MitoCIRCA : MitoChondrial daily Rhythms in metaboliC diseAses

The MitoCIRCA project on the molecular mechanisms of the daily metabolic adaptations will address key issues in understanding the epidemic of metabolic diseases. It can open awaited therapeutic avenues by identifying innovative chrono-pharmacology targets and by providing a strong physiological rational for chrononutrition.
MitoCIRCA project lead by David Jacobi is supported by Agence Nationale de la Recherche (2020-2022).

Circadian clocks are present in almost all life and this shows the importance of anticipation of external cues in physiology. The 2017 Nobel laureates Prs Hall, Rosbash, and Young pioneered the description of the molecular cogs of the clock with studies in Drosophila between 1984-98. Then, over the last two decades, a dynamized field of circadian physiology characterized clock-dependent control of the transcriptional, translational, or post-translational landscapes. This brought us to our current understanding of daily metabolic regulation in mammals. It also led to the knowledge that impairing the clock rhythms triggers a wide array of pathologies.
In this context, David Jacobi recently demonstrated that the hepatic circadian clock controls daily mitochondrial rhythms to maintain metabolic homeostasis. He showed that genetic alteration (Bmal1 KO) of the hepatic circadian clock obliterates mitochondrial daily rhythms and triggers metabolic complications. This would occur through loss of mitochondrial morphological changes such as the pre-programmed daily induction of mitochondrial fission that dissipates oxidative stress due to fuel burning during feeding. Also, altered mitophagy, the selective degradation of mitochondria by autophagy, would dampen mitochondrial repair mechanisms.

Recognising the circadian nature of mitochondria is opening avenues to understand physiopathology and to improve health care. However, an outstanding question is whether overnutrition, a known circadian disruptor, triggers metabolic diseases through altered mitochondrial daily rhythms. Therefore, Jacobi's team will now explore the physiopathological relevance of his previous findings by testing the hypothesis that altered MitoChondrial daily Rhythms trigger overnutrition-related metaboliC diseAses (MitoCIRCA project).