Medicinal chemistry and the design of therapeutics for the treatment of the iron overload and cardiodegeneration in Friedreich’s ataxia based on the dissection of the molecular pathology in the disease
Richardson, D.R. B.Sc (Hons), MSc., Ph.D., D.Sc., F.F.Sc., FRCPath (UK)
Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia (Link)
Abstract:
There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich's ataxia (FA). The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy.
Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting.
These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MIT-permeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function.
In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant.
Brief Biography:
Professor Des Richardson holds the Chair of Cancer Cell Biology at the University of Sydney, Australia, and is a National Health and Medical Research Council (NHMRC) of Australia Senior Principal Research Fellow.
He has published 409 articles, reviews, patents, chapters etc., over his career with >93% as first, senior or corresponding author (H-index: 82; >28,451 citations over entire career; with >16,541citations over the past 5 years and H-index: 60 over the past 5 years).
He is Executive Editor of BBA-General Subjects and has served on the Editorial Boards of 43 international journals, including J. Biol. Chem., Antioxidants Redox Signaling, Biochem. J., BBA-Mol Cell Res, Mol. Pharmacol., Pharmacol. Res., etc.
As a major translational research achievement, he has developed the anti-cancer and anti-metastatic drug, DpC, which overcomes P-glycoprotein mediated drug resistance.
This has led to commercialisation of DpC and the development of the international company, Oncochel Therapeutics LLC, USA and its Australian subsidiary, Oncochel Therapeutics Pty Ltd. Notably, DpC has entered multi-centre Phase I clinical trials for the treatment of advanced and resistant cancer.
These anti-cancer drugs target the lysosome via the P-glycoprotein transporter.