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Updated: Apr 14, 2026
A Mouse Model for Vascular Cognitive Impairment and Dementia Based on Needle-guided Asymmetric Bilateral Common Carotid Artery Stenosis
Published on: November 22, 2024
BNIP3/BNIP3L-Dependent Mitophagy Protects Against Hippocampal Neuronal Damage and Apoptosis in a Model of Vascular
Yujiao Wang1, Daojun Xie1, Shijia Ma1
1The First Clinical Medical College of Anhui University of Chinese Medicine, Hefei 230036, China.
Abstract:
Mitophagy serves as an essential quality control mechanism that maintains mitochondrial homeostasis through selective autophagic clearance of damaged organelles. Vascular dementia (VD) has been increasingly associated with mitophagy dysregulation in recent studies. However, the precise molecular mechanisms underlying mitophagy's involvement in VD pathogenesis remain poorly characterized. To elucidate the role of mitophagy in VD, we systematically examined the expression of key mitophagy pathways in hippocampal neurons of bilateral common carotid artery occlusion (BCCAO) rats and in oxygen-glucose deprivation (OGD)-treated HT22 cells. Intriguingly, under autophagy-deficient conditions, both BNIP3 and BNIP3L were markedly downregulated, whereas FUNDC1 expression increased; PINK1/Parkin levels remained unaltered. To further dissect the functional contributions of BNIP3 and BNIP3L, we administered the mitochondrial fission inhibitor Mdivi-1 to BCCAO model rats. Histopathological analysis revealed pronounced neuronal damage and apoptosis in the hippocampal region, which was further exacerbated upon Mdivi-1 treatment. In vitro, BNIP3 silencing significantly compromised cell viability, elevated reactive oxygen species (ROS) accumulation, disrupted mitochondrial membrane potential (ΔΨm), suppressed mitophagy, and increased apoptotic rates. Conversely, BNIP3 overexpression reversed these detrimental effects. Notably, treatment with the autophagy inhibitor 3-methyladenine (3-MA) diminished LC3B-Tomm20 colocalization and intensified apoptosis, reinforcing the critical role of BNIP3-mediated mitophagy in neuronal survival. Similarly, BNIP3L overexpression enhanced cell viability, attenuated ROS production, restored ΔΨm, and mitigated apoptosis, while 3-MA treatment again impaired mitophagic flux and worsened cell death. Collectively, these findings underscore the critical and distinct roles of BNIP3 and BNIP3L in maintaining mitochondrial homeostasis and neuronal survival under ischemic conditions.
Insights
This study reveals that BNIP3 and BNIP3L are crucial for mitophagy, protecting neurons from damage in vascular dementia models. Enhancing their function improves mitochondrial health and neuronal survival.
Area of Science:
- Neuroscience
- Cell Biology
- Mitochondrial Biology
Background:
- Mitophagy is vital for mitochondrial quality control and homeostasis.
- Dysregulation of mitophagy is implicated in vascular dementia (VD) pathogenesis.
- The specific roles of mitophagy pathways in VD remain unclear.
Purpose of the Study:
- To investigate the role of mitophagy, specifically BNIP3 and BNIP3L, in vascular dementia.
- To elucidate the molecular mechanisms of mitophagy in neuronal survival under ischemic conditions.
Main Methods:
- Examined mitophagy pathway expression in rat models (BCCAO) and cell models (OGD-treated HT22 cells).
- Assessed the impact of BNIP3 and BNIP3L modulation on neuronal viability, ROS levels, mitochondrial membrane potential, and apoptosis.
- Utilized autophagy inhibitors (3-MA) and mitochondrial fission inhibitors (Mdivi-1) to study mitophagy flux and neuronal damage.
Main Results:
- BNIP3 and BNIP3L were downregulated in autophagy-deficient conditions, while FUNDC1 increased; PINK1/Parkin were unchanged.
- Mdivi-1 exacerbated neuronal damage in BCCAO rats.
- BNIP3/BNIP3L overexpression protected against neuronal damage, reduced ROS, preserved mitochondrial membrane potential, and decreased apoptosis, effects counteracted by autophagy inhibition.
Conclusions:
- BNIP3 and BNIP3L play critical, distinct roles in maintaining mitochondrial homeostasis and neuronal survival during ischemic stress.
- Targeting BNIP3 and BNIP3L-mediated mitophagy presents a potential therapeutic strategy for vascular dementia.
