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

TY - JOUR

T1 - Homogentisic acid induces autophagy alterations leading to chondroptosis in human chondrocytes: Implications in Alkaptonuria

AU - Galderisi, Silvia

AU - Rossi, Martina

AU - Cicaloni, Vittoria

AU - Rossi, Ranieri

AU - Giustarini, Daniela

AU - Spiga, Ottavia

AU - Tinti, Laura

AU - Salvini, Laura

AU - Tinti, Cristina

AU - Braconi, Daniela

AU - Millucci, Lia

AU - Lupetti, Pietro

AU - Prischi, Filippo

AU - Bernardini, Giulia

AU - Santucci, Annalisa

N1 - Funding Information: The authors thank the Associazione Italiana Malati di Alcaptonuria (AimAKU; ORPHA263402), DevelopAKUre, DoE 2018–2022 and BiBiM. Publisher Copyright: © 2022

PY - 2022/3/15

Y1 - 2022/3/15

N2 - 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.

AB - 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.

KW - Alkaptonuria

KW - Apoptosis

KW - Autophagy

KW - Homogentisic acid

KW - Oxidative stress

UR - http://www.scopus.com/inward/record.url?scp=85123599626&partnerID=8YFLogxK

U2 - 10.1016/j.abb.2022.109137

DO - 10.1016/j.abb.2022.109137

M3 - Article

C2 - 35090868

AN - SCOPUS:85123599626

SN - 0003-9861

VL - 717

JO - Archives of biochemistry and biophysics

JF - Archives of biochemistry and biophysics

M1 - 109137

ER -