Circadian control of mitochondria OXPHOS activity, dynamics and turnover in vitro synchronized cells

Circadian rhythms driven by biological clocks regulate physiological processes in all living organisms by anticipating daily geophysical changes, thus enhancing environmental adaptation. The cellular time-keeping mechanism is controlled by a transcription-translation feedback loop involving a set of well-characterized transcription factors (with BMAL1/CLOCK being the master circadian clock transcription factors). This mechanism controls 50-60% of genes expressed in mammals including those that regulate cell metabolism. In previous studies, in an in-vitro synchronized cell model, we showed a temporal oscillation of the mitochondrial respiratory chain activity coupled to the ATP synthesis. This observation has been recently confirmed in a panel of different cell types (both primary and cancer-derived lines) indicating this as a general phenomenon. Notably, while primary cell types exhibited similar rhythmic respiratory profiles, cancer-derived cell lines displayed highly heterogeneous rhythmic changes highlighting the need for personalized chronotherapy. The mtDNA genes coding for respiratory chain complex subunits as well as of factors regulating mitochondrial dynamics and turnover revealing for all a BMAL-1-dependent rhythmic profile. Careful analysis of the oscillation phases, supported by confocal microscopy imaging, points to a balance between mitochondrial biogenesis and degradation to optimize the organelle functions.