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 BanerjeeShaoyi Liu, Hazel H. Szeto, Sandra Merscher, Flavia Fontanesi, Alessia Fornoni

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
JournalThe Journal of clinical investigation
Volume130
DOIs
StatePublished - Jul 22 2019

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Podocytes
Cardiolipins
Diabetic Nephropathies
Adenosine Triphosphate
Wounds and Injuries
Tangier Disease
Cholesterol
Acyltransferases
Oxidative Phosphorylation
Sterols
Oxygen Consumption
Small Interfering RNA
Phospholipids
Fibroblasts
Pharmacology
Mutation
Therapeutics

Keywords

  • Cholesterol
  • Chronic kidney disease
  • Metabolism
  • Mitochondria
  • Nephrology

ASJC Scopus subject areas

  • Medicine(all)

Cite this

ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes. / Ducasa, G. Michelle; Mitrofanova, Alla; Mallela, Shamroop K.; Liu, Xiaochen; Molina, Judith; Sloan, Alexis; Pedigo, Christopher E.; Ge, Mengyuan; Santos, Javier Varona; Hernandez, Yanio; Kim, Jin Ju; Maugeais, Cyrille; Mendez, Armando J.; Nair, Viji; Kretzler, Matthias; Burke, George W.; Nelson, Robert G.; Ishimoto, Yu; Inagi, Reiko; Banerjee, Santanu; Liu, Shaoyi; Szeto, Hazel H.; Merscher, Sandra; Fontanesi, Flavia; Fornoni, Alessia.

In: The Journal of clinical investigation, Vol. 130, 22.07.2019.

Research output: Contribution to journalArticle

Ducasa, GM, Mitrofanova, A, Mallela, SK, Liu, X, Molina, J, Sloan, A, Pedigo, CE, Ge, M, Santos, JV, Hernandez, Y, Kim, JJ, Maugeais, C, Mendez, AJ, Nair, V, Kretzler, M, Burke, GW, Nelson, RG, Ishimoto, Y, Inagi, R, Banerjee, S, Liu, S, Szeto, HH, Merscher, S, Fontanesi, F & Fornoni, A 2019, 'ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes', The Journal of clinical investigation, vol. 130. https://doi.org/10.1172/JCI125316
Ducasa, G. Michelle ; Mitrofanova, Alla ; Mallela, Shamroop K. ; Liu, Xiaochen ; Molina, Judith ; Sloan, Alexis ; Pedigo, Christopher E. ; Ge, Mengyuan ; Santos, Javier Varona ; Hernandez, Yanio ; Kim, Jin Ju ; Maugeais, Cyrille ; Mendez, Armando J. ; Nair, Viji ; Kretzler, Matthias ; Burke, George W. ; Nelson, Robert G. ; Ishimoto, Yu ; Inagi, Reiko ; Banerjee, Santanu ; Liu, Shaoyi ; Szeto, Hazel H. ; Merscher, Sandra ; Fontanesi, Flavia ; Fornoni, Alessia. / ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes. In: The Journal of clinical investigation. 2019 ; Vol. 130.
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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.",
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T1 - ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes

AU - Ducasa, G. Michelle

AU - Mitrofanova, Alla

AU - Mallela, Shamroop K.

AU - Liu, Xiaochen

AU - Molina, Judith

AU - Sloan, Alexis

AU - Pedigo, Christopher E.

AU - Ge, Mengyuan

AU - Santos, Javier Varona

AU - Hernandez, Yanio

AU - Kim, Jin Ju

AU - Maugeais, Cyrille

AU - Mendez, Armando J.

AU - Nair, Viji

AU - Kretzler, Matthias

AU - Burke, George W.

AU - Nelson, Robert G.

AU - Ishimoto, Yu

AU - Inagi, Reiko

AU - Banerjee, Santanu

AU - Liu, Shaoyi

AU - Szeto, Hazel H.

AU - Merscher, Sandra

AU - Fontanesi, Flavia

AU - Fornoni, Alessia

PY - 2019/7/22

Y1 - 2019/7/22

N2 - 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.

AB - 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.

KW - Cholesterol

KW - Chronic kidney disease

KW - Metabolism

KW - Mitochondria

KW - Nephrology

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