COA DEFICIENCY ASTROCYTE MODEL HIGHLIGHT THE ROLE OF MITOCHONDRIAL IRON TRIGGERING NEURODEGENERATION

We utilized hiPS-derived astrocytes of PANK2- and COASY-associated neurodegeneration (PKAN and CoPAN), two Neurodegeneration with Brain Iron Accumulation (NBIA) disorders caused by mutations in genes that codify for key enzymes in Coenzyme A biosynthetic chain reactions, to investigate the relationship between iron mitochondrial impairment and neuronal death. Both diseases are characterized by progressive neurodegeneration and a huge iron-accumulation in the globus pallidus of patients. A neurotoxic feature of PKAN astrocytes was already demonstrated in co-cultures experiments.

Both PKAN and CoPAN astrocytes showed cytosolic iron accumulation, alteration of iron metabolism and mitochondria morphology, and were prone to develop a stellate-like phenotype. The tendency to stellation seems to be correlated with the amount of up-taken transferrin, suggesting a potential impairment in membrane dynamics that could be at the basis of iron overload. Indeed, experiments aimed to analysis of constitutive exo-endocytosis led to the finding of a general impairment in the constitutive endosomal trafficking in PKAN astrocytes. Super-resolution microscopy experiments showed that a significantly lower number of transferrin-enriched vesicles were in contact with mitochondria in PKAN, thus confirming an impaired intracellular fate of cargo endosomes. Analysis of mitochondrial iron homeostasis and tubulin feature reveal that: i) mitochondria display an iron deficiency status caused by an impairment of iron deliver to mitochondria due to alteration of tubulin acetylation ii) mitochondrial iron deficiency cause cytosolic iron overload due to the restriction of ISC biosynthesis that affect iron-protein regulation. This highlighted the mitochondrial main role in iron homeostasis and its involvement in pathogenesis of CoA deficiency.