Necrostatin‐1 prevents the proapoptotic protein Bcl‐2/adenovirus E1B 19‐kDa interacting protein 3 from integration into mitochondria. Issue 6 (13th March 2020)

• Record Type: Journal Article
• Authors: Mu, Jiao; Weng, Jiequn; Yang, Chaoxian; Guan, Teng; Deng, Li; Li, Meiyu; Zhang, Guohui; Kong, Jiming
• Is Part Of: Journal of neurochemistry. Volume 156:Issue 6(2021)
• Page Start: 929
• Page End: 942
• Publication Date: 2020-03-13
• Subjects: BNIP3 -- mitochondria -- necroptosis -- Necrostatin‐1 -- neuron; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14993
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Necrostatin‐1 (Nec‐1) has previously been shown to protect neurons from death in traumatic and ischemic brain injuries. This study tests the hypothesis that Nec‐1 protects neural cells against traumatic and ischemic brain injuries through inhibition of the Bcl‐2/adenovirus E1B 19‐kDa interacting protein 3 (BNIP3). We have used biochemical and morphological techniques to determine the inhibition of Nec‐1 on BNIP3‐induced cell death and to identify its mechanism of action in in vivo and in vitro models of neurodegeneration. Here we show that Nec‐1 significantly increased neuronal viability following prolonged exposure to hypoxia in vitro, and attenuated myelin damage and neuronal death in traumatic brain injury and cerebral ischemia in Sprague‐Dawley rats. Nec‐1 alleviated traumatic brain injury‐induced up‐regulation of BNIP3 in mature oligodendrocytes. In isolated mitochondria, Nec‐1 prevented BNIP3 from integrating into mitochondria by modifying its binding sites on the mitochondria. Consequently, Nec‐1 robustly inhibited BNIP3‐induced collapse of mitochondrial membrane potential and reduced the opening probability of mitochondrial permeability transition pores. Nec‐1 also preserved mitochondrial ultrastructure and suppressed BNIP3‐induced nuclear translocation of apoptosis‐inducing factor. In conclusion, Nec‐1 protects neurons and oligodendrocytes against traumatic and ischemic brain injuries by targeting the BNIP3‐induced cell death pathway, and is a novel inhibitor for BNIP3. Cover Image for this issue: https://doi.org/10.1111/jnc.15056 . Abstract : Nec‐1 has been shown to inhibit necroptosis. The mitochondrial protein BNIP3 activates a type of caspase‐independent cell death that is similar to necroptosis. Here we show that Nec‐1 is protective against death of neurons and oligodendrocytes in traumatic/ ischemic brain injuries in rats by inhibiting BNIP3; Nec‐1 prevents BNIP3 from integration into mitochondria to block the BNIP3 cell death pathway. The data suggest that Nec‐1 is a novel inhibitor for BNIP3. Cover Image for this issue: https://doi.org/10.1111/jnc.15056 .