Iron Metabolism in Pancreatic Beta-Cell Function and Dysfunction

Marku, A.; Galli, A.; Marciani, P.; Dule, N.; Perego, C.; Castagna, M.; Cells 2021, 10, 2841. doi:10.3390/cells10112841 

Iron is an essential element involved in a variety of physiological functions. In the pancreatic beta-cells, being part of Fe-S cluster proteins, it is necessary for the correct insulin synthesis and processing. In the mitochondria, as a component of the respiratory chain, it allows the production of ATP and reactive oxygen species (ROS) that trigger beta-cell depolarization and potentiate the calcium-dependent insulin release. Iron cellular content must be finely tuned to ensure the normal supply but also to prevent overloading. Indeed, due to the high reactivity with oxygen and the formation of free radicals, iron excess may cause oxidative damage of cells that are extremely vulnerable to this condition because the normal elevated ROS production and the paucity in antioxidant enzyme activities. The aim of the present review is to provide insights into the mechanisms responsible for iron homeostasis in beta-cells, describing how alteration of these processes has been related to beta-cell damage and failure. Defects in iron-storing or -chaperoning proteins have been detected in diabetic conditions; therefore, the control of iron metabolism in these cells deserves further investigation as a promising target for the development of new disease treatments.

FDA refusal of Stealth Bio drug shows challenges of ultra-rare disease studies

https://medcitynews.com

The FDA refused to review Stealth BioTherapeutics’ Barth syndrome drug, telling the company results in a study of just eight patients are insufficient to support its submission. The impasse highlights the challenges of testing drugs for ultra-rare diseases. Barth is so rare that Stealth is unsure it can recruit patients to run a new study. Stealth said it is evaluating its next steps and expects to provide an update in early November. But Barth is not the only disease at stake. Elamipretide was developed as a way to treat mitochondrial problems in a range of disorders. Cardiomyopathy, the heart muscle weakness that develops in Barth, also develops in two other rare disorders, Duchenne muscular dystrophy and Friedreich’s ataxia. When Stealth reported its second quarter financial results in August, executives said they hope to begin testing elamipretide in Duchenne patients with cardiomyopathy in the first half of next year. An open label Phase 2a study is also expected in Friedreich’s ataxia. Stealth is also evaluating its drug in other diseases.

Mitochondrial Iron-Sulfur Cluster Biogenesis and Neurological Disorders

Arthavan Selvanathan, Bindu Parayil Sankaran; Mitochondrion, 2021, doi:10.1016/j.mito.2021.10.004.

This review focuses on the disorders of ISC biogenesis that have been described in the literature to-date. Key clinical, biochemical and neuroradiological features will be discussed, providing a reference point for clinicians diagnosing and managing these patients. Therapies are mostly supportive at this stage. However, the improved understanding of the pathophysiology of these conditions could pave the way for disease-modifying therapies in the near future.