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ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes
G Michelle Ducasa1, Alla Mitrofanova1,2, Shamroop K Mallela1
1Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA.
The Journal of Clinical Investigation
|July 23, 2019
Summary
ATP-binding cassette A1 (ABCA1) deficiency causes cardiolipin accumulation and mitochondrial dysfunction, leading to diabetic kidney disease (DKD). Therapies targeting ABCA1 or cardiolipin peroxidation may treat DKD.
Area of Science:
- Mitochondrial Biology
- Nephrology
- Lipid Metabolism
Background:
- ATP-binding cassette A1 (ABCA1) loss-of-function mutations cause cardiolipin accumulation in Tangier disease fibroblasts.
- ABCA1 expression is suppressed in diabetic kidney disease (DKD) glomeruli and podocytes exposed to DKD sera.
- ABCA1 deficiency in podocytes impairs mitochondrial function and oxidative phosphorylation (OXPHOS).
Purpose of the Study:
- To investigate the role of ABCA1 in diabetic kidney disease (DKD) pathogenesis.
- To determine if cardiolipin accumulation mediates ABCA1-dependent podocyte injury in DKD.
- To explore therapeutic strategies for DKD targeting ABCA1 or cardiolipin metabolism.
Main Methods:
- Utilized siRNA to knockdown ABCA1 in podocytes, assessing mitochondrial function and cardiolipin levels.
- Generated podocyte-specific Abca1 knockout mice to evaluate DKD susceptibility.
- Administered ABCA1 inducers and elamipretide (a cardiolipin peroxidation inhibitor) to treat DKD models.
- Investigated the role of free cholesterol by genetically deleting sterol-o-acyltransferase-1 (SOAT1).
Main Results:
- ABCA1 knockdown in podocytes reduced oxygen consumption and increased cardiolipin accumulation.
- Podocyte-specific Abca1 deletion exacerbated DKD susceptibility in mice.
- Pharmacological ABCA1 induction improved established DKD.
- Free cholesterol accumulation (via SOAT1 deletion) did not cause glomerular injury, indicating cardiolipin's central role.
- Elamipretide inhibited cardiolipin peroxidation, improving DKD in vivo and preventing podocyte injury in vitro and in vivo.
Conclusions:
- A pathway linking ABCA1 deficiency to cardiolipin-driven mitochondrial dysfunction in DKD is identified.
- Cardiolipin accumulation, not free cholesterol, mediates ABCA1-dependent podocyte injury in DKD.
- ABCA1 inducers and cardiolipin peroxidation inhibitors represent potential therapeutic strategies for DKD.
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