This paper is quite interesting from the point of ATH434, an iron chelator, ATH wants to work on Parkinson's disease. Parkinson's disease has been proven to be a mitochondrial disease and particularly in complex I. It is a free paper ( https://elifesciences.org/articles/75825 ) and there the editor explains the value of the paper. Additionally, there is also "eLife digest "evaluation of the paper.

Elife

. 2023 Feb 17;12:e75825.

doi: 10.7554/eLife.75825.

Iron status influences mitochondrial disease progression in Complex I-deficient mice

C J Kelly ¹, Reid K Couch ¹, Vivian T Ha ¹, Camille M Bodart ¹, Judy Wu ¹, Sydney Huff ¹, Nicole T Herrel ¹, Hyunsung D Kim ¹, Azaad O Zimmermann ¹, Jessica Shattuck ¹, Yu-Chen Pan ¹, Matt Kaeberlein ¹, Anthony S Grillo ¹

Affiliations expand

• PMID: 36799301

PMCID: PMC10030112 DOI: 10.7554/eLife.75825Free PMC article

Abstract

Mitochondrial dysfunction caused by aberrant Complex I assembly and reduced activity of the electron transport chain is pathogenic in many genetic and age-related diseases. Mice missing the Complex I subunit NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUFS4) are a leading mammalian model of severe mitochondrial disease that exhibit many characteristic symptoms of Leigh Syndrome including oxidative stress, neuroinflammation, brain lesions, and premature death. NDUFS4 knockout mice have decreased expression of nearly every Complex I subunit. As Complex I normally contains at least 8 iron-sulfur clusters and more than 25 iron atoms, we asked whether a deficiency of Complex I may lead to iron perturbations, thereby accelerating disease progression. Consistent with this, iron supplementation accelerates symptoms of brain degeneration in these mice, while iron restriction delays the onset of these symptoms, reduces neuroinflammation, and increases survival. NDUFS4 knockout mice display signs of iron overload in the liver including increased expression of hepcidin and show changes in iron-responsive element-regulated proteins consistent with increased cellular iron that were prevented by iron restriction. These results suggest that perturbed iron homeostasis may contribute to pathology in Leigh Syndrome and possibly other mitochondrial disorders.

Keywords: biochemistry; chemical biology; electron transport chain; iron overload; iron restriction; leigh syndrome; medicine; mitochondrial disease; mouse; neurometabolic.