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

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 2

Podocyte-specific Abca1 deficiency leads to lipid accumulation, and concomitant Soat1 deficiency leads to free cholesterol accumulation in the absence of albuminuria.

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Podocyte-specific Abca1 deficiency leads to lipid accumulation, and conc...
(A) Representative images of oil red O–stained kidney cortex sections for the detection of glomerular lipid droplets in WT and Abca1fl/fl mice (n = 3 per group). (B) Bar graph analysis showing the quantification of total cholesterol (TC), free cholesterol (FC), cholesterol esters (CEs), and triglyceride (TG) levels extracted from kidney cortex of WT (n = 3) and podocyte-specific Abca1fl/fl mice (n = 3) (fold change in microgram lipid per milligram of protein). (C) Representative images of PAS-stained sections utilized for quantification shown for glomerular area (μm) of WT (n = 5) and Abca1fl/fl (n = 3) mice. (D) Bar graph analysis showing the quantification of TC and CE content extracted from kidney cortex of WT (n = 3–4) and Abca1fl/fl Soat1–/– (DKO) mice (n = 5). (E) Representative images for PAS-stained sections of WT (n = 5) and DKO (n = 11) mice and quantification of the mesangial expansion score. (F) Albumin-to-creatinine ratios determined in 1-year-old WT (n = 8), Abca1fl/fl (n = 3), Soat1–/– (Soat1-KO, n = 5), Abca1fl/+ Soat1–/+ (DHET, n = 4), and Abca1fl/fl Soat1–/– (DKO, n = 6) mice. Scale bars: 25 μm. Two-tailed t test (B–D) or 1-way ANOVA followed by Tukey’s multiple comparisons test (E and F). *P < 0.05; **P < 0.01.