Circadian clocks are evolutionary ancient, essential physiological mechanisms for anticipation of external cues. Initiated with a discovery of the molecular cogs of the clock in Drosophila, distinguished by a recent Nobel Prize, the last two decades have seen a dynamized field of circadian physiology characterize clock-dependent control of the transcriptional, translational, post-translational and metabolic landscapes. This brought us to our current understanding of daily metabolic regulation in mammals and further established that impairing the clock rhythms triggers a wide array of pathologies. Chronodisruption, a chronic misalignment between internal clock and social life is seen in 20% of European workers and most of us are "socially jetlagged" by irregular sleep/wake and meal schedules. This translates into dramatic figures of fatty liver disease and insulin resistance affecting 20–30% of European adults.
In this context, we recently demonstrated that the hepatic circadian clock controls daily mitochondrial rhythms to maintain metabolic homeostasis. Genetic alteration of the hepatic circadian clock (mutant of essential clock gene Bmal1) obliterates mitochondrial daily rhythms and triggers metabolic complications. This occurs through loss of mitochondrial morphological changes such as the pre-programmed daily mitochondrial fission that is required to dissipate oxidative stress inflicted by fuel burning during feeding. In addition, altered mitophagy, a selective lysosomal degradation of mitochondria by autophagy, would dampen mitochondrial renewal.
Recognition of the circadian nature of mitochondria function opens 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, we will build on our previous findings and will test the hypothesis that altered MitoChondrial daily Rhythms trigger overnutrition-related metaboliC diseAses (MitoCIRCA proposal).
We propose an interdisciplinary research program to test the pathophysiologic role and therapeutic potential of targeting altered mitochondrial daily rhythms. First, we will determine at cellular and biochemical levels how overnutrition alters mitochondrial daily rhythms. We will use state-of-the-art technologies, including in vivo study of mitochondrial morphology and reactive oxygen species production in mouse liver. Second, we will examine whether enhancing mitochondrial quality control restores metabolic homeostasis in the liver. We will use mouse genetic models, including liver-specific Fis1 knock-out. Finally, we will assess the therapeutic potential of modulating mitochondrial dynamics in the liver to resolve liver metabolic diseases.
Our preliminary results in vivo back MitoCIRCA proposal. We have shown that in mouse liver high fat diet challenge inflicts: 1) early alterations of mitochondrial daily rhythms accompanied by increased oxidative stress, 2) alteration in mitochondria repair systems, and 3) in these conditions, promotion of mitochondrial fission and repair systems improved metabolic phenotype.
When completed, the MitoCIRCA research program will resolve key issues in understanding the epidemic of metabolic diseases. First, it will provide irrefutable evidence on whether overnutrition triggers early anomalies in daily functional rhythms of mitochondria. Second, it will demonstrate whether disturbed daily rhythms of hepatic mitochondria alter ROS production and mitochondrial quality control could explain the metabolic deffects of chronodisruption. Third, it might establish the mechanisms of mitochondria turnover through diurnal mitochondrial dynamics as an essential and targetable cog in the pathogenesis of metabolic diseases. Finally, MitoCIRCA project can open awaited therapeutic avenues by providing chrono-pharmacology targets as well as a strong rational for chrononutrition.
Monsieur David Jacobi (L'unité de recherche de l'institut du thorax)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM UMR 1087 / CNRS UMR 6291 L'unité de recherche de l'institut du thorax
Help of the ANR 314,064 euros
Beginning and duration of the scientific project: June 2020 - 36 Months