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Homogentisic acid induces autophagy alterations leading to chondroptosis in human chondrocytes: Implications in Alkaptonuria

Galderisi, Silvia and Milella, Maria Serena and Rossi, Martina and Cicaloni, Vittoria and Rossi, Ranieri and Giustarini, Daniela and Spiga, Ottavia and Tinti, Laura and Salvini, Laura and Tinti, Cristina and Braconi, Daniela and Millucci, Lia and Lupetti, Pietro and Prischi, Filippo and Bernardini, Giulia and Santucci, Annalisa (2022) 'Homogentisic acid induces autophagy alterations leading to chondroptosis in human chondrocytes: Implications in Alkaptonuria.' Archives of Biochemistry and Biophysics, 717. p. 109137. ISSN 0003-9861

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Alkaptonuria (AKU) is an ultra-rare genetic disease caused by a deficient activity of the enzyme homogentisate 1,2-dioxygenase (HGD) leading to the accumulation of homogentisic acid (HGA) on connective tissues. Even though AKU is a multi-systemic disease, osteoarticular cartilage is the most affected system and the most damaged tissue by the disease. In chondrocytes, HGA causes oxidative stress dysfunctions, which induce a series of not fully characterized cellular responses. In this study, we used a human chondrocytic cell line as an AKU model to evaluate, for the first time, the effect of HGA on autophagy, the main homeostasis system in articular cartilage. Cells responded timely to HGA treatment with an increase in autophagy as a mechanism of protection. In a chronic state, HGA-induced oxidative stress decreased autophagy, and chondrocytes, unable to restore balance, activated the chondroptosis pathway. This decrease in autophagy also correlated with the accumulation of ochronotic pigment, a hallmark of AKU. Our data suggest new perspectives for understanding AKU and a mechanistic model that rationalizes the damaging role of HGA.

Item Type: Article
Uncontrolled Keywords: Alkaptonuria; Homogentisic acid; Autophagy; Apoptosis; Oxidative stress
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 23 Mar 2022 13:09
Last Modified: 14 Apr 2022 07:49

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