HGA-Induced Oxidative Stress Impairs Autophagy via Lysosomal Dysfunction in Alkaptonuria
Pierfrancesco Mastroeni1, Alfonso Trezza1, Anna Visibelli1
1ONE-HEALTH Lab, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy.
Antioxidants (Basel, Switzerland)
|July 28, 2026
Summary
Alkaptonuria (AKU) involves homogentisic acid (HGA) buildup, causing oxidative stress and impaired autophagy in chondrocytes. Prolonged HGA exposure disrupts the autophagy-lysosomal pathway, leading to cell degeneration and cartilage damage in AKU.
Area of Science:
- Biochemistry
- Cell Biology
- Rare Diseases
Background:
- Alkaptonuria (AKU) is a rare metabolic disorder due to homogentisate 1,2-dioxygenase deficiency.
- Systemic accumulation of homogentisic acid (HGA) causes progressive tissue degeneration, including ochronosis and osteoarthropathy.
- Chronic HGA exposure induces oxidative stress and impairs autophagy, crucial for chondrocyte homeostasis.
Purpose of the Study:
- To investigate the mechanisms of autophagy dysregulation in AKU.
- To elucidate the role of homogentisic acid (HGA) in chondrocyte degeneration.
- To understand the interplay between oxidative stress and autophagy in AKU pathogenesis.
Main Methods:
- Utilized a human C20/A4 chondrocyte cell line treated with HGA as an in vitro AKU model.
- Verified findings in chondrocyte cells and cartilage tissue from AKU patient biopsies.
- Assessed oxidative stress markers (ROS, 4-HNE, mitochondrial superoxide) and autophagy markers (LC3, p62, LAMP1) using biochemical assays and live-cell imaging.
Main Results:
- HGA treatment induced time-dependent oxidative stress in chondrocytes.
- Early HGA exposure increased autophagy markers and lysosomal biogenesis.
- Prolonged HGA exposure led to impaired autophagic flux, lysosomal dysfunction, and accumulation of autophagic structures, indicating a transition to lysosomal failure.
Conclusions:
- Prolonged HGA exposure disrupts the balance between oxidative stress and autophagic flux in chondrocytes.
- The collapse of adaptive mechanisms, including autophagy, contributes to chondrocyte degeneration in AKU.
- Dysregulation of the autophagy-lysosomal pathway is a key factor in AKU-related cartilage damage.
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