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

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.

<p>Knockdown of hsa_circ_0059955 Induces Apoptosis and Cell Cycle Arrest in Nucleus Pulposus Cells via Inhibiting <em>Itchy E3 Ubiquitin Protein Ligase</em></p>

“…30 The mitochondrial apoptosis pathway is induced mainly by apoptotic signals. 31 Apoptotic signals could lead to the loss of MMP, and cause the release of cytochrome c from the mitochondria into the cytosol. 31,32 Bcl-2 family proteins could maintain the mitochondrial integrity, including proapoptotic protein Bax, and anti-apoptotic protein Bcl-2.…”

“…31 Apoptotic signals could lead to the loss of MMP, and cause the release of cytochrome c from the mitochondria into the cytosol. 31,32 Bcl-2 family proteins could maintain the mitochondrial integrity, including proapoptotic protein Bax, and anti-apoptotic protein Bcl-2. 33 Bax could trigger the release of cytochrome c into the cytosol via regulation of the mitochondrial permeability.…”

Quercetin Suppresses Apoptosis and Attenuates Intervertebral Disc Degeneration via the SIRT1-Autophagy Pathway

“…Rat NP cells were kindly generated and donated by Prof. Di Chen (Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences), and were maintained in DMEM/F12 (1:1) (DF12; Gibco, Grand Island, NY, United States) containing 10% fetal bovine serum (FBS; Invitrogen, Carlsbad, CA, United States) and 1% antibiotics (penicillin/streptomycin) (Gibco) in a 5% CO 2 incubator at 37°C ( Zheng et al, 2018 ; Xu X. et al, 2019 ). The complete culture medium was replaced every other day.…”

MicroRNAs as novel targets of sulforaphane in cancer therapy: The beginning of a new tale?

“…This compound is formed by glucoraphanin in the existence of the myrosinase enzymes. As an active compound, this naturally occurring nutraceutical compound is classified at the isothiocyanate group of organosulfur compounds (Xu et al, ). It seems that the extract of B. oleracea containing sulforaphane has a great anti‐inflammatory potential and significantly improves spatial learning (Subedi, Cho, Park, Choi, & Kim, ).…”

“…It seems that the extract of B. oleracea containing sulforaphane has a great anti‐inflammatory potential and significantly improves spatial learning (Subedi, Cho, Park, Choi, & Kim, ). It has been demonstrated that sulforaphane has the capability of decreasing the mitochondrial dysfunction and improving aging deficiencies (Xu et al, ). In addition to anti‐inflammatory and antiaging effects, sulforaphane has shown a number of other pharmacological potentials such as antidiabetic (Wang et al, ), antioxidant (Subedi et al, ), antitumor (Negrette‐Guzmán, ), hepatoprotection (Saleh, Mansour, Hashad, & Bakeer, ), and cardioprotection (Angeloni et al, ).…”