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

• Published in: Archives of biochemistry and biophysics 2022-03, Vol.717, p.109137-109137, Article 109137
• Main Authors: Galderisi, Silvia, Milella, Maria Serena, Rossi, Martina, Cicaloni, Vittoria, Rossi, Ranieri, Giustarini, Daniela, Spiga, Ottavia, Tinti, Laura, Salvini, Laura, Tinti, Cristina, Braconi, Daniela, Millucci, Lia, Lupetti, Pietro, Prischi, Filippo, Bernardini, Giulia, Santucci, Annalisa
• Format: Article
• Language: English
• Subjects: Alkaptonuria; Alkaptonuria - metabolism; Alkaptonuria - prevention & control; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Biomarkers - metabolism; Cartilage, Articular - drug effects; Cell Line; Chondrocytes - cytology; Homogentisate 1,2-Dioxygenase - metabolism; Homogentisic acid; Homogentisic Acid - metabolism; Homogentisic Acid - pharmacology; Humans; Ochronosis - metabolism; Oxidative stress; Oxidative Stress - drug effects; Signal Transduction
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2022.109137

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. •In an in vitro model of Alkaptonuria, HGA cells treatment leads the activation of the autophagic pathway.•In long-term HGA cells treatment, there is a block of autophagic flux and the activation of apoptotic pathway.•HGA induces in cells oxidative stress, mitochondrial damage, nucleolar morphology alteration and ochronotic pigment deposition.