Leriglitazone improves iron homeostasis and ferroptotic markers in frataxin-deficient dorsal root ganglia neurons

Abstract

Friedreich ataxia (FA) is a neurodegenerative disease characterized by degeneration of the large sensory neurons and spinocerebellar tracts, muscle weakness, and hypertrophic cardiomyopathy. It is caused by a deficiency of the mitochondrial protein frataxin, leading to iron dyshomeostasis, defective energy production, and oxidative stress. Peroxisome proliferator-activated receptor gamma (PPARγ) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways play crucial roles in regulating mitochondrial function and protecting against oxidative stress, and their dysregulation contributes to neuronal degeneration in FA. In this study, we used frataxin-deficient primary cultures of dorsal root ganglia neurons to better understand the mechanism of action of leriglitazone, a novel brain-penetrant, full, and selective PPARγ agonist, by assessing the rescue of several cellular markers altered under frataxin deficiency. Leriglitazone improved most of the analyzed parameters, including cell survival, mitochondrial respiratory activity, iron homeostasis, and oxidative stress. Moreover, increased lipid peroxidation, a key marker of ferroptosis, was almost completely rescued by leriglitazone. NRF2 and PPARγ coactivator 1 alpha (PGC1 α ) levels that were decreased in frataxin-deficient neurons were normalized by leriglitazone. Interestingly, the combination of leriglitazone and the NRF2 activator omaveloxolone, a drug that has been approved to treat FA, was able to rescue both survival and mitochondrial function. In summary, our f indings in this neuronal model suggest that targeting the PPARγ pathway with leriglitazone may be a promising therapeutic strategy for FA by improving mitochondrial function, bioenergetic cell alterations, and iron homeostasis. Likewise, a combination therapy with omaveloxolone may be an alternative for FA patients.

This work was supported by: 1) Grant CPP2021–008554 funded by MICIU/AEI /10.13039/501100011033 and by the European Union NextGenerationEU/ PRTR; 2) Grant PID2020–118296RB-I00 funded by MICIU/AEI /10.13039/501100011033; 3) Grant PDC2021–120758-I00 funded by MICIU/AEI /10.13039/501100011033 and by the European Union NextGenerationEU/ PRTR; 4) Grant PID2023–148128OB-I00 funded by MICIU/AEI /10.13039/501100011033 and by FEDER, EU; 5) Project 2021-SGR 00323 funded by Generalitat de Catalunya. Marta Portillo-Carrasquer received a PhD fellowship from the Generalitat de Catalunya. Arabela Sanz-Alcázar received first a Ph.D. fellowship from the Generalitat de Catalunya and after, she held predoctoral fellowship “Ajuts al Personal Investigador en Formació " from IRBLleida/Diputació de Lleida. Maria Pazos received a PhD fellowship from the Universitat de Lleida. Luiza Olivera Jorge received a predoctoral fellowship “Ajuts de suport a departaments i unitats de recerca universitaris per a la contractació de personal investigador predoctoral en formación (FI-SDUR 2023).