Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets

Konrad Teodor Sawicki, Adam De Jesus and Hossein Ardehali; Circulation Research. 2023;132:379–396, doi:10.1161/CIRCRESAHA.122.321667 

 Iron dysregulation ranges from iron deficiency to iron overload and is seen in many types of cardiovascular disease, including heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, and Friedreich’s ataxia. Recently, the use of intravenous iron therapy has been advocated in patients with heart failure and certain criteria for iron deficiency. Here, we provide an overview of systemic and cellular iron homeostasis in the context of cardiovascular physiology, iron deficiency, and iron overload in cardiovascular disease, current therapeutic strategies, and future perspectives.

Deficient mitochondrial respiration impairs sirtuin activity in dorsal root ganglia in Friedreich Ataxia mouse and cell models

Arabela Sanz-Alcazar, Elena Britti, Fabien Delaspre, Marta Medina-Carbonero, Maria Pazos-Gil, Jordi Tamarit, Joaquim ROS, Elisa Cabiscol bioRxiv 2023.02.01.526688; doi:10.1101/2023.02.01.526688

In the present study, we found that in primary cultures of DRG neurons as well as in DRGs from the FXNI151F mouse model, frataxin deficiency resulted in lower activity and levels of the electron transport complexes, mainly complexes I and II. As a consequence, the NAD+/NADH ratio was reduced and SirT3, a mitochondrial NAD+-dependent deacetylase, was impaired. We identified alpha tubulin as the major acetylated protein from DRG homogenates whose levels were increased in FXNI151F mice compared to WT mice.

Multifaceted nanoparticles: emerging mechanisms and therapies in neurodegenerative diseases

Mistretta, M., Farini, A., Torrente, Y., & Villa, C. (2023). Brain : a journal of neurology, awad014. Advance online publication. doi:10.1093/brain/awad014 

 This review focuses on the use of nanosystems as an encouraging therapeutic approach targeting molecular pathways involved in localized and systematic neurodegenerative diseases. Among this latter, Friedreich's ataxia is an untreatable complex multisystemic disorder and the most spread type of ataxia, that represents a test case to validate the clinical potential of therapeutic strategies based on nanoparticles with pleiotropic effects.

Decreased mitochondrial respiration in cardiac fibers isolated from a mouse model of Friedreich’s ataxia

PT Pierce, X Wang, A Rivera, A Cooper, H Van Remmen, J Brown, PF Vitiello, The American Journal of the Medical Sciences, Volume 365, Supplement 1, 2023, Pages S194-S195, ISSN 0002-9629, doi:10.1016/S0002-9629(23)00372-5. 

Since mitochondrial complex activities of cardiac fibers from FRDAkD mice were impaired without changes in mitochondrial mass, we hypothesize that bioenergetic changes could be attributable to altered fragmentation of the mitochondrial network. This is the first set of data providing ex vivo evidence of mitochondrial respiratory defects during FXN knockdown associated with FRDA. Furthermore, these findings highlight that there are tissue-specific mechanisms during FXN loss since cardiac and skeletal muscle fibers had differential bioenergetic responses.

Foot and Ankle Biomechanics

Morgan E. Leslie, Joseph M. Iaquinto, Chapter 31 - Neurological Foot Pathology, Editor(s): William R. Ledoux, Scott Telfer, Academic Press, 2023, Pages 489-506, ISBN 9780128154496, doi:10.1016/B978-0-12-815449-6.00047-0. 

This chapter provides an overview of pathologies involving neurological mechanisms affecting foot and ankle biomechanics including stroke, cerebral palsy, toe walking, peripheral neuropathy, foot drop, tarsal tunnel syndrome, Morton’s neuroma, Charcot foot, Charcot-Marie-Tooth disease, Friedreich’s ataxia, and poliomyelitis.

Interactions of reactive sulfur species with metalloproteins

ndrea Domán, Éva Dóka, Dorottya Garai, Virág Bogdándi, György Balla, József Balla, Péter Nagy; Redox Biology, 2023, 102617, ISSN 2213-2317, doi:10.1016/j.redox.2023.102617. 

The current review summarizes the interactions of RSS with protein metal centers and their biological implications with special emphasis on mechanistic aspects, sulfide-mediated signaling, and pathophysiological consequences. A deeper understanding of the biological actions of reactive sulfur species on a molecular level is primordial in H2S-related drug development and the advancement of redox medicine.

Peroxisome proliferator-activated receptor (PPAR) agonists as a potential therapy for inherited metabolic disorders

Bianca Seminotti, Mateus Grings, Nícolas Manzke Glänzel, Jerry Vockley, Guilhian Leipnitz; Biochemical Pharmacology, 2023, 115433, ISSN 0006-2952, doi:10.1016/j.bcp.2023.115433. 

