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ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes
G. Michelle Ducasa, … , Flavia Fontanesi, Alessia Fornoni
G. Michelle Ducasa, … , Flavia Fontanesi, Alessia Fornoni
Published July 22, 2019
Citation Information: J Clin Invest. 2019;129(8):3387-3400. https://doi.org/10.1172/JCI125316.
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Research Article Metabolism Nephrology

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

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Abstract

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.

Authors

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

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Figure 5

Treatment with an Abca1 inducer (A30) ameliorates podocyte injury and DKD.

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Treatment with an Abca1 inducer (A30) ameliorates podocyte injury and DK...
(A) Quantification of cytotoxicity normalized to viability for NP (n = 13) and P (n = 14) sera–treated, or untreated (NT, n = 3) ABCA1-overexpressing (ABCA1 OE) podocytes compared with empty vector transfected (EV) podocytes. (B–F) Db/+, vehicle-treated db/db, and Abca1 inducer–treated (A30-treated) db/db mice were analyzed for (B) albumin-to-creatinine ratios determined at start of treatment (14 weeks), after 2 weeks of treatment (16 weeks), and at time of sacrifice after 4 weeks of treatment (18 weeks) (n = 5–6 per group); (C) BUN (n = 5–6 per group); (D) podocyte number per glomerular cross section (n = 3–4 per group) determined by WT1 staining; (E) mesangial expansion score quantification determined from PAS staining (n = 5–6 per group); and (F) podocyte foot processes per μm of GBM (n = 3 per group) determined from TEM images. (G–I) Representative images of (G) WT1 staining (scale bars: 25 μm); (H) PAS staining (scale bars: 25 μm); and (I) TEM to identify podocyte foot processes (marked with orange arrows) per μm of GBM (scale bars: 500 nm). (J) Kidney cortex cholesterol content determination in form of TC, FC, and CEs (n = 5–6 per group). (K) Quantification of the relative cardiolipin species rich in linoleic acid (LA) or docosahexaenoic acid (DHA) analyzed via mass spectrometry and normalized to total lipids extracted from db/+, db/db vehicle, and db/db A30 kidney cortex (n = 5–6 per group). Two-tailed t test (A) or 1-way ANOVA followed by Tukey’s test (all other panels). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

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