Circadian Rhythms and Mitochondria: Connecting the Dots

Laura Sardon Puig, Miriam Valera-Alberni, Carles Cantó, Nicolas J Pillon, Laura Sardon Puig, Miriam Valera-Alberni, Carles Cantó, Nicolas J Pillon

Abstract

Circadian rhythms provide a selective advantage by anticipating organismal nutrient needs and guaranteeing optimal metabolic capacity during active hours. Impairment of circadian rhythms is associated with increased risk of type 2 diabetes and emerging evidence suggests that metabolic diseases are linked to perturbed clock machinery. The circadian clock regulates many transcriptional-translational processes influencing whole cell metabolism and particularly mitochondrial activity. In this review, we survey the current literature related to cross-talks between mitochondria and the circadian clock and unravel putative molecular links. Understanding the mechanisms that link metabolism and circadian responses to transcriptional modifications will provide valuable insights toward innovative therapeutic strategies to combat the development of metabolic disease.

Keywords: AMPK; HIF1α; acetylation; circadian rhythm; metabolism; mitochondria dynamics.

Figures

FIGURE 1
FIGURE 1
Circadian interactions between the clock and mitochondrial dynamics. In humans, CLOCK:BMAL1 dimers peak at the end of the day (active phase) while PER:CRY are elevated at the end of the dark phase. During the active phase, nutrient availability decreases NAD+ levels and increases ATP content, decreasing the activity of sirtuins and AMPK, respectively. At the same time, the elevated oxygen content inhibits HIF1α and increases reactive oxygen species production. During that phase, the central clock promotes the transcription of NAMPT and NRF2, which will progressively build up the levels NAD+ and antioxidant defenses. At the end of the active phase and during the fasting phase, NAD+ levels are higher, while ATP levels decrease. This leads to activation of sirtuins and AMPK and the promotion of mitochondrial fusion. Activation of sirtuins deacetylates the core clock components, while the decreased oxygen levels promote the activation of HIF1 which bind to the promoters and activates the clock genes. Elongated mitochondria promote coupling and efficient ATP production, starting a new cycle.

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