Peroxisomal proliferator-activated receptors (PPARs) consist of a group of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ) that regulate multiple cellular functions and processes, including response to oxidative stress, inflammation, lipid metabolism, and mitochondrial bioenergetics and biogenesis. In this context, the activation of PPARs has been shown to stimulate oxidative phosphorylation and reduce reactive species levels. Thus, pharmacological treatment with PPAR activators, such as fibrates, has gained much attention in the last 15 years. This review summarizes preclinical (animal models and patient-derived cells) and clinical data on the effect of PPARs in IMDs.

A new FRDA mouse model [Fxnnull:YG8s(GAA) > 800] with more than 800 GAA repeats

Kalef-Ezra E, Edzeamey FJ, Valle A, Khonsari H, Kleine P, Oggianu C, Al-Mahdawi S, Pook MA and Anjomani Virmouni S (2023) . Front. Neurosci. 17:930422. doi: 10.3389/fnins.2023.930422 

We found statistically significant behavioral deficits, together with reduced levels of frataxin mRNA and protein, and aconitase activity in YG8JR mice compared with control Y47JR mice. YG8JR mice exhibit intergenerational GAA repeat instability by the analysis of parent and offspring tissue samples. Somatic GAA repeat instability was also detected in individual brain and cerebellum tissue samples. In addition, increased DNA methylation of CpG U13 was identified in FXN GAA repeat region in the brain, cerebellum, and heart tissues. Furthermore, we show decreased histone H3K9 acetylation and increased H3K9 methylation of YG8JR cerebellum tissues within the FXN gene, upstream and downstream of the GAA repeat region compared to Y47JR controls.

A Gene-Edited Cell Therapy for an Incurable Disease: Researchers Receive USD 4.8M Grant to Treat Friedreich’s Ataxia

By: Rebecca Roberts - Jan. 23, 2023. Professor Stephanie Cherqui of University of California San Diego’s School of Medicine recently received a prestigious grant from the Californian Institute of Regenerative Medicine, which will allow her and her team to bring her novel CRISPR therapy for the fatal neurodegenerative disease Friedreich’s ataxia to the clinic. Cherqui’s novel treatment for FRDA is an ex vivo gene-edited autologous cell therapy. The process begins with extracting haematopoietic stem and progenitor cells (HSPCs) from the peripheral blood of patients before excising the trinucleotide repeat hyperexpansion in intron 1 of the FXN gene from the cells. This edit involves delivering a ribonucleoprotein (RNP) complex consisting of Cas9 and two sgRNAs – one guide for either end of the trinucleotide expansion. In their original proof-of-concept study, the team were able to achieve editing efficiencies of more than 50% in the HSPCs of FRDA patients. Edited HSPCs display restored expression of frataxin and mitochondrial function, and can be transplanted back to patients as a one-time, curative therapy. »Because this mutation is located within an intron in the FXN gene, it is a good target for gene correction by removing this expansion using CRISPR-Cas9. In addition, this approach would be valid for all FRDA patients, because they all carry a trinucleotide expansion mutation,« Cherqui elaborates. Edited HSPCs are currently used for the treatment of blood disorders such as sickle cell disease and β-thalassemia. However, Cherqui’s work is novel because it offers proof that these cells can be used to treat conditions like FRDA. Edited HSPCs are able to proliferate and differentiate into macrophages and microglia in vivo in mice, and traffic to the necessary tissues throughout the body and brain of FRDA patients. The early data shows that transplantation of the corrected HSPCs in mice prevents disease progression. The therapy will be aimed at the treatment of babies and children in whom the disease has not yet caused significant damage, however, Cherqui says they may also be able to halt disease progression in adult patients.

A Gene-Edited Cell Therapy for an Incurable Disease: Researchers Receive USD 4.8M Grant to Treat Friedreich’s Ataxia

Protoporphyrin IX Binds to Iron(II)-Loaded and to Zinc-Loaded Human Frataxin

Bernardo-Seisdedos G, Schedlbauer A, Pereira-Ortuzar T, Mato JM, Millet O.; Life (Basel). 2023 Jan 12;13(1):222. doi: 10.3390/life13010222. PMID: 36676171. 

We demonstrate that frataxin also binds Zn2+ in a structurally similar way to Fe2+, but with lower affinity. In turn, both Fe2+-loaded and Zn2+-loaded frataxins specifically associate to protoporphyrin IX with micromolar affinity, while apo-frataxin does not bind to the porphyrin. Protoporphyrin IX association to metal-loaded frataxin shares the binding epitope with ferrochelatase.