Gestational diabetes & diabetes in pregnancy
α7 Nicotinic acetylcholine receptor activation rescues mitochondrial dysfunction in gestational diabetes mellitus by competing with p66Shc for VDAC1 binding
Authors' conclusion
This study identifies a non-canonical role for α7nAChR in maintaining mitochondrial Ca2⁺ homeostasis by competitively regulating VDAC1-p66Shc interactions under hyperglycaemic conditions. The findings reveal a mechanistic link between α7nAChR dysfunction, mitochondrial Ca2⁺ overload and cellular senescence in GDM placentas. Targeting α7nAChR with pharmacological agents such as GTS-21 may offer a novel therapeutic approach to ameliorate mitochondrial dysfunction and placental pathology in GDM by restoring Ca2⁺ dynamics.
Study context
- Population
- Placental samples from gestational diabetes mellitus (GDM) pregnancies, with in vitro and murine models of hyperglycaemia
- Comparison
- Pharmacological α7nAChR activation vs hyperglycaemic conditions
- Outcome
- Role of α7nAChR in regulating mitochondrial Ca2⁺ homeostasis in trophoblasts under hyperglycaemic stress
Methodological detailsclinical placental samples, in vitro models, murine models, RNA-seq
- Clinical placental samples
- In vitro models
- Murine models
- RNA-seq
Main finding
As reported in the abstract
α7nAChR expression, mitochondrial morphology and Ca2⁺ signalling; α7nAChR–VDAC1–p66Shc interactions
- Reduced α7nAChR expression, mitochondrial vacuolisation and dysregulated Ca2⁺ signalling pathways in GDM placentas
- Under hyperglycaemia, disrupted α7nAChR-VDAC1 interactions facilitated competitive binding of pro-oxidant p66Shc to VDAC1, promoting pathological Ca2⁺ transfer from endoplasmic reticulum to mitochondria via mitochondrial-associated endoplasmic reticulum membranes
- Mitochondrial permeability transition pore overactivation, loss of mitochondrial membrane potential and induction of cellular senescence
- α7nAChR activation with PNU or GTS-21 restored α7nAChR-VDAC1 coupling, attenuated p66Shc-mediated oxidative stress and reversed mitochondrial Ca2⁺ overload
- RNA-seq: PNU normalised gene expression profiles associated with endoplasmic reticulum stress and cellular senescence
Original publication
α7 Nicotinic acetylcholine receptor activation rescues mitochondrial dysfunction in gestational diabetes mellitus by competing with p66Shc for VDAC1 binding. Diabetologia. Published 15 December 2025. doi:10.
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