Circadian rhythms in mitochondrial respiration

Abstract

Many physiological processes are regulated with a 24-h periodicity to anticipate the environmental changes of daytime to nighttime and vice versa. These 24-h regulations, commonly termed circadian rhythms, among others control the sleep-wake cycle, locomotor activity and preparation for food availability during the active phase (daytime for humans and nighttime for nocturnal animals). Disturbing circadian rhythms at the organ or whole-body level by social jetlag or shift work, increases the risk to develop chronic metabolic diseases such as type 2 diabetes mellitus. The molecular basis of this risk is a topic of increasing interest. Mitochondria are essential organelles that produce the majority of energy in eukaryotes by converting lipids and carbohydrates into ATP through oxidative phosphorylation. To adapt to the ever-changing environment, mitochondria are highly dynamic in form and function and a loss of this flexibility is linked to metabolic diseases. Interestingly, recent studies have indicated that changes in mitochondrial morphology (i.e., fusion and fission) as well as generation of new mitochondria are dependent on a viable circadian clock. In addition, fission and fusion processes display diurnal changes that are aligned to the light/darkness cycle. Besides morphological changes, mitochondrial respiration also displays diurnal changes. Disturbing the molecular clock in animal models leads to abrogated mitochondrial rhythmicity and altered respiration. Moreover, mitochondrial-dependent production of reactive oxygen species, which plays a role in cellular signaling, has also been linked to the circadian clock. In this review, we will summarize recent advances in the study of circadian rhythms of mitochondria and how this is linked to the molecular circadian clock.

Keywords: circadian clock; circadian rhythm; mitochondria; mitochondrial functioning; respiration.

Figure 1

The molecular circadian clock and tissue-specific clocks in the body. CLOCK and BMAL1 form a heterodimer that binds to E-box regulatory sequences PER/CRY and other genes. PER and CRY form a repressor complex, which inhibitsCLOCK-BMAL1 when sufficient levels are reached. The second feedback loop involves nuclear orphan receptors, which bind to the retinoic acid-related orphan receptor response elements (ROREs) in CLOCK and BMAL1 regulatory sequences. Retinoid-related orphan receptor (ROR) activates transcription of CLOCK and BMAL1. The CLOCK-BMAL1 complex induces transcription of REVERBA and REVERBB (REV), which subsequently compete with ROR, in order to inhibit transcription of CLOCK and BMAL1. Circadian clocks exist in almost every cell and exhibit tissue-specific rhythmicity, orchestrated by the central circadian clock in the suprachiasmatic nucleus. Synchronization takes place via neural, hormonal and behavioral signals.

Figure 2

Model for circadian regulation of mitochondrial homeostasis. To maintain healthy mitochondria, mitochondria are continuously formed and removed during the active phase. The CLOCK-BMAL1 complex stimulates mitochondrial biogenesis and mitophagy through activation of SIRT1. Mitochondrial biogenesis is regulated by transcription factor PGC1A. Newly formed mitochondria fuse to form a tubular network. Mitophagy is preceded by mitochondrial fission in order to form fragmented mitochondria which can be taken up by an autophagosome. Both fusion and fission are influenced by CLOCK-BMAL1. A number of regulatory proteins regulate fusion (OPA1, MFN1/2), fission (FIS1, DRP1) and mitophagy (PINK1, BNIP1, PARKIN) processes.

Figure 3

Mitochondrial respiration and ROS production show rhythmic activity. Mitochondrial respiration is the result of electron transfer to molecular oxygen as final step in the electron transport chain (ETC). Respiration is experimentally determined by measuring OCR. In addition, ¹⁴C-labeled substrates can be used to assess mitochondrial energy production by measuring ¹⁴CO₂. Substrate transport (CPT1/2, PDH) and catabolic processes (β-oxidation, TCA cycle) also exhibit circadian rhythms and are under control of the circadian clock. Consequently, mitochondrial respiration is rhythmic in various cell and animal models. Mitochondria are also a source of ROS that are produced in various sites, such as complex I of the ETC. Superoxides (O₂ ⁻) are scavenged by superoxidedismutase (SOD) and reduced to H₂O₂. Several antioxidant proteins such as peroxiredoxins (PRXIII) subsequently eliminate H₂O₂. Also antioxidant proteins and ROS production display circadian activity. Additionally, feeding behavior, including diet composition, also affects mitochondrial processes.