SPG7-Mediated Regulation of mPTP and Mitochondrial Flickering in COPD: A Bioinformatics-Based Prediction of Mechanistic Framework.

Authors

Anran Xu, Yaping Lv, Shaobin Li, Xinhui Zhang, Jirong Zhang, Chengyan Zhan, Yanqi Cheng, Ling Tang, Chen Zhang, Siyang Xiang, Hong Fang, Donghua Zhou

Published in

International journal of chronic obstructive pulmonary disease. Volume 21. Pages 597903. Epub Jun 29, 2026.

Abstract

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.
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.
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.
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.

PMID:
42404999
Bibliographic data and abstract were imported from PubMed on 06 Jul 2026.

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