1. Academic Validation
  2. Lipocalin-2 induces mitochondrial dysfunction in renal tubular cells via mTOR pathway activation

Lipocalin-2 induces mitochondrial dysfunction in renal tubular cells via mTOR pathway activation

  • Cell Rep. 2023 Aug 24;42(9):113032. doi: 10.1016/j.celrep.2023.113032.
Eloïse Marques 1 Maraiza Alves Teixeira 1 Clément Nguyen 1 Fabiola Terzi 1 Morgan Gallazzini 2
Affiliations

Affiliations

  • 1 Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Cité, Institut Necker Enfants Malades, 160 Rue de Vaugirard, 75015 Paris, France.
  • 2 Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Cité, Institut Necker Enfants Malades, 160 Rue de Vaugirard, 75015 Paris, France. Electronic address: morgan.gallazzini@inserm.fr.
Abstract

Mitochondrial dysfunction is a critical process in renal epithelial cells upon kidney injury. While its implication in kidney disease progression is established, the mechanisms modulating it remain unclear. Here, we describe the role of Lipocalin-2 (LCN2), a protein expressed in injured tubular cells, in mitochondrial dysfunction. We show that LCN2 expression decreases mitochondrial mass and function and induces mitochondrial fragmentation. Importantly, while LCN2 expression favors DRP1 mitochondrial recruitment, DRP1 inhibition antagonizes LCN2's effect on mitochondrial shape. Remarkably, LCN2 promotes mitochondrial fragmentation independently of its secretion or transport iron activity. Mechanistically, intracellular LCN2 expression increases mTOR activity, and rapamycin inhibits LCN2's effect on mitochondrial shape. In vivo, Lcn2 gene inactivation prevents mTOR activation and mitochondrial length decrease observed upon ischemia-reperfusion-induced kidney injury (IRI) in Lcn2+/+ mice. Our data identify LCN2 as a key regulator of mitochondrial dynamics and further elucidate the mechanisms leading to mitochondrial dysfunction.

Keywords

CP: Metabolism; Lipocalin-2; kidney; mTOR pathway; mitochondrial dynamics.

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