Circadian Clock NAD ⁺ Cycle Drives Mitochondrial Oxidative Metabolism in Mice

Abstract

Circadian clocks are self-sustained cellular oscillators that synchronize oxidative and reductive cycles in anticipation of the solar cycle. We found that the clock transcription feedback loop produces cycles of nicotinamide adenine dinucleotide (NAD+) biosynthesis, adenosine triphosphate production, and mitochondrial respiration through modulation of mitochondrial protein acetylation to synchronize oxidative metabolic pathways with the 24-hour fasting and feeding cycle. Circadian control of the activity of the NAD+-dependent deacetylase sirtuin 3 (SIRT3) generated rhythms in the acetylation and activity of oxidative enzymes and respiration in isolated mitochondria, and NAD+ supplementation restored protein deacetylation and enhanced oxygen consumption in circadian mutant mice. Thus, circadian control of NAD+ bioavailability modulates mitochondrial oxidative function and organismal metabolism across the daily cycles of fasting and feeding.

Immunometabolism: Is it under the eye of the clock?

“…Cry1/Cry2 double knock out mice exhibit arrhythmia in free running conditions. As discussed earlier however, CRY1 and CRY2 can impact on cellular metabolism with the double knockout MEFs exhibiting increased mitochondrial ATP, NAD+, FAO and decreased levels of glycolytic lactate [95]. It may be that the cryptochrome proteins promote a more glycolytic phenotype through negative regulation of the BMAL1:CLOCK heterodimer.…”

“…4B). Mouse embryonic fibroblast (MEF) and liver cells lacking Bmal1 display a pro-glycolytic phenotype, evidenced by lower mitochondrial ATP production and higher production of lactate [95]. Levels of the oxioreductase factor nicotinamide adenine dinucleotide (NAD+) and fatty acid oxidation (FAO), which display a circadian rhythm in WT mice, were diminished in cells lacking Bmal1 leading to increased triglycerides.…”

“…[66,116] Clock 19 Global • Obese and display impaired glucose sensitivity with insulin resistance and reduced islet size [112,113] • Increased plasma triglyceride and glucose levels [85,114] • Increased fibrotic damage in model of pulmonary fibrosis [87] • Impaired anti-oxidant defense [87] Cry1/Cry2 Global • Increased NAD+ and ATP. Decreased lactate and triglycerides in MEFs [95] • Greater inflammatory damage in CIA model [146] • Increased Cxcl1. Il-6 and Tnf˛ RNA.…”

“…Decreased triglycerides [95] Pancreas • Diabetes due to loss of glucose induced insulin secretion [76] • Increased ROS [76] Myeloid…”

PLGA‐PNIPAM Microspheres Loaded with the Gastrointestinal Nutrient NaB Ameliorate Cardiac Dysfunction by Activating Sirt3 in Acute Myocardial Infarction

“…Sirt3, one subtype of the Sirt family, is located in the mitochondria, which indicates that NaB may be related to Sirt3. Previous reports have demonstrated that Sirt3 can promote the mobilization of cellular energy stores and protects cells in low‐energy states, acting as an important protector of cell viability 16. Whether Sirt3 plays an important protective role in AMI is unknown.…”