2. Academic Validation
  3. Period3 modulates the NAD+-SIRT3 axis to alleviate depression-like behaviour by enhancing NAMPT activity in mice

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

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: xiexiaoxian502@gmail.com.
  • 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: biolpsychiatry@126.com.
  • 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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