Akt-GSK3β-mPTP pathway regulates the mitochondrial dysfunction contributing to odontoblasts apoptosis induced by glucose oxidative stress

Wu, Danni; Yan, Lei; Zheng, Chuchu; Ren, Xuekun; Pan, Yihuai; Huang, Shengbin; Pan, Lijun; Li, Zongli

doi:10.1038/s41420-022-00981-y

Cited by 15 publications

(8 citation statements)

References 43 publications

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“…In rodent cardiomyocytes and human embryonic kidney cells, GSK3β has been reported as a modulator of mPTP via phosphorylation of CypD (Ser191) [ 13 ]. The CypD-ANT complex has been identified as a key component of mPTP opening [ 24 , 25 ]. In rat cardiomyocytes, p-GSK3β (Ser9) binds to ANT, decreasing the binding between CypD and ANT [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…In cardiac myocytes and preodontoblasts, GSK3β up-regulates the opening of the mitochondrial permeability transition pore (mPTP), facilitating the formation of cyclophilin D (CypD) and adenine nucleotide translocator (ANT) complex. This results in mPTP opening [ 24 , 25 ]. CypD as a sensitizer of the mPTP opening negatively regulates mitochondrial ATP production [ 1 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of mitochondrial cyclophilin D, a downstream target of glycogen synthase kinase 3α, improves sperm motility

Park,

Gye

2024

Reprod Biol Endocrinol

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Background Cyclophilin D (CypD) negatively regulates ATP production by opening of the mitochondrial permeability transition pore. This study aimed to understand the role of CypD in sperm motility regulation. Methods Changes in CypD during sperm capacitation and its interaction with glycogen synthase kinase 3α (GSK3α), a key kinase regulating sperm motility, were examined in mouse spermatozoa. The effects of CypD inhibitor cyclosporin A (CsA) and GSK3 inhibitor 6-bromo-indirubin-3'-oxime (BIO) on sperm motility, p-GSK3α(Ser21), mitochondrial permeability transition pore (mPTP), mitochondrial membrane potential (MMP), and ATP production were examined. The effect of proteasome inhibitor MG115 on the cellular levels of CypD was examined. Results In cauda epididymal spermatozoa, GSK3α was found in both cytosolic and mitochondrial fractions whereas CypD was primarily found in the mitochondrial fraction together with ATP synthase F1 subunit alpha (ATP5A), a mitochondrial marker. GSK3α and CypD were co-localized in the sperm midpiece. Interaction between GSK3α and CypD was identified in co-immunoprecipitation. CsA, a CypD inhibitor, significantly increased sperm motility, tyrosine phosphorylation, mPTP closing, MMP, and ATP levels in spermatozoa, suggesting that CypD acts as a negative regulator of sperm function. Under capacitation condition, both GSK3α and CypD were decreased in spermatozoa but ATP5A was not. The GSK3 inhibitor BIO markedly increased p-GSK3α(Ser21) and decreased CypD but significantly increased mPTP closing, MMP, ATP production, and motility of spermatozoa. This suggests that inhibitory phosphorylation of GSK3α is coupled with degradation of CypD, potentiating the mitochondrial function. Degradation of CypD was attenuated by MG115, indicative of involvement of the ubiquitin proteasome system. Conclusions During sperm capacitation, CypD act as a downstream target of GSK3α can be degraded via the ubiquitin proteasome system, stimulating mitochondrial function and sperm motility.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of mitochondrial cyclophilin D, a downstream target of glycogen synthase kinase 3α, improves sperm motility

Park,

Gye

2024

Reprod Biol Endocrinol

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“…It is re ected in the production of less mitochondrial reactive oxygen species (mtROS) and reactive oxygen species (ROS) when stimulated by oxidative stress again [14]. ROS is a pro-in ammatory mediator, and ROS is mainly transported to the cytoplasm by mtROS through mitochondrial permeability transition pore (mPTP), so mtROS is also considered as a pro-in ammatory mediator [15]. However, the latest research shows that low concentration of mtROS also has anti-in ammatory and antioxidant properties [14].…”

Section: Introductionmentioning

confidence: 99%

MPC1 regulates endotoxin tolerance of macrophages through mitochondrial oxidative stress resistance

