Clock-genes and mitochondrial respiratory activity: Evidence of a reciprocal interplay

Abstract

In the past few years mounting evidences have highlighted the tight correlation between circadian rhythms and metabolism. Although at the organismal level the central timekeeper is constituted by the hypothalamic suprachiasmatic nuclei practically all the peripheral tissues are equipped with autonomous oscillators made up by common molecular clockworks represented by circuits of gene expression that are organized in interconnected positive and negative feed-back loops. In this study we exploited a well-established in vitro synchronization model to investigate specifically the linkage between clock gene expression and the mitochondrial oxidative phosphorylation (OxPhos). Here we show that synchronized cells exhibit an autonomous ultradian mitochondrial respiratory activity which is abrogated by silencing the master clock gene ARNTL/BMAL1. Surprisingly, pharmacological inhibition of the mitochondrial OxPhos system resulted in dramatic deregulation of the rhythmic clock-gene expression and a similar result was attained with mtDNA depleted cells (Rho0). Our findings provide a novel level of complexity in the interlocked feedback loop controlling the interplay between cellular bioenergetics and the molecular clockwork. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

Homeostatic effects of exercise and sleep on metabolic processes in mice with an overexpressed skeletal muscle clock

“…In regards to mitochondrial oxidation, silencing Bmal1 expression in vivo and ex vivo silences mitochondrial oxidation [5, 34]. Arresting mitochrondrial oxidation can also downregulate Bmal1 expression [34].…”

“…Arresting mitochrondrial oxidation can also downregulate Bmal1 expression [34]. In regards to insulin signaling, developmentally knocking-out or pharmacologically-arresting Bmal1 expression alters blood glucose levels, insulin sensitivity in skeletal muscle, and downregulates GLUT4 and glucose regulatory genes in skeletal muscle.…”

Circadian rhythms in mitochondrial respiration

“…Therefore, it is not surprising that important functions of cellular energy metabolism, such as mitochondrial respiration are under circadian control. Disrupting Bmal1 transcription by siRNA in a liver-derived cell line (HepG2) led to a decrease in mitochondrial respiration ( Scrima et al 2016 ). In mice, genetic ablation of Bmal1 at the whole-body level resulted in a decreased oxygen consumption rate (OCR) in isolated liver mitochondria ( Peek et al 2013 ).…”

The importance of determining circadian parameters in pharmacological studies

“…These TFs, via transcriptional and translational feedback loops, regulate their own transcription, which leads to ≈24‐hr oscillations in their gene and protein expression in all cells, tissues, and organs. In addition, the CCN elements coordinate the transcription of many other genes, clock‐controlled genes (CCGs), in a circadian‐ and organ‐specific manner, regulating a variety of biological processes, at both the cell and tissue levels, such as cell division, bioenergetics, autophagy, metabolism, redox balance, hormone regulation, and immune responses (El‐Athman et al, ; Fuhr et al, ; Relógio et al, ; Scrima et al, ; Zhang, Lahens, Ballance, Hughes, & Hogenesch, ; reviewed in Pilorz et al, ). These cellular peripheral clocks, distributed throughout the body, are further coordinated by a central pacemaker, located at the suprachiasmatic nuclei (SCNs) in the hypothalamus (Albrecht, ).…”