Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge

Kazunari Nohara, Venkata Mallampalli, Travis Nemkov, Marvin Wirianto, Jiah Yang, Youqiong Ye, Yuxiang Sun, Leng Han, Karyn A. Esser, Eugenia Mileykovskaya, Angelo D’Alessandro, Carla B Green, Joseph S Takahashi, William Dowhan, Seung Hee Yoo, Zheng Chen

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Circadian disruption aggravates age-related decline and mortality. However, it remains unclear whether circadian enhancement can retard aging in mammals. We previously reported that the small molecule Nobiletin (NOB) activates ROR (retinoid acid receptor-related orphan receptor) nuclear receptors to potentiate circadian oscillation and protect against metabolic dysfunctions. Here we show that NOB significantly improves metabolic fitness in naturally aged mice fed with a regular diet (RD). Furthermore, NOB enhances healthy aging in mice fed with a high-fat diet (HF). In HF skeletal muscle, the NOB-ROR axis broadly activates genes for mitochondrial respiratory chain complexes (MRCs) and fortifies MRC activity and architecture, including Complex II activation and supercomplex formation. These mechanisms coordinately lead to a dichotomous mitochondrial optimization, namely increased ATP production and reduced ROS levels. Together, our study illustrates a focal mechanism by a clock-targeting pharmacological agent to optimize skeletal muscle mitochondrial respiration and promote healthy aging in metabolically stressed mammals.

Original languageEnglish (US)
Article number3923
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

skeletal muscle
respiration
Muscle
Respiration
Skeletal Muscle
Nutrition
Aging of materials
diets
Mammals
Retinoids
High Fat Diet
Electron Transport
mammals
fats
Fats
mice
Acids
Mitochondrial Genes
Cytoplasmic and Nuclear Receptors
acids

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge. / Nohara, Kazunari; Mallampalli, Venkata; Nemkov, Travis; Wirianto, Marvin; Yang, Jiah; Ye, Youqiong; Sun, Yuxiang; Han, Leng; Esser, Karyn A.; Mileykovskaya, Eugenia; D’Alessandro, Angelo; Green, Carla B; Takahashi, Joseph S; Dowhan, William; Yoo, Seung Hee; Chen, Zheng.

In: Nature communications, Vol. 10, No. 1, 3923, 01.12.2019.

Research output: Contribution to journalArticle

Nohara, K, Mallampalli, V, Nemkov, T, Wirianto, M, Yang, J, Ye, Y, Sun, Y, Han, L, Esser, KA, Mileykovskaya, E, D’Alessandro, A, Green, CB, Takahashi, JS, Dowhan, W, Yoo, SH & Chen, Z 2019, 'Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge', Nature communications, vol. 10, no. 1, 3923. https://doi.org/10.1038/s41467-019-11926-y
Nohara, Kazunari ; Mallampalli, Venkata ; Nemkov, Travis ; Wirianto, Marvin ; Yang, Jiah ; Ye, Youqiong ; Sun, Yuxiang ; Han, Leng ; Esser, Karyn A. ; Mileykovskaya, Eugenia ; D’Alessandro, Angelo ; Green, Carla B ; Takahashi, Joseph S ; Dowhan, William ; Yoo, Seung Hee ; Chen, Zheng. / Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge. In: Nature communications. 2019 ; Vol. 10, No. 1.
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