Circadian Rheb oscillation alters the dynamics of hepatic mTORC1 activity and mitochondrial morphology

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.

Mitochondrial autophagy in the sleeping brain

“…Further studies consolidated the hypothesis of a clockdependent regulation of mitochondrial fission in different tissues and cells, and add another layer of complexity by demonstrating that post translational modifications of profission protein DRP1, phosphorylation (Schmitt et al, 2018) and ubiquitination (Yuan et al, 2021) in particular, regulate mitochondrial dynamic in anticipation of predictable metabolic clues, although mechanistically this relationship has not been fully depicted. The reciprocal correlation between the clock and DRP1dependent fission is corroborated by numerous evidences: cells lacking DRP1 do not display circadian oscillation of oxidative phosphorylation and ATP level; in PER1/2 KO cells lacking a functional circadian clock, the mitochondrial network remains fragmented, and ATP levels and ox/phos stop oscillating; and finally, pharmacological or genetic inhibition of mitochondrial fission significantly increases period length, and abrogates circadian oscillation in Bmal1 and Per1/2 gene expression (Schmitt et al, 2018).…”