EXPLORING MITOCHONDRIAL AND REDOX VULNERABILITY IN FRIEDREICH'S ATAXIA USING GOLD NANOCLUSTERS IN HUMAN CELLULAR MODELS

Friedreich’s ataxia (FRDA) is a rare autosomal recessive neurodegenerative disorder caused by transcriptional silencing of the FXN gene, leading to frataxin deficiency, impaired iron–sulfur cluster biogenesis, mitochondrial dysfunction, and chronic oxidative stress. Despite significant advances in the understanding of FRDA pathophysiology, the identification of reliable cellular models for mechanistic studies and preclinical screening remains a major challenge. Peripheral and central nervous system-derived models capture distinct and often complementary aspects of disease biology. In this study, we employed gold nanoclusters (Au8-pXs), endowed with redox-active properties, as an exploratory tool to interrogate mitochondrial and oxidative stress-related pathways across different cellular models of FRDA. Patient-derived peripheral blood mononuclear cells (PBMCs) were used as an accessible and clinically relevant system to assess nanoparticle association, viability, mitochondrial membrane potential, and stress responses under basal and experimentally induced mitochondrial stress conditions. While PBMCs exhibited limited basal phenotypes, functional alterations became detectable only upon strong metabolic or oxidative challenges, highlighting both their translational potential and intrinsic limitations as a surrogate model. To extend these observations to a disease-relevant central nervous system context, induced pluripotent stem cell-derived microglia were employed. Compared to PBMCs, microglia displayed a higher sensitivity to mitochondrial perturbations and a more robust engagement of pathways related to redox homeostasis, mitochondrial quality control, and cellular stress responses, supporting their value as a complementary and mechanistically informative model in FRDA research. Overall, this work positions Au8-pXs as a useful preclinical probe to explore mitochondrial and redox vulnerability in FRDA and provides a comparative framework for the use of peripheral versus CNS-derived cellular systems. These findings underscore the importance of model selection in FRDA studies and support the integration of advanced cellular platforms to better capture disease-relevant mechanisms and guide future therapeutic investigations.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2026

Author dc:creator

• ODDONE, REBECCA

Contributors dc:contributor

• TUTOR: Y.Torrente ; COORDINATORE DEL DOTTORATO: M. S. Clerici
• R. Oddone
• TORRENTE, YVAN
• CLERICI, MARIO SALVATORE

• Settore MEDS-12/A - Neurologia

Statement dc:rights

• info:eu-repo/semantics/openAccess
• license:Creative commons
• license uri:http://creativecommons.org/licenses/by-sa/4.0/

Language dc:language

eng

Handle dc:identifier

https://hdl.handle.net/2434/1238737

OAI identifier oai:identifier

oai:air.unimi.it:2434/1238737