CE13 - Biologie Cellulaire, biologie du développement et de l’évolution

Investigating the relationships between the Sideroflexin family of mitochondrial metabolites transporters, iron homeostasis and ferroptosis. – SiFeMi

Submission summary

Mitochondrial dysfunction is a hallmark of numerous major human diseases including neurodegenerative diseases. Mitochondria is a key organelle for iron metabolism, being the place of heme and iron-sulfur (Fe-S) clusters biogenesis, two iron-containing cofactors involved in key cellular pathways. Iron, an essential but also highly reactive element, can participate to the generation of the harmful reactive oxygen species and ultimately cell death by ferroptosis. Ferroptosis has raised interest of the scientific community for its potential as a new therapeutic target in cancers and neurodegenerative diseases.
The FeMiSid project aims at understanding the role of sideroflexins (SFXN) in iron metabolism. SFXN form a family of mitochondrial carriers that remain poorly characterized. Since SFXN exist in all eukaryotes, we hypothesize that they are essential for mitochondrial activities. Accordingly, loss-of-function mutations of human SFXN4 cause the COXPD18 syndrome, a rare mitochondrial disease. Recent studies provided evidence for a role of SFXN in iron metabolism but the molecular bases of this regulatory activity are not fully depicted. There are five family members in humans and their functions are still unclear, especially in brain physiology and pathology. Whereas SFXN1 and SFXN3 may be deregulated in Alzheimer’s (AD) and Parkinson’s (PD) diseases, their respective roles in neuronal physiopathology remain largely unknown.
The FeMiSid project focuses more specifically on SFXN1, that was recently described as the mitochondrial serine transporter, thus playing a central role in the one-carbon metabolism (OCM). OCM is a universal metabolic pathway and its perturbation favors cancer cell hyperproliferation and neuronal defects. Given that mitochondrial activities are impaired during neurodegeneration and that an accumulation of brain iron as well as a neuronal death by ferroptosis were described in some neurodegenerative disease (such as AD and PD), our main objectives are to uncover the role of SFXN1: 1) in iron metabolism; 2) in heme and Fe-S clusters biogenesis; 3) in the cellular response to oxidative stress and ferroptosis; 4) in neuronal physiology and neurodegeneration.
To address these main questions, a consortium of experts on mitochondrial physiology and neurodegenerative diseases has been formed allowing the generation of interesting preliminary results on human cells, but also on yeast and fruit fly, that display only one and two SFXN genes respectively. Additionally, Drosophila and rodent models will be used to study SFXN effect on neurodegeneration in whole organisms.
The innovative FeMiSid project focuses on a relatively free niche and will certainly yield major progresses on the role of mitochondria in physiopathology. Data obtained may impact different scientific fields given the wide involvement of mitochondria in human disease (including neurodegenerative diseases, cancer, diabetes, cardiovascular pathologies). Especially, our project could give valuable information on the role of mitochondria and SFXN in AD and PD etiology, the most common neurodegenerative diseases. In the long term, we hope that the knowledge of SFXN functions may permit the design of new therapeutic avenues for neurodegenerative diseases or other diseases involving mitochondrial impairment.

Project coordinator


The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


I2BC Institut de Biologie Intégrative de la Cellule
ICSN Institut de Chimie des Substances Naturelles
LMN Laboratoire de maladies neurodégénératives : mécanismes, thérapies, imagerie

Help of the ANR 565,644 euros
Beginning and duration of the scientific project: September 2021 - 48 Months

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