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Download filePACS-2 Ameliorates Tubular Injury by Facilitating Endoplasmic Reticulum-Mitochondria Contact and Mitophagy in Diabetic Nephropathy
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posted on 2022-02-08, 16:25 authored by Chenrui Li, Li Li, Ming Yang, Jinfei Yang, Chanyue Zhao, Yachun Han, Hao Zhao, Na Jiang, Ling Wei, Ying Xiao, Yan Liu, Xiaofen Xiong, Yiyun Xi, Shilu Luo, Fei Deng, Wei Chen, Shuguang Yuan, Xuejing Zhu, Li Xiao, Lin SunMitochondria-associated endoplasmic reticulum membrane
(MAM) is emerging as a novel insight into tubular injury in diabetic
nephropathy (DN), but the precise mechanism remains unclear. Here, we demonstrate that the expression of phosphofurin
acidic cluster sorting protein 2 (PACS-2), a critical regulator of MAM
formation, is significantly decreased in renal tubules
of patients with DN, which is positively correlated with renal function and
negatively correlated with degrees of tubulointerstitial lesions. Conditional deletion of Pacs-2 in proximal tubules (PT)
aggravates albuminuria and tubular injury in streptozotocin (STZ)-induced diabetic
mice. Mitochondrial fragmentation,
MAM disruption and defective mitophagy accompanied by altered expression of
mitochondrial dynamics and mitophagic protein including DRP1 and BECN1 are
observed in tubules from diabetic mice, while these changes are more pronounced in
PT-specific Pacs-2 knockout mice. In vitro, overexpression of PACS-2 in HK-2 cells alleviates excessive
mitochondrial fission induced by high glucose through blocking mitochondrial
recruitment of DRP1, and subsequently restores MAM integrity and enhances
mitophagy. Mechanistically, PACS-2 binds to BECN1 and mediates the
relocalization of BECN1 to MAM where it promotes the formation of
mitophagosome. Together, these data
highlight an important but previously unrecognized role of PACS-2 in
ameliorating tubular injury in DN by facilitating MAM formation and
mitophagy.