Liu,

Qi,

Zeng

et al. 2024

Preprint

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Increasing evidence highlights the crucial role of endotoxin tolerance in the regulation of the sepsis, yet its underlying mechanisms remain poorly understood. Here, we provide evidence to support a novel role for the mitochondrial pyruvate carrier1 (MPC1)-mediated mitochondrial oxidative stress resistance in regulation of endotoxin tolerance in macrophages. We observed a decrease in MPC1 expression in both in vitro and in vivo sepsis models, while LPS-tolerant macrophages exhibited increased MPC1 levels. Overexpression of MPC1 significantly reduced LPS-induced inflammatory responses and oxidative stress, suggesting its anti-inflammatory properties. Intriguingly, we found that overexpression of MPC1 did not foster endotoxin tolerance in macrophages. Furthermore, we found that overexpression of MPC1 inhibited mitochondrial oxidative stress resistance mediated by mitochondrial reactive oxygen species (mtROS), which weakened the resistance of macrophages to LPS secondary stimulation, and then inhibited endotoxin tolerance. Despite mtROS typically acting as pro-inflammatory mediators, our findings indicate that mtROS production, regulated via the SIRT3/SOD2 pathway, is essential for MPC1's control over mitochondrial oxidative stress resistance and endotoxin tolerance. Collectively, these findings uncover novel mechanisms through which MPC1 modulates inflammation and induces endotoxin tolerance, underscoring the potential of targeting MPC1 in sepsis treatment.

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“…Mitochondrial ROS (mtROS) have been increasingly shown to be involved in immune‐related responses in recent years as key signaling molecules that regulate intracellular oxidative stress, and their generation is closely related to mitochondrial permeability transition pore (mPTP) 34 . The mPTP has considerable importance in regulating mitochondrial homeostasis, maintaining mitochondrial biological functions, participating in glucose oxidative stress, and playing a vital role in NETosis generation 35,36 . The precise involvement of mPTP and FPR2 in neutrophil‐generated NETs during DR remains uncertain at present and requires a more thorough investigation.…”

Section: Introductionmentioning

confidence: 99%

“…34 The mPTP has considerable importance in regulating mitochondrial homeostasis, maintaining mitochondrial biological functions, participating in glucose oxidative stress, and playing a vital role in NETosis generation. 35,36 The precise involvement of mPTP and FPR2 in neutrophilgenerated NETs during DR remains uncertain at present and requires a more thorough investigation. Further exploration of this complex interplay between these factors could lead to a greater understanding of the underlying pathological mechanisms involved in the process of DR.…”

Section: Introductionmentioning

confidence: 99%

LL37/FPR2 regulates neutrophil mPTP promoting the development of neutrophil extracellular traps in diabetic retinopathy

Lou,

Chen,

Chen

et al. 2024

The FASEB Journal

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Diabetic retinopathy (DR) is characterized by chronic, low‐grade inflammation. This state may be related to the heightened production of neutrophil extracellular traps (NETs) induced by high glucose (HG). Human cathelicidin antimicrobial peptide (LL37) is an endogenous ligand of G protein‐coupled chemoattractant receptor formyl peptide receptor 2 (FPR2), expressed on neutrophils and facilitating the formation and stabilization of the structure of NETs. In this study, we detected neutrophils cultured under different conditions, the retinal tissue of diabetic mice, and fibrovascular epiretinal membranes (FVM) samples of patients with proliferative diabetic retinopathy (PDR) to explore the regulating effect of LL37/FPR2 on neutrophil in the development of NETs during the process of DR. Specifically, HG or NG with LL37 upregulates the expression of FPR2 in neutrophils, induces the opening of mitochondrial permeability transition pore (mPTP), promotes the increase of reactive oxygen species and mitochondrial ROS, and then leads to the rise of NET production, which is mainly manifested by the release of DNA reticular structure and the increased expression of NETs‐related markers. The PI3K/AKT signaling pathway was activated in neutrophils, and the phosphorylation level was enhanced by FPR2 agonists in vitro. In vivo, increased expression of NETs markers was detected in the retina of diabetic mice and in FVM, vitreous fluid, and serum of PDR patients. Transgenic FPR2 deletion led to decreased NETs in the retina of diabetic mice. Furthermore, in vitro, inhibition of the LL37/FPR2/mPTP axis and PI3K/AKT signaling pathway decreased NET production induced by high glucose. These results suggested that FPR2 plays an essential role in regulating the production of NETs induced by HG, thus may be considered as one of the potential therapeutic targets.

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Akt-GSK3β-mPTP pathway regulates the mitochondrial dysfunction contributing to odontoblasts apoptosis induced by glucose oxidative stress

Cited by 15 publications

References 43 publications

Inhibition of mitochondrial cyclophilin D, a downstream target of glycogen synthase kinase 3α, improves sperm motility

Inhibition of mitochondrial cyclophilin D, a downstream target of glycogen synthase kinase 3α, improves sperm motility

MPC1 regulates endotoxin tolerance of macrophages through mitochondrial oxidative stress resistance

LL37/FPR2 regulates neutrophil mPTP promoting the development of neutrophil extracellular traps in diabetic retinopathy

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