. Increased nuclear presence and insertions of mtDNA in cancer cells or aging tissues, which are often associated with disrupted circadian oscillators- may thus arise from the loss of a physiological rhythm in mitochondrial-network remodeling.

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