Abstract
The morphological structure and metabolic activity of mitochondria are coordinately regulated by circadian mechanisms. However, the mechanistic interplay between circadian mechanisms and mitochondrial architecture remains poorly understood. Here, we demonstrate circadian rhythmicity of Rheb protein in liver, in line with that of Per2. Using genetic mouse models, we show that Rheb, a small GTPase that binds mTOR, is critical for circadian oscillation of mTORC1 activity in liver. Disruption of Rheb oscillation in hepatocytes by persistent expression of Rheb transgene interrupted mTORC1 oscillation. We further show that Rheb-regulated mTORC1 altered mitochondrial fission factor DRP1 in liver, leading to altered mitochondrial dynamics. Our results suggest that Rheb/mTORC1 regulated DRP1 oscillation involves ubiquitin-mediated proteolysis. This study identifies Rheb as a nodal point that couples circadian clock and mitochondrial architecture for optimal mitochondrial metabolism.
Keywords:
DRP1; Rheb/mTORC1; circadian clock; mitochondrial dynamics.
© 2020 Federation of European Biochemical Societies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Circadian Clocks / genetics*
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Dynamins / genetics*
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Dynamins / metabolism
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Gene Expression Regulation
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HEK293 Cells
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Hepatocytes / metabolism
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Hepatocytes / ultrastructure
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Humans
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Liver / cytology
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Liver / metabolism
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Lysosomes / metabolism
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Mechanistic Target of Rapamycin Complex 1 / genetics*
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Mechanistic Target of Rapamycin Complex 1 / metabolism
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Mice
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Mice, Transgenic
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Mitochondria / genetics
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Mitochondria / metabolism
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Mitochondria / ultrastructure
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Mitochondrial Dynamics / genetics
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Period Circadian Proteins / genetics*
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Period Circadian Proteins / metabolism
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Protein Binding
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Ras Homolog Enriched in Brain Protein / deficiency
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Ras Homolog Enriched in Brain Protein / genetics*
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Regulatory-Associated Protein of mTOR / deficiency
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Regulatory-Associated Protein of mTOR / genetics
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Signal Transduction
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TOR Serine-Threonine Kinases / genetics*
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TOR Serine-Threonine Kinases / metabolism
Substances
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Per2 protein, mouse
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Period Circadian Proteins
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Ras Homolog Enriched in Brain Protein
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Regulatory-Associated Protein of mTOR
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Rheb protein, mouse
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Rptor protein, mouse
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mTOR protein, mouse
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Dnm1l protein, mouse
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Dynamins