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Theranostics 2019; 9(8):2252-2267. doi:10.7150/thno.30658 This issue Cite

Research Paper

Progerin accumulation in nucleus pulposus cells impairs mitochondrial function and induces intervertebral disc degeneration and therapeutic effects of sulforaphane

Xiaolong Xu^1#, Di Wang^1#, Chao Zheng^1#, Bo Gao^1#, Jing Fan¹, Pengzhen Cheng¹, Baohua Liu², Liu Yang^1,3✉, Zhuojing Luo^1,3✉

1. Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China
2. Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen 518060, People's Republic of China
3. Medical Research Institute, Northwestern Polytechnical University, Xi'an 710072, People's Republic of China
^#These authors contributed equally to this work.

✉ Corresponding authors: Liu Yang, Ph.D., Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China. E-mail: yangliuedu.cn. Tel: 86-29-84775291. Zhuojing Luo, Ph.D., Institute of Orthopedic Surgery, Fourth Military Medical University, Xi'an, People's Republic of China. E-mail: zjluoedu.cn. Tel:86-13809188665. More

Abstract

Progerin, a truncated unprocessed lamin A protein, causes tissue aging and degeneration. In this study we explored the role of progerin in the pathogenesis of intervertebral disc degeneration (IDD). We also examined the effect of sulforaphane (SFN) on progerin accumulation and mitochondrial dysfunction in IDD.

Methods: The role of progerin in IDD was explored using human nucleus pulposus (NP) tissues, rat NP cells, and Lmna G609G knock-in mice. Immunostaining, X-ray imaging, and Western blotting were performed to assess the phenotypes of intervertebral discs. Alterations in senescence and apoptosis were evaluated by SA-β-galactosidase, immunofluorescence, flow cytometry, and TUNEL assays. Mitochondrial function was investigated by JC-1 staining, transmission electron microscopy, and determination of the level of ATP and the activities of mitochondrial enzymes.

Results: The progerin level was elevated in degenerated human NP tissues. Lmna G609G/G609G mice displayed IDD, as evidenced by increased matrix metalloproteinase-13 expression and decreased collagen II and aggrecan expression and disc height. Furthermore, progerin overexpression in rat NP cells induced mitochondrial dysfunction (decreased ATP synthesis, mitochondrial membrane potential, and activities of mitochondrial complex enzymes), morphologic abnormalities, and disrupted mitochondrial dynamic (abnormal expression of proteins involved in fission and fusion), resulting in apoptosis and senescence. SFN ameliorated the progerin-induced aging defects and mitochondrial dysfunction in NP cells and IDD in Lmna G609G/G609G mice.

Conclusions: Progerin is involved in the pathogenesis of IDD. Also, SFN alleviates progerin‑induced IDD, which is associated with amelioration of aging defects and mitochondrial dysfunction. Thus, SFN shows promise for the treatment of IDD.

Keywords: Intervertebral disc degeneration, progerin, mitochondria, sulforaphane

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