The inhibition of PINK1/Drp1-mediated mitophagy by hyperglycemia leads to impaired osteoblastogenesis in diabetes

Xiao-Jing Chen; Yu-Ying Yang; Zheng-Can Pan; Jing-Zun Xu; Tao Jiang; Lin-Lin Zhang; Ke-Cheng Zhu; Deng Zhang; Jia-Xi Song; Chun-Xiang Sheng; Li-Hao Sun; Bei Tao; Jian-Min Liu; Hong-Yan Zhao

doi:10.1016/j.isci.2024.111519

The inhibition of PINK1/Drp1-mediated mitophagy by hyperglycemia leads to impaired osteoblastogenesis in diabetes

iScience. 2024 Dec 3;28(1):111519. doi: 10.1016/j.isci.2024.111519. eCollection 2025 Jan 17.

Authors

Xiao-Jing Chen^{1

2

3}, Yu-Ying Yang^{1

2}, Zheng-Can Pan^{1

2}, Jing-Zun Xu^{1

2}, Tao Jiang^{1

2}, Lin-Lin Zhang^{1

2}, Ke-Cheng Zhu^{1

2}, Deng Zhang^{1

2}, Jia-Xi Song^{1

2}, Chun-Xiang Sheng^{1

2}, Li-Hao Sun^{1

2}, Bei Tao^{1

2}, Jian-Min Liu^{1

2}, Hong-Yan Zhao^{1

2}

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Impaired bone quality and increased fracture risk are cardinal features of the skeleton in diabetes mellitus. Hyperglycemia-induced oxidative stress is proposed as a potential underlying mechanism, but the precise pathogenic mechanism remains incompletely understood. In this investigation, osteoblasts under high glucose exhibited heightened levels of reactive oxygen species, impaired mitochondrial membrane potential, and profound inhibition of late-stage osteoblast differentiation. Further analyses uncovered that high glucose resulted in the downregulation of the PINK1/Drp1 pathway in osteoblasts, consequently leading to impaired mitophagy. Conversely, the upregulation of PINK1/Drp1 pathway activated mitophagy, which restored the differentiation capacity of osteoblasts. Notably, in an STZ-induced diabetic mouse model, BMP9 upregulated the expression of PINK1/Drp1 in the bone tissue, leading to an improvement in bone quality and bone mineral density. These findings suggest that the PINK1/Drp1 pathway might be a potential therapeutic target to enhance osteogenic differentiation and treat diabetic osteoporosis.

Keywords: Cell biology; Molecular biology; Physiology.