Three-Dimensional Human Mucopolysaccharidosis IVA Chondrocyte Culture Reveals Significant Impairments in the Lysosomal-Mitochondrial Crosstalk

Authors

Andrés Felipe Leal
Sampurna Saikia
Shaukat A. Khan
Shunji Tomatsu, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

10-1-2025

Comments

This article is the author’s final published version in Scientific Reports, Volume 15, Issue 1, 2025, Article number 34140.

The published version is available at https://doi.org/10.1038/s41598-025-04871-y. Copyright © The Author(s) 2025.

Abstract

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder (LSD) caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase enzyme. MPS IVA patients suffer from skeletal dysplasia due to the abnormal function of chondrocytes. Given the interactions of lysosomes with various intracellular organelles, it is not surprising that lysosomal dysfunction can lead to improper functioning of lysosome-interacting organelles such as mitochondria. Mitochondrial alterations have been evaluated in several LSDs; nevertheless, they have not been fully addressed in MPS IVA. In this study, we assessed the mitochondrial alterations in MPS IVA chondrocytes using a three-dimensional culture approach. Our findings revealed that MPS IVA chondrocytes exhibited an increased mitochondrial-triggered apoptosis profile, mitochondrial depolarization, and heightened oxidative stress. Additionally, the proteins associated with mitophagy, PINK1/Parkin, were significantly reduced in MPS IVA chondrocytes, whereas LC3-II and p62 were elevated. Our assessment of mitochondrial dynamics revealed increased levels of Drp1 and Fis1 along with decreased levels of Opa1. Regarding biogenesis, the mitochondrial regulators TFAM and PGC-α were upregulated in MPS IVA chondrocytes. Finally, MPS IVA chondrocytes showed a metabolic shift from mitochondrial respiration towards a glycolytic profile. Collectively, these data indicate that alterations in mitochondrial homeostasis may play a critical role in the pathogenesis of MPS IVA.

Recommended Citation

Leal, Andrés Felipe; Saikia, Sampurna; Khan, Shaukat A.; and Tomatsu, Shunji, "Three-Dimensional Human Mucopolysaccharidosis IVA Chondrocyte Culture Reveals Significant Impairments in the Lysosomal-Mitochondrial Crosstalk" (2025). Department of Pediatrics Faculty Papers. Paper 186.
https://jdc.jefferson.edu/pedsfp/186

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

41034280

Language

English