Journal of diabetes research · 2026
Disruption of Mitophagy-Related Gene Expression in Gestational Diabetes Mellitus: A Transcriptomic and Machine Learning Approach.
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Bouati Souhaib, Ameen Shaima, Al Dain Marzouka Nour, Alhantoobi Fadwah, Masuadi Emad, Mohammed Ghada, Mousa Noha Ahmed, Mahmoud Shahad, Seoud Muhieddine, Mirghani Hisham, Alnaqbi Halima, Pathan Ayman, Saber-Ayad Maha, Osman Wael
Аннотация
BACKGROUND: Gestational diabetes mellitus (GDM) is a pregnancy-associated metabolic disorder linked to adverse maternal and fetal outcomes. Mitochondrial dysfunction is a recognized feature of GDM, yet the role of mitophagy-the selective degradation of damaged mitochondria-remains insufficiently understood.
OBJECTIVE: This study examined the expression and regulatory patterns of mitophagy-related genes (MRGs) in GDM using publicly available transcriptomic datasets.
METHODS: Transcriptomic datasets available in public repositories were analyzed to explore MRG expression and regulatory dynamics in GDM. RNA-seq data from two datasets: GSE203346 (placental and cord blood samples) and GSE154414 (placental samples) were analyzed to identify differentially expressed mitophagy genes. Additionally, maternal circulating blood RNA-seq data from GSE154377 were included for machine learning analysis. These datasets, which encompassed samples collected across multiple trimesters, facilitated a comparative evaluation of MRG expression dynamics in both placental tissue and maternal blood throughout pregnancy. A curated list of 65 MRGs was evaluated using edgeR and DESeq2 for differential expressions (DEs). Temporal expression dynamics were modeled with the multiclassPairs package in R using GSE154377.
RESULTS: Consistent downregulation of four critical MRGs-MUL1, PINK1, TOMM7, and ATF4-was observed in GDM placental tissue (GSE154414) and in both placental tissue and fetal umbilical cord blood (GSE203346) but not in maternal peripheral blood. In healthy pregnancies, these genes exhibited distinct temporal regulation across gestation, a pattern disrupted in GDM. Classifier models based on MRG expression accurately predicted gestational stage in controls (accuracy > 85%) but performed poorly in GDM (accuracy < 50%). Functional enrichment analyses revealed impaired mitochondrial protein import, autophagy, and oxidative stress responses.
CONCLUSION: These findings suggest that mitophagy dysregulation is an early and persistent defect in GDM, with MUL1, PINK1, TOMM7, and ATF4 emerging as potential biomarkers and therapeutic targets. The results support the hypothesis that mitochondrial quality control failure contributes to the pathogenesis of GDM with similar patterns shown in both placental and cord blood tissues. However, these genes were not significantly altered in plasma, highlighting tissue context as a critical factor in detecting mitophagy-related dysregulation.
OBJECTIVE: This study examined the expression and regulatory patterns of mitophagy-related genes (MRGs) in GDM using publicly available transcriptomic datasets.
METHODS: Transcriptomic datasets available in public repositories were analyzed to explore MRG expression and regulatory dynamics in GDM. RNA-seq data from two datasets: GSE203346 (placental and cord blood samples) and GSE154414 (placental samples) were analyzed to identify differentially expressed mitophagy genes. Additionally, maternal circulating blood RNA-seq data from GSE154377 were included for machine learning analysis. These datasets, which encompassed samples collected across multiple trimesters, facilitated a comparative evaluation of MRG expression dynamics in both placental tissue and maternal blood throughout pregnancy. A curated list of 65 MRGs was evaluated using edgeR and DESeq2 for differential expressions (DEs). Temporal expression dynamics were modeled with the multiclassPairs package in R using GSE154377.
RESULTS: Consistent downregulation of four critical MRGs-MUL1, PINK1, TOMM7, and ATF4-was observed in GDM placental tissue (GSE154414) and in both placental tissue and fetal umbilical cord blood (GSE203346) but not in maternal peripheral blood. In healthy pregnancies, these genes exhibited distinct temporal regulation across gestation, a pattern disrupted in GDM. Classifier models based on MRG expression accurately predicted gestational stage in controls (accuracy > 85%) but performed poorly in GDM (accuracy < 50%). Functional enrichment analyses revealed impaired mitochondrial protein import, autophagy, and oxidative stress responses.
CONCLUSION: These findings suggest that mitophagy dysregulation is an early and persistent defect in GDM, with MUL1, PINK1, TOMM7, and ATF4 emerging as potential biomarkers and therapeutic targets. The results support the hypothesis that mitochondrial quality control failure contributes to the pathogenesis of GDM with similar patterns shown in both placental and cord blood tissues. However, these genes were not significantly altered in plasma, highlighting tissue context as a critical factor in detecting mitophagy-related dysregulation.