Period3 modulates the NAD+-SIRT3 axis to alleviate depression-like behaviour by enhancing NAMPT activity in mice

  • J Adv Res. 2025 Feb 1:S2090-1232(25)00062-1. doi: 10.1016/j.jare.2025.01.043.
Xiaoxian Xie  1 ,  Haoshen Xu  2 ,  Ruonan Shu  2 ,  Shulin Du  3 ,  Haidan Fan  4 ,  Mengya Zhang  2 ,  Lei Sun  2 ,  Jiafeng Zhou  2 ,  Liangliang Wang  5 ,  Zezhi Li  6 ,  Daniel C Anthony  7
Affiliations
  • 1. Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai 201108, China; Department of Pharmacology, University of Oxford, Mansfield Road OX1 3QT, Oxford, UK; Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, Shanghai Mental Health Center, Shanghai 201108, China. Electronic address: [email protected].
  • 2. College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China.
  • 3. Department of Nutritional and Metabolic Psychiatry, Affliated Brain Hospital, Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China.
  • 4. College of Animal Science, South China Agricultural University, Guangzhou 510640, China.
  • 5. College of Ecology, Lishui University, Lishui 323000, China.
  • 6. Department of Nutritional and Metabolic Psychiatry, Affliated Brain Hospital, Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China. Electronic address: [email protected].
  • 7. Department of Pharmacology, University of Oxford, Mansfield Road OX1 3QT, Oxford, UK.
PMID: 39894345 DOI: 10.1016/j.jare.2025.01.043
Abstract

Introduction: PERIOD (PER)3 deficiency is associated with depression-like behaviors, but the underlying mechanisms remain unclear.

Objectives: This study aims to elucidate the role and mechanism of PER3 in regulating depression-like behaviors in mice.

Methods: Depression-like behaviors were assessed using the sucrose preference test, tail suspension test, and forced swimming test. Metabolomic analysis was conducted on hippocampal tissues from Per3 knockout mice using chromatography-mass spectrometry. The regulatory role of PER3 on the expression of nicotinamide phosphoribosyltransferase (NAMPT) was investigated through co-immunoprecipitation and chromatin immunoprecipitation assays.

Results: Metabolomic analysis revealed that Per3 deficiency disrupts mitochondrial function, as evidenced by reduced activities of key tricarboxylic acidcycle Enzymes (Succinate Dehydrogenase, citrate synthase, and α-ketoglutarate dehydrogenase), diminished expression of mitochondrial respiratory chain complexes I-V, and decreased nicotinamide adenine dinucleotide (NAD)+ levels in Per3 knockout mice. Supplementation with the NAD+ precursor nicotinamide rescued mitochondrial function and alleviated depression-like behaviors in Per3 knockout mice. Similar effects were observed with intraperitoneal administration of the NAMPT activator P7C3-A20, while these effects were abolished by the NAMPT Inhibitor FK866. Mechanistically, PER3 was found to regulate NAMPT expression by binding to E-box elements within its intronic regions in conjunction with BMAL1. This interaction enhanced NAD+ production, activating SIRT3 to mitigate mitochondrial dysfunction in Per3 knockout mice.

Conclusions: These findings uncover a novel mechanism by which PER3 ameliorates depressive behaviors through the regulation of NAMPT-controlled NAD+ levels and mitochondrial function, underscoring the critical role of PER3 in depression-related pathophysiology.

Keywords
Depression-like behavior; Energy metabolism; Mitochondrial complex; NAD(+); Per3; SIRT3.
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