BNIP3L, also known as NIX, is a mitochondrial outer membrane protein that serves as a mitophagy receptor. Mitophagy is a process that maintains mitochondrial quantity by eliminating dysfunctional or superfluous mitochondria through autophagy machinery. BNIP3L-mediated mitophagy is involved in a variety of physiological and pathological processes, playing a crucial role in cellular development and specialization [3,6].

In ischemic brains, proteasome-mediated degradation of BNIP3L leads to mitophagy deficiency, and carfilzomib, a proteasome inhibitor, can reverse BNIP3L degradation and restore mitophagy, protecting against ischemic brain injury, which is abolished in bnip3l-/-mice [1]. In glucocorticoid-treated hippocampal neurons, SH-SY5Y cells, and ICR mice, glucocorticoids downregulate BNIP3L, resulting in inhibited mitophagy and synaptic defects, while NIX enhancer pre-treatment can elevate mitophagy and synaptic density [2]. In optic nerve oligodendrocyte differentiation, BNIP3L-mediated mitophagy is required for mitochondrial remodeling, and in cardiac progenitor cell differentiation, mitophagy mediated by BNIP3L and FUNDC1 is important for mitochondrial network reorganization [4,5].

In conclusion, BNIP3L-mediated mitophagy is essential for mitochondrial homeostasis during various cellular differentiation processes and in maintaining normal physiological functions. Studies using bnip3l-/-or other loss-of-function models have revealed its significance in diseases such as ischemic brain injury, stress-related mood disorders, and sepsis-associated encephalopathy, providing potential therapeutic targets for these conditions [1,7,8].

References:

1. Wu, Xiaoli, Zheng, Yanrong, Liu, Mengru, Chen, Zhong, Zhang, Xiangnan. 2020. BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains. In Autophagy, 17, 1934-1946. doi:10.1080/15548627.2020.1802089. https://pubmed.ncbi.nlm.nih.gov/32722981/

2. Choi, Gee Euhn, Lee, Hyun Jik, Chae, Chang Woo, Lim, Jae Ryong, Han, Ho Jae. 2021. BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects. In Nature communications, 12, 487. doi:10.1038/s41467-020-20679-y. https://pubmed.ncbi.nlm.nih.gov/33473105/

3. Li, Yue, Zheng, Wanqing, Lu, Yangyang, Chen, Zhong, Zhang, Xiangnan. 2021. BNIP3L/NIX-mediated mitophagy: molecular mechanisms and implications for human disease. In Cell death & disease, 13, 14. doi:10.1038/s41419-021-04469-y. https://pubmed.ncbi.nlm.nih.gov/34930907/

4. Yazdankhah, Meysam, Ghosh, Sayan, Shang, Peng, Zack, Donald J, Sinha, Debasish. 2021. BNIP3L-mediated mitophagy is required for mitochondrial remodeling during the differentiation of optic nerve oligodendrocytes. In Autophagy, 17, 3140-3159. doi:10.1080/15548627.2020.1871204. https://pubmed.ncbi.nlm.nih.gov/33404293/

5. Lampert, Mark A, Orogo, Amabel M, Najor, Rita H, Sussman, Mark A, Gustafsson, Åsa B. 2019. BNIP3L/NIX and FUNDC1-mediated mitophagy is required for mitochondrial network remodeling during cardiac progenitor cell differentiation. In Autophagy, 15, 1182-1198. doi:10.1080/15548627.2019.1580095. https://pubmed.ncbi.nlm.nih.gov/30741592/

6. Marinković, Mija, Novak, Ivana. 2021. A brief overview of BNIP3L/NIX receptor-mediated mitophagy. In FEBS open bio, 11, 3230-3236. doi:10.1002/2211-5463.13307. https://pubmed.ncbi.nlm.nih.gov/34597467/

7. Zhao, Lina, Song, Yu, Zhang, Ying, Li, Yun, Xie, Keliang. 2022. HIF-1α/BNIP3L induced cognitive deficits in a mouse model of sepsis-associated encephalopathy. In Frontiers in immunology, 13, 1095427. doi:10.3389/fimmu.2022.1095427. https://pubmed.ncbi.nlm.nih.gov/36569834/

8. Lu, Jia-Jing, Wu, Peng-Fei, He, Jin-Gang, Wang, Fang, Chen, Jian-Guo. 2023. BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α. In Molecular psychiatry, 28, 5062-5076. doi:10.1038/s41380-023-02008-z. https://pubmed.ncbi.nlm.nih.gov/36914810/