Journal Article

ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes

Mitrofanova, Alla, Sloan, Alexis, Inagi, Reiko, Fontanesi, Flavia, Liu, Shaoyi, Santos, Javier Varona, Kim, Jin-Ju, Merscher, Sandra, Szeto, Hazel H., Fornoni, Alessia, Mendez, Armando J., Kretzler, Matthias, Nelson, Robert G., Banerjee, Santanu, Liu, Xiaochen, Molina, Judith, Ducasa, G. Michelle, Burke, George W., Maugeais, Cyrille, Nair, Viji, Pedigo, Christopher E., Mallela, Shamroop K., Ge, Mengyuan, Hernandez, Yanio, Ishimoto, Yu

2019

Overview

Fibroblasts from patients with Tangier disease carrying ATP-binding cassette A1 (ABCA1) loss-of-function mutations are characterized by cardiolipin accumulation, a mitochondrial-specific phospholipid. Suppression of ABCA1 expression occurs in glomeruli from patients with diabetic kidney disease (DKD) and in human podocytes exposed to DKD sera collected prior to the development of DKD. We demonstrated that siRNA ABCA1 knockdown in podocytes led to reduced oxygen consumption capabilities associated with alterations in the oxidative phosphorylation (OXPHOS) complexes and with cardiolipin accumulation. Podocyte-specific deletion of Abca1 (Abca1fl/fl) rendered mice susceptible to DKD, and pharmacological induction of ABCA1 improved established DKD. This was not mediated by free cholesterol, as genetic deletion of sterol-o-acyltransferase-1 (SOAT1) in Abca1fl/fl mice was sufficient to cause free cholesterol accumulation but did not cause glomerular injury. Instead, cardiolipin mediates ABCA1-dependent susceptibility to podocyte injury, as inhibition of cardiolipin peroxidation with elamipretide improved DKD in vivo and prevented ABCA1-dependent podocyte injury in vitro and in vivo. Collectively, we describe a pathway definitively linking ABCA1 deficiency to cardiolipin-driven mitochondrial dysfunction. We demonstrated that this pathway is relevant to DKD and that ABCA1 inducers or inhibitors of cardiolipin peroxidation may each represent therapeutic strategies for the treatment of established DKD.

• Publisher: American Society for Clinical Investigation
• Subject: ABCA1 protein / Acyltransferase / Animals / Apoptosis / ATP Binding Cassette Transporter 1 - deficiency / ATP Binding Cassette Transporter 1 - metabolism / ATP-binding protein / Biochemistry / Biomedical research / Biopsy / Cardiolipin / Cardiolipins - genetics / Cardiolipins - metabolism / Cholesterol / Cytochrome / Development and progression / Diabetes / Diabetes mellitus / Diabetic Nephropathies - genetics / Diabetic Nephropathies - metabolism / Diabetic Nephropathies - pathology / Fibroblasts / Humans / Kidney diseases / Lipid Peroxidation / Lipids / Membrane lipids / Metabolism / Mice / Mitochondria / Mitochondria - genetics / Mitochondria - metabolism / Mitochondria - pathology / Mitochondrial DNA / Mutation / Oxidative phosphorylation / Oxygen consumption / Peroxidation / Phospholipids / Phosphorylation / Podocytes / siRNA / Sterol O-Acyltransferase - genetics / Sterol O-Acyltransferase - metabolism / Sterols / Type 2 diabetes