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

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

doi:10.1172/JCI125316

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

Journal article

Open access

Peer reviewed

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

G. Michelle Ducasa, Alla Mitrofanova, Shamroop K Mallela, Xiaochen Liu, Judith Molina, Alexis Sloan, Christopher E Pedigo, Mengyuan Ge, Javier Varona Santos, Yanio Hernandez, …

The Journal of clinical investigation, Vol.129(8), pp.3387-3400

2019-08-01

DOI: https://doi.org/10.1172/JCI125316

PMCID: PMC6668702

PMID: 31329164

Abstract

Nephrology

Mitochondria

Chronic kidney disease

Metabolism

Cholesterol

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 (Abca1 fl/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 Abca1 fl/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.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.55 Urology & Nephrology - General; 1.55.820 IgA Nephropathy
Web Of Science research areas: Medicine, Research & Experimental
ESI research areas: Clinical Medicine

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Title: ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes
Creators: G. Michelle Ducasa - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Alla Mitrofanova - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Shamroop K Mallela - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Xiaochen Liu - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Judith Molina - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Alexis Sloan - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Christopher E Pedigo - Department of Internal Medicine, Yale University, New Haven, Connecticut, USA
Mengyuan Ge - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Javier Varona Santos - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Yanio Hernandez - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Jin-Ju Kim - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Cyrille Maugeais - Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
Armando J Mendez - Diabetes Research Institute, University of Miami, Miami, Florida, USA
Viji Nair - Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
Matthias Kretzler - Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
George W Burke - Department of Surgery, University of Miami, Miami, Florida, USA
Robert G Nelson - NIDDK, Phoenix, Arizona, USA
Yu Ishimoto - Division of CKD Pathophysiology, University of Tokyo, Tokyo, Japan
Reiko Inagi - Division of CKD Pathophysiology, University of Tokyo, Tokyo, Japan
Santanu Banerjee - Department of Surgery, University of Miami, Miami, Florida, USA
Shaoyi Liu - Social Profit Network Research Lab, Alexandria LaunchLabs, New York, New York, USA
Hazel H Szeto - Social Profit Network Research Lab, Alexandria LaunchLabs, New York, New York, USA
Sandra Merscher - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Flavia Fontanesi - Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida, USA
Alessia Fornoni - Katz Family Division of Nephrology and Hypertension/ Drug Discovery Center, Department of Medicine, University of Miami, Miami, Florida, USA
Publication Details: The Journal of clinical investigation, Vol.129(8), pp.3387-3400
Publisher: American Society for Clinical Investigation
Grant note: R01CA227493 / NIH R01DK117599 / NIH R01DK104753 / NIH 16PRE30200010 / ;
Academic Unit: Miller School of Medicine; Biochemistry & Molecular Biology Research; Diabetes Research Institute (DRI); Miami Transplant Institute; Peggy and Harold Katz Family Drug Discovery Center; UMMG Department of Surgery; UMMG Dept of Medicine - Nephrology & Hypertension Div; UMMG Dept of Surgery - Div of Surgical Oncology
Language: English
Resource Type: Journal article
PMID: 31329164
PMCID: PMC6668702
Record Identifier: 991031577104402976