PACS-2 Ameliorates Tubular Injury by Facilitating Endoplasmic Reticulum-Mitochondria Contact and Mitophagy in Diabetic Nephropathy

• DOI: 10.2337/figshare.19122614
• Publication Date: 2022-02-08T17:04:03Z
• Authors: 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 Sun
• Keywords: BECN1; MFN2; Autophagosome

<a>Mitochondria-associated endoplasmic reticulum membrane (MAM) is emerging as a novel insight into tubular injury in diabetic nephropathy (DN), but the precise mechanism remains unclear. </a>Here, we demonstrate that expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), critical regulator MAM formation, significantly decreased <a>renal tubules</a> patients with DN, which positively correlated renal function and negatively degrees tubulointerstitial lesions. Conditional deletion Pacs-2 proximal tubules (PT) aggravates albuminuria streptozotocin (STZ)-induced mice. Mitochondrial fragmentation, disruption defective mitophagy accompanied by altered mitochondrial dynamics mitophagic including DRP1 BECN1 are observed from mice, while these changes more pronounced PT-specific knockout <i>In vitro</i>, overexpression PACS-2 HK-2 cells alleviates excessive fission induced high glucose through blocking recruitment DRP1, subsequently restores integrity enhances mitophagy. Mechanistically, binds to mediates relocalization where it promotes formation mitophagosome. Together, data highlight an important previously unrecognized role ameliorating DN facilitating