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Diurnal Rhythms Spatially and Temporally Organize Autophagy.

ABSTRACT: Circadian rhythms are a hallmark of physiology, but how such daily rhythms organize cellular catabolism is poorly understood. Here, we used proteomics to map daily oscillations in autophagic flux in mouse liver and related these rhythms to proteasome activity. We also explored how systemic inflammation affects the temporal structure of autophagy. Our data identified a globally harmonized rhythm for basal macroautophagy, chaperone-mediated autophagy, and proteasomal activity, which concentrates liver proteolysis during the daytime. Basal autophagy rhythms could be resolved into two antiphase clusters that were distinguished by the subcellular location of targeted proteins. Inflammation induced by lipopolysaccharide reprogrammed autophagic flux away from a temporal pattern that favors cytosolic targets and toward the turnover of mitochondrial targets. Our data detail how daily biological rhythms connect the temporal, spatial, and metabolic aspects of protein catabolism.

SUBMITTER: Ryzhikov M

PROVIDER: S-EPMC6442472 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Diurnal Rhythms Spatially and Temporally Organize Autophagy.

Ryzhikov Mikhail M Ehlers Anna A Steinberg Deborah D Xie Wenfang W Oberlander Eitan E Brown Samuel S Gilmore Petra E PE Townsend Reid R RR Lane William S WS Dolinay Tamas T Nakahira Kiichi K Choi Augustine M K AMK Haspel Jeffrey A JA

Cell reports 20190201 7

Circadian rhythms are a hallmark of physiology, but how such daily rhythms organize cellular catabolism is poorly understood. Here, we used proteomics to map daily oscillations in autophagic flux in mouse liver and related these rhythms to proteasome activity. We also explored how systemic inflammation affects the temporal structure of autophagy. Our data identified a globally harmonized rhythm for basal macroautophagy, chaperone-mediated autophagy, and proteasomal activity, which concentrates l ...[more]

PMID: 30759397

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Project description:Melatonin regulates diurnal changes in locomotor activity in vertebrates, but the molecular mechanism for this neurohormonal regulation of behavior is poorly understood. Here we show that 7alpha-hydroxypregnenolone, a previously undescribed avian neurosteroid, mediates melatonin action on diurnal locomotor rhythms in quail. In this study, we first identified 7alpha-hydroxypregnenolone and its stereoisomer 7beta-hydroxypregnenolone in quail brain. These neurosteroids have not been described previously in avian brain. We then demonstrated that 7alpha-hydroxypregnenolone acutely increased quail locomotor activity. To analyze the production of 7alpha-hydroxypregnenolone, cytochrome P450(7alpha), a steroidogenic enzyme of this neurosteroid, was also identified. Subsequently, we demonstrated diurnal changes in 7alpha-hydroxypregnenolone synthesis in quail. 7Alpha-Hydroxypregnenolone synthesis and locomotor activity in males were much higher than in females. This is the first demonstration in any vertebrate of a clear sex difference in neurosteroid synthesis. This sex difference in 7alpha-hydroxypregnenolone synthesis corresponded to the sex difference in locomotion. We show that only males exhibited marked diurnal changes in 7alpha-hydroxypregnenolone synthesis, and these changes occurred in parallel with changes in locomotor activity. Finally, we identified melatonin as a key component of the mechanism regulating 7alpha-hydroxypregnenolone synthesis. Increased synthesis of 7alpha-hydroxypregnenolone occurred in males in vivo after melatonin removal via pinealectomy and orbital enucleation (Px plus Ex). Conversely, decreased synthesis of this neurosteroid occurred after melatonin administration to Px plus Ex males. This study demonstrates that melatonin regulates synthesis of 7alpha-hydroxypregnenolone, a key factor for induction of locomotor activity, thus inducing diurnal locomotor changes in male birds. This is a previously undescribed role for melatonin.

Dataset Information

Diurnal Rhythms Spatially and Temporally Organize Autophagy.

Publications

Diurnal Rhythms Spatially and Temporally Organize Autophagy.

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