Int J Biol Sci 2022; 18(10):4026-4042. doi:10.7150/ijbs.73493 This issue

Research Paper

AKAP1 contributes to impaired mtDNA replication and mitochondrial dysfunction in podocytes of diabetic kidney disease

Jun Feng1,2*, Zhaowei Chen1,2*, Yiqiong Ma1,2, Xueyan Yang1,2, Zijing Zhu1,2, Zongwei Zhang1,2, Jijia Hu1,2, Wei Liang1,2, Guohua Ding1,2✉

1. Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
2. Nephrology and Urology Research Institute of Wuhan University, Wuhan, Hubei, China.
*Co-first authors.

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Citation:
Feng J, Chen Z, Ma Y, Yang X, Zhu Z, Zhang Z, Hu J, Liang W, Ding G. AKAP1 contributes to impaired mtDNA replication and mitochondrial dysfunction in podocytes of diabetic kidney disease. Int J Biol Sci 2022; 18(10):4026-4042. doi:10.7150/ijbs.73493. Available from https://www.ijbs.com/v18p4026.htm

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Abstract

Graphic abstract

Podocyte injury is involved in the onset and progression of diabetic kidney disease (DKD) and is associated with mitochondrial abnormalities. Defective mitochondrial DNA (mtDNA) replication results in mitochondrial dysfunction. However, whether podocyte mtDNA replication is impaired in DKD is still unclear. A-kinase anchoring protein 1 (AKAP1) is localized in the outer mitochondrial membrane (OMM) and acts as a regulator and conductor of mitochondrial signals. Herein, we investigated the role of AKAP1 in high glucose-induced mtDNA replication. Decreased mtDNA replication and mitochondrial dysfunction occurred in podocytes of DKD. AKAP1 expression was up-regulated, and protein kinase C (PKC) signaling was activated under hyperglycemic conditions. AKAP1 recruited PKC and mediated La-related protein 1 (Larp1) phosphorylation, which reduced the expression of mitochondrial transcription factor A (TFAM), a key factor in mtDNA replication. In addition, mtDNA replication, mitochondrial function and podocyte injury were rescued by knocking down AKAP1 expression and the PKC inhibitor enzastaurin. In contrast, AKAP1 overexpression worsened the impairment of mtDNA replication and podocyte injury. In conclusion, our study revealed that AKAP1 phosphorylates Larp1 via PKC signaling activation to decrease mtDNA replication, which accelerates mitochondrial dysfunction and podocyte injury in DKD.

Keywords: AKAP1, Larp1, PKC, mtDNA replication, mitochondria, podocyte, diabetic kidney disease