(3) A Novel Pathological Iron Crystallite within Mitochondria that is Formed Through Dysregulation of Iron Metabolism Due to the Genetic Loss of Frataxin

Richardson’s third paradigm-shifting research centered on understanding mitochondrial iron metabolism and the concept of how the mitochondrion was damaged by iron in the cardio-and neuro-degenerative disease, Friedreich’s ataxia, where there is a decrease in frataxin expression. While frataxin was known to facilitate iron sulphur cluster and heme synthesis, and that its loss markedly decreased these processes, the reason why loss of frataxin induced mitochondrial iron-loading was paradoxical and totally unknown. 

Through the dissection of cellular and mitochondrial iron metabolism, Richardson demonstrated that the dysregulation of iron metabolism in the mitochondrion due to the loss of frataxin, leads to a full reprogramming of cytoplasmic iron metabolism that results in iron being sent to the mitochondrion to try and rescue the defect in mitochondrial iron sulphur cluster and heme synthesis.

This includes marked up-regulation of the transferrin receptor 1 (Tfr1) to increase cellular iron uptake and iron trafficking away from cytoplasmic iron pools (e.g., ferritin) to be directed to the mitochondrion in an effort to rescue the metabolic defect, i.e., the critical decrease in iron containing haem and iron sulphur clusters (Fig. 4).

Unfortunately, while this rescue is effective, it leads to cytoplasmic iron depletion and a massive excess of toxic iron being transported to the mitochondrion. This newly delivered iron then cannot be utilized due to the defective synthesis of iron sulphur clusters and haem (due to the loss of frataxin in this disease), resulting in mitochondrial iron overload.

This paradoxical situation was demonstrated by Richardson to lead to toxic iron accumulation as a unique non-crystalline iron(III) phosphate mineral (Fig. 5) without a protein shell that explains the redox stress observed in this organelle during this disease and could lead to the cardiac degeneration observed in Friedreich’s ataxia and potentially the neurodegeneration. 

In fact, Richardson demonstrated in vivo using special mitochondrial chelators and a mouse model that removing the mitochondrial iron could improve cardiac function (PNAS 2008).