Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins

Abstract

Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied MS-based quantitative proteomics on isolated mitochondria from mice killed throughout the day and identified extensive oscillations in the mitochondrial proteome. Remarkably, the majority of cycling mitochondrial proteins peaked during the early light phase. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and are dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or on a high-fat diet. We propose that PERIOD proteins optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby, serve as a rheostat for mitochondrial nutrient utilization.M itochondria serve as major suppliers of cellular energy through nutrient oxidation. One of the major challenges that mitochondria face is the adaptation to changes in nutrient supply and energy demand. An inability of mitochondria to deal with altered nutrient environment is associated with metabolic diseases, such as diabetes and obesity (1, 2).Mitochondria oxidize carbohydrates and lipids to generate ATP by a process known as oxidative phosphorylation. Pyruvate and fatty acids are transported from the cytoplasm into the mitochondrial matrix, where they are catabolized into acetyl CoA. Pyruvate is converted to acetyl CoA through the action of the pyruvate dehydrogenase complex (PDC), whereas fatty acids are oxidized through a cycle of reactions that trim two carbons at a time, generating one molecule of acetyl CoA in each cycle [i.e., fatty acid oxidation (FAO)]. The acetyl groups are then fed into the Krebs cycle for additional degradation, and the process culminates with the transfer of acetyl-derived high-energy electrons along the respiratory chain.Mounting evidence suggests that circadian clocks orchestrate our daily physiology and metabolism (3-6). The mammalian circadian timing system consists of a central pacemaker in the brain that is entrained by daily light-dark cycles and synchronizes subsidiary oscillators in virtually all cells of the body, in part by driving rhythmic feeding behavior. The core clock molecular circuitry relies on interlocked transcription-translation feedback loops that generate daily oscillations of gene expression in cultured cells and living animals (7). Many transcriptomes (8-12) and more recently, several proteomics (13-15) and metabolomics studies (16-21) highlighted the pervasive circadian control of metabolism.Rest-activity and feeding-fasting cycles that naturally occur throughout the day impose pronounced changes in nutrient s...

Systems Chronobiology: Global Analysis of Gene Regulation in a 24-Hour Periodic World

“…Future studies investigating the circadian dynamics of the distribution of proteins across different cellular subcompartments might be more informative. Interestingly, recent findings suggest that mitochondria also show circadian proteome content mediated by the PERIOD complex (Neufeld-Cohen et al 2016). Finally, critical posttranslational mechanisms such as protein folding, transport, and biochemical modifications are not discussed here.…”

Circadian clock, nutrient quality, and eating pattern tune diurnal rhythms in the mitochondrial proteome

“…Therefore, identifying specific rhythmic nodes in mitochondrial metabolic processes is important for understanding diurnal regulation of metabolism. In PNAS, Neufeld-Cohen et al (11) use a time series proteomics approach in purified liver mitochondria to identify mitochondrial proteins that exhibit daily oscillations, and test their relevance in mitochondrial function under specific genetic, diet, and eating pattern modulation.…”

“…However, circadian liver proteomics studies have failed to identify a sufficient number of mitochondrial components as rhythmic (10). By enriching liver mitochondria before proteomics analyses, Neufeld-Cohen et al (11) identify nearly 38% of 590 mitochondrial proteins detected as cyclic. As opposed to poor correlation between rhythmic mRNA and protein levels identified in previous proteomics studies of whole liver extract, they found that nearly 86% of rhythmic mitochondrial proteins also had corresponding rhythmic mRNAs.…”

A New Perspective for Parkinson’s Disease: Circadian Rhythm

“…Mitochondrion is the target of most neurotoxins of PD and its dysfunction is associated with PD-related genes, such as PINK1, DJ-1, and PARKIN. One recent research showed that the function of mitochondrial respiration displayed in a diurnal manner, which was regulated by the clock proteins [119]. Second, the circadian system may also be disrupted by PD progression.…”