Frataxin is Reduced in Friedreich Ataxia Patients and is Associated with Mitochondrial Membranes

TLDR

Friedreich ataxia is a progressive neurodegenerative disorder caused by loss‑of‑function mutations in the frataxin gene. The study aims to unravel frataxin function. Monoclonal antibodies were developed against different regions of frataxin. The antibodies revealed a processed 18‑kDa frataxin protein that is markedly reduced in Friedreich ataxia patients, localizes to mitochondrial membranes and crests, and whose N‑terminal targeting sequence resides in the first 20 amino acids, suggesting that frataxin loss leads to oxidative damage.

Abstract

Friedreich ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the frataxin gene. In order to unravel frataxin function we developed monoclonal antibodies raised against different regions of the protein. These antibodies detect a processed 18 kDa protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients. By immunocytofluorescence and immunocytoelectron microscopy we show that frataxin is located in mitochondria, associated with the mitochondrial membranes and crests. Analysis of cellular localization of various truncated forms of frataxin expressed in cultured cells and evidence of removal of an N-terminal epitope during protein maturation demonstrated that the mitochondrial targetting sequence is encoded by the first 20 amino acids. Given the shared clinical features between Friedreich ataxia, vitamin E deficiency and some mitochondriopathies, our data suggest that a reduction in frataxin results in oxidative damage.