Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice.
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.
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Clara Bien
CB
Peek
Alison H
AH
Affinati
Kathryn Moynihan
KM
Ramsey
Hsin-Yu
HY
Kuo
Wei
W
Yu
Laura A
LA
Sena
Olga
O
Ilkayeva
Biliana
B
Marcheva
Yumiko
Y
Kobayashi
Chiaki
C
Omura
Daniel C
DC
Levine
David J
DJ
Bacsik
David
D
Gius
Christopher B
CB
Newgard
Eric
E
Goetzman
Navdeep S
NS
Chandel
John M
JM
Denu
Milan
M
Mrksich
Joseph
J
Bass
D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology*; D004734:Energy Metabolism; D005215:Fasting; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C525046:Sirt3 protein, mouse; D009243:NAD; D056566:Sirtuin 3