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Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
Published on: June 1, 2022
SPG7-Mediated Regulation of mPTP and Mitochondrial Flickering in COPD: A Bioinformatics-Based Prediction of
Anran Xu1, Yaping Lv2, Shaobin Li1
1Department of Traditional Chinese Medicine Preventive Health Care, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People's Republic of China.
Background:
During the staged progression of chronic obstructive pulmonary disease (COPD), mitophagy homeostasis is disrupted and exhibits a typical dual role. Mitophagy is tightly regulated by ion channel-controlled mitochondrial membrane potential (ΔΨm) and may associate with mitochondrial permeability transition pore (mPTP) dynamics. However, this regulatory mechanism remains largely unknown, and the stage-specific requirements of mitophagy in COPD progression have yet to be established.
Methods:
This study proposed a novel theoretical framework from prior literature. Using public databases, we linked mPTP-related genes to COPD state transitions via differential analysis and Mendelian randomization (MR). Key biomarkers were validated through gene enrichment, functional annotation, immune infiltration, and single-cell RNA sequencing (scRNA-seq) to assess biological significance. Finally, molecular docking confirmed their potential roles.
Results:
We preliminarily aligned the "mitochondria-cell survival architecture" hypothesis with COPD progression. Compared with stable COPD (STCOPD), acute exacerbation of COPD (AECOPD) showed massive type II alveolar epithelial (AT2) cell death, hyperinflammation, increased energy demand, and impaired intercellular communication, consistent with activated ubiquitin-proteasome system (UPS), mitochondrial gene expression, macroautophagy initiation, and vesicle trafficking. Six biomarkers (including SPG7) were associated with AECOPD (AUC=0.705, 95% CI 0.554-0.705). SPG7 was positively correlated with AECOPD (OR=1.126, 95% CI 1.008-1.257), while the other five showed negative correlations. These markers were enriched in ion channel and G protein-coupled receptors (GPCRs) pathways. SPG7 expression paralleled energy demand and strongly interacted with AFG3L2 and PPIF, implicating it in mPTP regulation.
Conclusion:
This study preliminarily supports the mitochondria-cell survival hypothesis. Bioinformatic analysis suggests that mPTP-triggered mitochondrial flickering maintains mitochondrial quality control. Furthermore, transient mPTP opening via SPG7-mediated CypD activation may constitute an independent protective pathway, potentially involving unique SPG7-CypD modifications. However, non-significant colocalization limits study robustness, necessitating rigorous experimental validation of these predictions.
Insights
Chronic obstructive pulmonary disease (COPD) progression disrupts mitophagy. This study identifies SPG7 as a potential biomarker for acute exacerbations of COPD (AECOPD), suggesting a protective role for mitochondrial permeability transition pore opening.
Area of Science:
- Mitochondrial biology
- Pulmonary medicine
- Bioinformatics
Background:
- Mitophagy homeostasis is disrupted during chronic obstructive pulmonary disease (COPD) progression, playing a dual role.
- The regulation of mitophagy by mitochondrial membrane potential (ΔΨm) and mitochondrial permeability transition pore (mPTP) dynamics in COPD is not well understood.
- Stage-specific roles of mitophagy in COPD progression require further investigation.
Purpose of the Study:
- To investigate the role of mPTP-related genes in COPD progression.
- To identify potential biomarkers for COPD state transitions.
- To explore the underlying mechanisms of mitophagy regulation in COPD.
Main Methods:
- Utilized differential analysis and Mendelian randomization (MR) to link mPTP-related genes with COPD.
- Validated key biomarkers through gene enrichment, functional annotation, immune infiltration, and single-cell RNA sequencing (scRNA-seq).
- Employed molecular docking to confirm the potential roles of identified biomarkers.
Main Results:
- Acute exacerbation of COPD (AECOPD) is characterized by increased AT2 cell death, hyperinflammation, and energy demand.
- Six biomarkers, including SPG7, were associated with AECOPD; SPG7 showed a positive correlation.
- SPG7 expression correlated with energy demand and interacted with AFG3L2 and PPIF, suggesting a role in mPTP regulation.
Conclusions:
- The study supports the mitochondria-cell survival hypothesis in COPD.
- Bioinformatic analysis indicates mPTP-triggered mitochondrial flickering maintains quality control.
- Transient mPTP opening via SPG7-mediated CypD activation may offer a protective pathway in COPD, requiring experimental validation.
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