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AKAP1 contributes to impaired mtDNA replication and mitochondrial dysfunction in podocytes of diabetic kidney disease
Jun Feng1,2, Zhaowei Chen1,2, Yiqiong Ma1,2
1Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
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.
Insights
A-kinase anchoring protein 1 (AKAP1) impairs mitochondrial DNA replication in diabetic kidney disease (DKD) by activating protein kinase C (PKC) signaling. This AKAP1-PKC pathway exacerbates podocyte injury and mitochondrial dysfunction in DKD.
Area of Science:
- Nephrology
- Mitochondrial Biology
- Molecular Medicine
Background:
- Diabetic kidney disease (DKD) involves podocyte injury and mitochondrial dysfunction.
- Mitochondrial DNA (mtDNA) replication defects contribute to mitochondrial dysfunction, but their role in podocyte injury in DKD remains unclear.
- A-kinase anchoring protein 1 (AKAP1) regulates mitochondrial signals.
Purpose of the Study:
- To investigate the role of AKAP1 in high glucose-induced mtDNA replication in podocytes.
- To elucidate the molecular mechanism by which AKAP1 affects mtDNA replication and podocyte injury in DKD.
Main Methods:
- Examined mtDNA replication, mitochondrial function, and podocyte injury in DKD models.
- Assessed AKAP1 expression and protein kinase C (PKC) signaling under hyperglycemic conditions.
- Investigated the effects of AKAP1 knockdown, PKC inhibition (enzastaurin), and AKAP1 overexpression on podocyte function and mtDNA replication.
Main Results:
- DKD podocytes exhibited decreased mtDNA replication and mitochondrial dysfunction.
- High glucose upregulated AKAP1 expression and activated PKC signaling.
- AKAP1 recruited PKC, leading to Larp1 phosphorylation and reduced TFAM expression, impairing mtDNA replication.
- Knocking down AKAP1 or inhibiting PKC rescued mtDNA replication, mitochondrial function, and podocyte injury.
- AKAP1 overexpression exacerbated podocyte injury and mtDNA replication impairment.
Conclusions:
- AKAP1 phosphorylates Larp1 via PKC activation, reducing TFAM and impairing mtDNA replication in DKD.
- This mechanism accelerates mitochondrial dysfunction and podocyte injury in diabetic kidney disease.
- Targeting the AKAP1-PKC pathway may offer a therapeutic strategy for DKD.
