VCP/p97 cofactor UBXN1/SAKS1 regulates mitophagy by modulating MFN2 removal from mitochondria

Mengus, Chantal; Neutzner, Melanie; Bento, Ana C.; Bippes, Claudia C.; Kohler, Corina; Decembrini, Sarah; Häusel, Jessica; Hemion, Charles; Sironi, Lara; Frank, Stephan; Scholl, Hendrik P. N.; Neutzner, Albert

doi:10.1080/15548627.2021.1922982

Cited by 21 publications

(14 citation statements)

References 47 publications

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“…MFN2 is a gene facilitating mitochondrial fusion (Han et al, 2021). It inhibits mitochondrial fission and is being a target protein for mitophagy (Mengus et al, 2021). Despite no evidence reporting the association between diabetes and MFN2 in the cardiac fibroblast, it has been reported that MFN2 was reduced in diabetes condition in various cell types (Bach et al, 2005;Sebastian et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: High Glucose Activated Cardiac Fibroblasts by a Disruption of Mitochondria-Associated Membranes

Zhang¹,

Lin²,

Chen³

et al. 2021

Front. Physiol.

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Cardiac fibrosis is evident even in the situation without a significant cardiomyocyte loss in diabetic cardiomyopathy and a high glucose (HG) level independently activates the cardiac fibroblasts (CFs) and promotes cell proliferation. Mitochondrial respiration and glycolysis, which are key for cell proliferation and the mitochondria-associated membranes (MAMs), are critically involved in this process. However, the roles and the underlying mechanism of MAMs in the proliferation of HG-induced CFs are largely unknown. The proliferation and apoptosis of CFs responding to HG treatment were evaluated. The MAMs were quantified, and the mitochondrial respiration and cellular glycolytic levels were determined using the Seahorse XF analyzer. The changes of signal transducer and activator of transcription 3 (STAT3) and mitofusin-2 (MFN2) in responding to HG were also determined, the effects of which on cell proliferation, MAMs, and mitochondrial respiration were assessed. The effects of STAT3 on MFN2 transcription was determined by the dual-luciferase reporter assay (DLRA) and chromatin immunoprecipitation (CHIP). HG-induced CFs proliferation increased the glycolytic levels and adenosine triphosphate (ATP) production, while mitochondrial respiration was inhibited. The MAMs and MFN2 expressions were significantly reduced on the HG treatment, and the restoration of MFN2 expression counteracted the effects of HG on cell proliferation, mitochondrial respiration of the MAMs, glycolytic levels, and ATP production. The mitochondrial STAT3 contents were not changed by HG, but the levels of phosphorylated STAT3 and nuclear STAT3 were increased. The inhibition of STAT3 reversed the reduction of MFN2 levels induced by HG. The DLRA and CHIP directly demonstrated the negative regulation of MFN2 by STAT3 at the transcription levels via interacting with the sequences in the MFN2 promoter region locating at about −400 bp counting from the start site of transcription. The present study demonstrated that the HG independently induced CFs proliferation via promoting STAT3 translocation to the nucleus, which switched the mitochondrial respiration to glycolysis to produce ATP by inhibiting MAMs in an MFN2-depression manner.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: High Glucose Activated Cardiac Fibroblasts by a Disruption of Mitochondria-Associated Membranes

Zhang¹,

Lin²,

Chen³

et al. 2021

Front. Physiol.

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“…Mitophagy is activated in senescent cells [36]. Mitochondrial depolarization is a hallmark of mitophagy [37]. Furthermore, Drp1 plays a key role in mitophagy progression.…”

Section: Extraction and Culture Of Foreskin Fibroblastsmentioning

confidence: 99%

Metformin Attenuates UVA-Induced Skin Photoaging by Suppressing Mitophagy and the PI3K/AKT/mTOR Pathway

Chen

Zhang

Yang

et al. 2022

IJMS

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Ultraviolet (UV) radiation is a major cause of photoaging that can induce DNA damage, oxidative stress, and cellular aging. Metformin (MF) can repair DNA damage, scavenge reactive oxygen species (ROS), and protect cells. However, the mechanism by which MF inhibits cell senescence in chronic skin damage induced by UVA is unclear. In this study, human foreskin fibroblasts (HFFs) treated with UVA were used as an in vitro model and UVA-induced skin photoaging in Kunming mice was used as an in vivo model to investigate the potential skin protective mechanism of MF. The results revealed that MF treatment attenuated UVA-induced cell viability, skin aging, and activation of the PI3K/AKT/mTOR signaling pathway. Furthermore, MF treatment alleviated the mitochondrial oxidative stress and decreased mitophagy. Knockdown of Parkin by siRNA increased the clearance of MF in senescent cells. The treatment of Kunming mice with MF at a dose of 10 mg/kg/day significantly reduced UVA-induced skin roughness, epidermal thinning, collagen degradation, and skin aging. In conclusion, our experimental results suggest that MF exerts anti-photoaging effects by inhibiting mitophagy and the PI3K/AKT/mTOR signaling pathway. Therefore, our study improves the current understanding of the protective mechanism of MF against photoaging.

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“…Furthermore, in 2017 Zhang and colleagues demonstrated that the inhibition of VCP mutants in vivo suppresses mitochondrial defects, cell death and muscle damage ( 173 ). In this function VCP is assisted by different cofactors: UBXD1 translocates to mitochondria and promotes the VCP recruitment ( 174 ), whereas the cofactor UBXN1/SAKS1 facilitates Mfn2 degradation from mitochondria ( 175 ).…”

Section: Vcp and Mitochondrial Quality Controlmentioning

confidence: 99%

The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis—Frontotemporal Dementia

et al. 2022

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Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurological diseases which, respectively, and primarily affect motor neurons and frontotemporal lobes. Although they can lead to different signs and symptoms, it is now evident that these two pathologies form a continuum and that hallmarks of both diseases can be present within the same person in the so-called ALS-FTD spectrum. Many studies have focused on the genetic overlap of these pathologies and it is now clear that different genes, such as C9orf72, TARDBP, SQSTM1, FUS, and p97/VCP can be mutated in both the diseases. VCP was one of the first genes associated with both FTD and ALS representing an early example of gene overlapping. VCP belongs to the type II AAA (ATPases Associated with diverse cellular activities) family and is involved in ubiquitinated proteins degradation, autophagy, lysosomal clearance and mitochondrial quality control. Since its numerous roles, mutations in this gene lead to different pathological features, first and foremost TDP-43 mislocalization. This review aims to outline recent findings on VCP roles and on how its mutations are linked to the neuropathology of ALS and FTD.

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VCP/p97 cofactor UBXN1/SAKS1 regulates mitophagy by modulating MFN2 removal from mitochondria

Cited by 21 publications

References 47 publications

RETRACTED: High Glucose Activated Cardiac Fibroblasts by a Disruption of Mitochondria-Associated Membranes

RETRACTED: High Glucose Activated Cardiac Fibroblasts by a Disruption of Mitochondria-Associated Membranes

Metformin Attenuates UVA-Induced Skin Photoaging by Suppressing Mitophagy and the PI3K/AKT/mTOR Pathway

The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis—Frontotemporal Dementia

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