Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins

Adi Neufeld-Cohen, Maria S. Robles, Rona Aviram, Gal Manella, Yaarit Adamovich, Benjamin Ladeuix, Dana Nir, Liat Rousso-Noori, Yael Kuperman, Marina Golik, Matthias Mann, Gad Asher

Research output: Contribution to journalArticlepeer-review

178 Scopus citations


Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied MS-based quantitative proteomics on isolated mitochondria from mice killed throughout the day and identified extensive oscillations in the mitochondrial proteome. Remarkably, the majority of cycling mitochondrial proteins peaked during the early light phase. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and are dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or on a high-fat diet. We propose that PERIOD proteins optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby, serve as a rheostat for mitochondrial nutrient utilization.

Original languageEnglish
Pages (from-to)E1673-E1682
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
StatePublished - 22 Mar 2016
Externally publishedYes


ACKNOWLEDGMENTS: We thank K. Mayr, I. Paron, and G. Sowa for their assistance with the MS measurements and D. Wischnewski and M. Elimelech for technical help. We also thank A. Gross and H. Reinke for their valuable comments on the manuscript. A.N.-C. and Y.A. received a postdoctoral fellowship from the Feinberg Graduate School, Weizmann Institute of Science. The work performed in the laboratory of G.A. was supported by Israel Science Foundation Grant ISF 138/12, the Abish-Frenkel Foundation, Human Frontier Science Program (HFSP) Career Development Award HFSP CDA00014/2012, and European Research Council Grant ERC-2011 METACYCLES 310320.

FundersFunder number
Abish-Frenkel Foundation
Feinberg Graduate School
European Research CouncilERC-2011 METACYCLES 310320
Human Frontier Science ProgramCDA00014/2012
Weizmann Institute of Science
Israel Science FoundationISF 138/12


    • Circadian rhythm
    • Metabolism
    • Mitochondria
    • PERIOD proteins
    • Proteomics


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