Nrf2 activation by pyrroloquinoline quinone inhibits natural aging-related intervertebral disk degeneration in mice

Qi Xue; Jie Li; Ran Qin; Mingying Li; Yiping Li; Jing Zhang; Rong Wang; David Goltzman; Dengshun Miao; Renlei Yang

doi:10.1111/acel.14202

Nrf2 activation by pyrroloquinoline quinone inhibits natural aging-related intervertebral disk degeneration in mice

Aging Cell. 2024 May 23:e14202. doi: 10.1111/acel.14202. Online ahead of print.

Authors

Qi Xue^{1

2}, Jie Li¹, Ran Qin³, Mingying Li⁴, Yiping Li¹, Jing Zhang¹, Rong Wang², David Goltzman⁵, Dengshun Miao^{1

2}, Renlei Yang¹

Affiliations

¹ Department of Plastic Surgery, Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
² The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China.
³ Department of Orthopaedics, Nanjing First Hospital, Nanjing, China.
⁴ Shenzhen Key Laboratory for Systemic Aging and Intervention, Shenzhen University, Shenzhen, China.
⁵ Calcium Research Laboratory, McGill University Health Centre and Department of Medicine, McGill University, Montreal, Quebec, Canada.

PMID: 38780001
DOI: 10.1111/acel.14202

Abstract

Age-related intervertebral disk degeneration (IVDD) involves increased oxidative damage, cellular senescence, and matrix degradation. Pyrroloquinoline quinone (PQQ) is a water-soluble vitamin-like compound with strong anti-oxidant capacity. The goal of this study was to determine whether PQQ can prevent aging-related IVDD, and the underlying mechanism. Here, we found that dietary PQQ supplementation for 12 months alleviated IVDD phenotypes in aged mice, including increased disk height index and reduced histological scores and cell loss, without toxicity. Mechanistically, PQQ inhibited oxidative stress, cellular senescence, and senescence-associated secretory phenotype (SASP) in the nucleus pulposus and annulus fibrosus of aged mice. Similarly, PQQ protected against interleukin-1β-induced matrix degradation, reactive oxygen species accumulation, and senescence in human nucleus pulposus cells (NPCs) in vitro. Molecular docking predicted and biochemical assays validated that PQQ interacts with specific residues to dissociate the Keap1-Nrf2 complex, thereby increasing nuclear Nrf2 translocation and activation of Nrf2-ARE signaling. RNA sequencing and luciferase assays revealed Nrf2 can transcriptionally upregulate Wnt5a by binding to its promoter, while Wnt5a knockdown prevented PQQ inhibition of matrix metalloproteinase-13 in NPCs. Notably, PQQ supplementation failed to alleviate aging-associated IVDD phenotypes and oxidative stress in aged Nrf2 knockout mice, indicating Nrf2 is indispensable for PQQ bioactivities. Collectively, this study demonstrates Nrf2 activation by PQQ inhibits aging-induced IVDD by attenuating cellular senescence and matrix degradation. This study clarifies Keap1-Nrf2-Wnt5a axis as the novel signaling underlying the protective effects of PQQ against aging-related IVDD, and provides evidence for PQQ as a potential agent for clinical prevention and treatment of natural aging-induced IVDD.

Keywords: IVDD; Keap1–Nrf2 signaling; Wnt5a; aging; pyrroloquinoline quinone.

Abstract

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