Portillo-Carrasquer, M. | bioRxiv Science

bioRxiv2024

SYSTEMIC FRATAXIN DEFICIENCY CAUSES TISSUE-DEPENDENT IRON HOMEOSTASIS ALTERATIONS: IMPLICATIONS FOR FRIEDREICH ATAXIA

Friedreich Ataxia (FA) is a cardio-neurodegenerative disease caused by mutations in the frataxin gene, which result in low frataxin expression. It is well-established that frataxin deficiency affects iron homeostasis, but the tissue-specificity of these alterations is poorly understood. In this study, we have analyzed iron homeostasis alterations in the FXNI151F mouse model, which presents systemic frataxin deficiency and neurological defects resembling FA patients. Iron overload is observed in the brain from 21-week old FXNI151F mice, both males and females, and it does not further accumulate in older animals. It is also observed in livers from 39-week old mutant females, but not in males. Iron signaling is altered in all tissues: in brain and liver Iron Regulatory Protein 1 (IRP1) content is decreased, while in heart increased IRP2 and decreased specific aconitase 2 activity are observed. Remarkably, these cardiac alterations are partially restored in 39- week-old animals, suggesting that the heart is activating an iron-deficiency response to compensate for deficient iron-sulfur biogenesis. Our findings demonstrate that frataxin deficiency affects iron homeostasis in a time dependent and tissue-specific manner, and that the pathological mechanisms in FA comprise both iron accumulation and limited iron availability. Understanding this specificity is crucial for the design of iron-related therapeutic interventions aiming to improve FA symptomatology.

biochemistry↗

bioRxiv2024

Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3beta in the impairment of the NRF2 response

Friedreich ataxia (FA) is a rare neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin. Frataxin has been related in iron homeostasis, energy metabolism, and oxidative stress. Ferroptosis has recently been shown to be involved in FA cellular degeneration; however, its role in dorsal root ganglion (DRG) sensory neurons, the cells that are affected the most and the earliest, is mostly unknown. In this study, we used primary cultures of frataxin-deficient DRG neurons as well as DRG from the FXNI151F mouse model to study ferroptosis and its regulatory pathways. A lack of frataxin induced upregulation of transferrin receptor 1 and decreased ferritin and mitochondrial iron accumulation, a source of oxidative stress. However, there was impaired activation of NRF2, a key transcription factor involved in the antioxidant response pathway. Decreased total and nuclear NRF2 explains the downregulation of both SLC7A11 (a member of the system Xc, which transports cystine required for glutathione synthesis) and glutathione peroxidase 4, responsible for increased lipid peroxidation, the main markers of ferroptosis. Such dysregulation could be due to the increase in KEAP1 and pGSK3{beta} (Tyr216), which promote cytosolic localization and degradation of NRF2. Moreover, there was a deficiency in the LKB1/AMPK pathway, which would also impair NRF2 activity. AMPK acts as a positive regulator of NRF2 and it is activated by the upstream kinase LKB1. The levels of LKB1 were reduced when frataxin decreased, in agreement with reduced pAMPK (Thr172), the active form of AMPK. SIRT1, a known activator of LKB1, was also reduced when frataxin decreased. In conclusion, this study demonstrated that frataxin deficiency in DRG neurons disrupts iron homeostasis and the intricate regulation of molecular pathways affecting NRF2 activation and the cellular response to oxidative stress, leading to ferroptosis.

neuroscience↗