Urolithin A-induced mitophagy suppresses apoptosis and attenuates intervertebral disc degeneration via the AMPK signaling pathway

Lin, Jialiang; Zhuge, Jinru; Zheng, Xuan-Qi; Wu, Yuhao; Zhang, Zengjie; Xu, Tianzhen; Meftah, Zaher; Xu, Hongming; Wu, Yaosen; Tian, Naifeng; Gao, Weiyang; Zhou, Yifei; Zhang, Xiaolei; Wang, Xiangyang

doi:10.1016/j.freeradbiomed.2020.02.024

Cited by 97 publications

(74 citation statements)

References 40 publications

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“…Urolithins are microbiota-derived gut metabolites, which are converted from ellagitannins available in pomegranate and some types of berries with anti-senescent and antidegenerative properties in NP cells and IVD, respectively [143][144][145]. In particular, urolithin A has shown to be a potent mitophagy activator, being able to preserve IVD cell homeostasis [146]. In NP cells, urolithin A suppressed intrinsic apoptosis pathway and relatively restored ΔΨ m level which was lost by TBHP treatment.…”

Section: Non-canonical Pathwaymentioning

confidence: 99%

Targeting mitochondrial dysfunction with small molecules in intervertebral disc aging and degeneration

2021

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The prevalence of rheumatic and musculoskeletal diseases (RMDs) including osteoarthritis (OA) and low back pain (LBP) in aging societies present significant cost burdens to health and social care systems. Intervertebral disc (IVD) degeneration, which is characterized by disc dehydration, anatomical alterations, and extensive changes in extracellular matrix (ECM) composition, is an important contributor to LBP. IVD cell homeostasis can be disrupted by mitochondrial dysfunction. Mitochondria are the main source of energy supply in IVD cells and a major contributor to the production of reactive oxygen species (ROS). Therefore, mitochondria represent a double-edged sword in IVD cells. Mitochondrial dysfunction results in oxidative stress, cell death, and premature cell senescence, which are all implicated in IVD degeneration. Considering the importance of optimal mitochondrial function for the preservation of IVD cell homeostasis, extensive studies have been done in recent years to evaluate the efficacy of small molecules targeting mitochondrial dysfunction. In this article, we review the pathogenesis of mitochondrial dysfunction, aiming to highlight the role of small molecules and a selected number of biological growth factors that regulate mitochondrial function and maintain IVD cell homeostasis. Furthermore, molecules that target mitochondria and their mechanisms of action and potential for IVD regeneration are identified. Finally, we discuss mitophagy as a key mediator of many cellular events and the small molecules regulating its function.

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Section: Non-canonical Pathwaymentioning

confidence: 99%

Targeting mitochondrial dysfunction with small molecules in intervertebral disc aging and degeneration

2021

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“…The majority of the findings showing a direct regulation of these two processes support the idea that mitophagy occurs as a pro-survival mechanism. Prevention of mitophagy, by Parkin and/or PINK1 inhibition, or by cyclosporine A or 3-MA treatment, induced CytC release and caspase activity, stimulating apoptosis ( Tian et al, 2019 ; Kang et al, 2020 ; Li C. et al, 2020 ; Lin et al, 2020 ). Consistently, mitophagy induction via Urolithin A or FCCP treatment prevented apoptosis ( Tian et al, 2019 ; Lin et al, 2020 ).…”

Section: Mitophagy: a Pro-survival Or A Pro-apoptotic Mechanism?mentioning

confidence: 99%

Role of Mitofusins and Mitophagy in Life or Death Decisions

Joaquim

Escobar-Henriques

2020

Front. Cell Dev. Biol.

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Mitochondria entail an incredible dynamism in their morphology, impacting death signaling and selective elimination of the damaged organelles. In turn, by recycling the superfluous or malfunctioning mitochondria, mostly prevalent during aging, mitophagy contributes to maintain a healthy mitochondrial network. Mitofusins locate at the outer mitochondrial membrane and control the plastic behavior of mitochondria, by mediating fusion events. Besides deciding on mitochondrial interconnectivity, mitofusin 2 regulates physical contacts between mitochondria and the endoplasmic reticulum, but also serves as a decisive docking platform for mitophagy and apoptosis effectors. Thus, mitofusins integrate multiple bidirectional inputs from and into mitochondria and ensure proper energetic and metabolic cellular performance. Here, we review the role of mitofusins and mitophagy at the crossroad between life and apoptotic death decisions. Furthermore, we highlight the impact of this interplay on disease, focusing on how mitofusin 2 and mitophagy affect non-alcoholic fatty liver disease.

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“…In mammals, there are two main apoptotic pathways: the extrinsic (also called death receptor) and the intrinsic (also called mitochondrial) (Wajant, 2002). It is acknowledged that oxidative stress-induced mitochondrial dysfunction is one of the important mechanisms that trigger the intrinsic pathway of apoptosis in NP cells (Lin et al, 2020). An oxidative injury leads to decrease in mitochondrial membrane potential and ATP production, and increase in mitochondrial outer membrane permeability, followed by the release of cytochrome c and activation of caspase cascade, which eventually leads to apoptosis (Chen et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

CRISPR/dCas9-Mediated Parkin Inhibition Impairs Mitophagy and Aggravates Apoptosis of Rat Nucleus Pulposus Cells Under Oxidative Stress

Lan

Zheng

et al. 2021

Front. Mol. Biosci.

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ObjectiveThe aim of this study is to explore the role of Parkin in intervertebral disk degeneration (IDD) and its mitophagy regulation mechanism.Study design and methodsRat nucleus pulposus (NP) cells were stimulated with hydrogen peroxide (H2O2) to a mimic pathological condition. Apoptosis and mitophagy were assessed by Western blot, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and immunofluorescence staining. The CRISPR–dCas9–KRAB system was used to silence the expression of Parkin.ResultIn this study, we found that Parkin was downregulated in rat NP cells under oxidative stress. In addition, treatment with H2O2 resulted in mitochondrial dysfunction, autophagy inhibition, and a significant increase in the rate of apoptosis of NP cells. Meanwhile, mitophagy inhibition enhanced H2O2-induced apoptosis. Furthermore, repression of Parkin significantly attenuated mitophagy and exacerbated apoptosis.ConclusionThese results suggested that Parkin may play a protective role in alleviating the apoptosis of NP cells via mitophagy, and that targeting Parkin may provide a promising therapeutic strategy for the prevention of IDD.

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Urolithin A-induced mitophagy suppresses apoptosis and attenuates intervertebral disc degeneration via the AMPK signaling pathway

Cited by 97 publications

References 40 publications

Targeting mitochondrial dysfunction with small molecules in intervertebral disc aging and degeneration

Targeting mitochondrial dysfunction with small molecules in intervertebral disc aging and degeneration

Role of Mitofusins and Mitophagy in Life or Death Decisions

CRISPR/dCas9-Mediated Parkin Inhibition Impairs Mitophagy and Aggravates Apoptosis of Rat Nucleus Pulposus Cells Under Oxidative Stress

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