Abstract
Mitochondrial fission factor (Mff) has been demonstrated to play a role in the activation of mitochondrial cleavage and mitochondrial death, denoting its role in the regulation of mitochondrial quality control. Recent evidence suggested that the mRNA translation of Mff is under the negative regulation by the RNA-binding protein Pumilio2 (Pum2). This study was designed to examine the role of Pum2 and Mff in the governance of mitochondrial quality control in a murine model of acute ischemic kidney injury. Our results indicated that genetic deletion of Mff overtly attenuated ischemic acute kidney injury (AKI)–induced renal failure through inhibition of pro-inflammatory response, tubular oxidative stress, and ultimately cell death in the kidney. Furthermore, Mff inhibition effectively preserved mitochondrial homeostasis through amelioration of mitochondrial mitosis, restoration of Sirt1/3 expression, and boost of mitochondrial respiration. Western blot analysis revealed that levels of Pum2 were significantly downregulated by ischemic AKI, inversely coinciding with levels of Mff. Overexpression of Pum2 reduced ischemic AKI-mediated Mff upregulation and offered protection on renal tubules through modulation of mitochondrial quality control. Taken together, our data have unveiled the molecular mechanism of the Pum2-Mff axis in mitochondrial quality control in a mouse model of ischemic AKI. These data indicated the therapeutic potential of Pum2 activation and Mff inhibition in the management of ischemic AKI.
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This work was supported in part by China Postdoctoral Science Foundation (2019TQ0128) and the NSFC (81900252, 81900254 and 91749128).
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HZ, JW, and JR were involved in the conception and design of the study, performance of experiments, data analysis and interpretation, and manuscript writing. RBL and JW were involved in development of the methodology. HZ and PJZ acquired the data. JW and ST analyzed and interpreted data. JR and HZ obtained financial support, supervised the study, and approved the final manuscript.
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Wang, J., Zhu, P., Toan, S. et al. Pum2-Mff axis fine-tunes mitochondrial quality control in acute ischemic kidney injury. Cell Biol Toxicol 36, 365–378 (2020). https://doi.org/10.1007/s10565-020-09513-9
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DOI: https://doi.org/10.1007/s10565-020-09513-9