Mitochondria-associated endoplasmic reticulum membranes promote mitochondrial fission through AKAP1-Drp1 pathway in podocytes under high glucose conditions

• Published in: Experimental cell research Vol. 424; no. 2; p. 113512
• Main Authors: Li, Xuehong, Yang, Qinglan, Liu, Sirui, Song, Shicong, Wang, Cheng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.03.2023
• Subjects: A Kinase Anchor Proteins - metabolism; Diabetic nephropathy; Dynamins - metabolism; Endoplasmic Reticulum - metabolism; Glucose - metabolism; Glucose - pharmacology; MAM; Mitochondria; Mitochondria - metabolism; Mitochondrial Dynamics; Podocyte; Podocytes - metabolism; ESRD; T2DM; IP3R; DN; AKAPs; Drp1; AKAP1; Mitochondria; Opa1; OE; STZ; Mfn1; Diabetic nephropathy; Mfn2; Fis1; PKA; siRNA; ER; OMM; Podocyte; CVD; MMP; ROS; MAM; MAMs; NG; VDAC1; HG
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2023.113512

Excessive mitochondrial fission in podocytes is a critical feature of diabetic nephropathy (DN). Mitochondria-associated endoplasmic reticulum membranes (MAMs) are contact sites between the endoplasmic reticulum (ER) and mitochondria, which are suggested to be related to mitochondrial function. However, the role of MAMs in mitochondrial dynamics disorder in podocytes remains unknown. Here, we firstly reported a novel mechanism of MAMs' effects on mitochondrial dynamics in podocytes under diabetic conditions. Increased MAMs were found in diabetic podocytes in vivo and in vitro, which were positively correlated with excessive mitochondrial fission. What's more, we also found that A-kinase anchoring protein 1 (AKAP1) was located in MAMs, and its translocation to MAMs was increased in podocytes cultured with high glucose (HG). In addition, AKAP1 knockdown significantly reduced mitochondrial fission and attenuated high glucose induced-podocyte injury through regulating phosphorylation of dynamin-related protein 1 (Drp1) and its subsequent mitochondrial translocation. On the contrary, AKAP1 overexpression in these podocytes showed the opposite effect. Finally, pharmacological inhibition of Drp1 alleviated excessive mitochondrial fission and podocyte damage in AKAP1 overexpressed podocytes. Our data suggest that MAMs were increased in podocytes under diabetic conditions, leading to excessive mitochondrial fission and podocyte damage through AKAP1-Drp1 signaling. •MAMs were increased and contributed to excessive mitochondrial fission in diabetic podocytes.