The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn 2+ trafficking
Oct 25, 2023Autophagy
How the NLRX1-SLC39A7 Complex Controls Mitochondrial Movement and Recycling to Revitalize the Spine's Disc by Managing Mitochondrial Zinc Transport
Loss of NLRX1 is correlated with nucleus pulposus cell senescence and .
NLRX1 loss leads to disordered mitochondrial quality in nucleus pulposus cells.
Mitochondrial collapse in NLRX1-defective cells activates the PINK1-PRKN pathway, resulting in excessive .
NLRX1 interacts with the zinc transporter SLC39A7, influencing mitochondrial zinc trafficking and dynamics.
Restoring NLRX1 function may help regulate mitochondrial fission and fusion, supporting mitochondrial homeostasis.
The NLRX1-SLC39A7 complex plays a critical role in managing damaged mitochondria, which could rejuvenate intervertebral discs.
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(IDD) is the most critical pathological factor in the development of low back pain. The maintenance of nucleus pulposus (NP) cell and intervertebral disc integrity benefits largely from well-controlled mitochondrial quality, surveilled by mitochondrial dynamics (fission and fusion) and , but the outcome is cellular context-dependent that remain to be clarified. Our studies revealed that the loss of NLRX1 is correlated with NP cell senescence and IDD progression, which involve disordered mitochondrial quality. Further using animal and in vitro tissue and cell models, we demonstrated that NLRX1 could facilitate mitochondrial quality by coupling mitochondrial dynamic factors (p-DNM1L, L-OPA1:S-OPA1, OMA1) and mitophagy activity. Conversely, mitochondrial collapse occurred in NLRX1-defective NP cells and switched on the compensatory PINK1-PRKN pathway that led to excessive mitophagy and aggressive NP cell senescence. Mechanistically, NLRX1 was originally shown to interact with zinc transporter SLC39A7 and modulate mitochondrial Zntrafficking via the formation of an NLRX1-SLC39A7 complex on the mitochondrial membrane of NP cells, subsequently orchestrating mitochondrial dynamics and mitophagy. The restoration of NLRX1 function by gene overexpression or pharmacological agonist (NX-13) treatment showed great potential for regulating mitochondrial fission with synchronous fusion and mitophagy, thus sustaining mitochondrial homeostasis, ameliorating NP cell senescence and rejuvenating intervertebral discs. Collectively, our findings highlight a working model whereby the NLRX1-SLC39A7 complex coupled mitochondrial dynamics and mitophagy activity to surveil and target damaged mitochondria for degradation, which determines the beneficial function of the mitochondrial surveillance system and ultimately rejuvenates intervertebral discs.3-MA: 3-methyladenine; Baf-A: bafilomycin A; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; DNM1L/DRP1: dynamin 1 like; EdU: 5-Ethynyl-2'-deoxyuridine; HE: hematoxylin-eosin; IDD: intervertebral disc degeneration; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MKI67/Ki67: marker of proliferation Ki-67; LBP: low back pain; MMP: mitochondrial membrane potential; MFN1: mitofusin 1; MFN2: mitofusin 2; MFF: mitochondrial fission factor; NP: nucleus pulposus; NLRX1: NLR family member X1; OMA1: OMA1 zinc metallopeptidase; OPA1: OPA1 mitochondrial dynamin like GTPase; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxidative species; SASP: senescence-associated secretory phenotype; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SO: safranin o; TBHP: tert-butyl hydroperoxide; TP53/p53: tumor protein p53; SLC39A7/ZIP7: solute carrier family 39 member 7; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23. 2+ Abbreviations: 1 1
Key numbers
3
Cell senescence markers increase
Increased levels of senescence markers TP53, CDKN1A, and CDKN2A observed in degenerated NP cells.
100 μM TBHP
Mitochondrial membrane potential recovery
Mitochondrial membrane potential loss was induced by 100 μM TBHP in NP cells.
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