Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia

Abstract

Friedreich ataxia (FRDA), the most common of the inherited ataxias, is an autosomal recessive degenerative disorder, characterized clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon ref lexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs. FRDA is caused by a GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 in 97% of patients. The FRDA gene encodes a widely expressed 210-aa protein, frataxin, which is located in mitochondria and is severely reduced in FRDA patients. Frataxin function is still unknown but the knockout of the yeast frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration and loss of mtDNA associated with elevated intramitochondrial iron. Here we report in vivo evidence of impaired mitochondrial respiration in skeletal muscle of FRDA patients. Using phosphorus magnetic resonance spectroscopy we demonstrated a maximum rate of muscle mitochondrial ATP production (V max ) below the normal range in all 12 FRDA patients and a strong negative correlation between mitochondrial V max and the number of GAA repeats in the smaller allele. Our results show that FRDA is a nuclear-encoded mitochondrial disorder affecting oxidative phosphorylation and give a rationale for treatments aimed to improve mitochondrial function in this condition.Friedreich ataxia (FRDA) is the most common form of inherited ataxia with a frequency of 1 in 50,000 live births. FRDA is an autosomal recessive degenerative disorder, characterized clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon reflexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs (1). Cardiomyopathy as defined by echocardiography is present in more than 60% of FRDA patients (2). The cause of FRDA is a GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 (3). Ninetyseven percent of FRDA patients are homozygous for the GAA expansion, the remainder carrying a repeat expansion in one FRDA allele and a point mutation in the other (2, 3).The FRDA gene encodes a widely expressed 210-aa protein, frataxin, which is located in mitochondria (4-6) and is severely reduced in FRDA patients (4). Although frataxin function is still unknown, yeast strains carrying a disruption in the frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration (5-8) and loss of mtDNA (7, 8) associated with elevated intramitochondrial iron (5,8).In view of the mitochondrial localization of frataxin (4-6), the evidence from the YFH1 knockout model for mitochondrial dysfunction (5-8), and the similarities of the cardinal clinical features present in FRDA with primary mitochondrial diseases (9), we used in vivo 31 phosphorus magnetic resonance spectroscopy ( 31 P-MRS) to test for the presence of mitochondrial dysfunction in skeletal muscle of 12 FRDA patients. Skeletal muscle is an ideal tissue in which to assess in vi...

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

“…It is reasonable that the choice of glucose‐lowering therapy should take into account potential interactions between medications and the multi‐system comorbidities that can occur in FA. For example, several investigators have suggested that patients with disorders that affect the mitochondria, as FA does,3, 4 exercise caution when using biguanides such as Metformin 23…”

“…In 96% of individuals with FA, disease is caused by homozygous expanded guanine‐adenine‐adenine (GAA) repeats in the FXN gene 2. Pathologic GAA repeat expansions in FXN lead to decreased expression of the encoded gene product frataxin, a protein vital to the assembly and function of iron–sulfur–cluster‐containing enzymes and ATP production within mitochondria 3, 4…”

Frataxin activates mitochondrial energy conversion and oxidative phosphorylation

“…We and others have described decreased ATP production in postexercise skeletal muscle in FA patients (6,7). The reasons for this observation are unknown.…”

“…Additionally, patients with FA (4) as well as heterozygous relatives of FA patients (5) exhibit an early-onset insulin resistance. Furthermore, we and others have demonstrated decreased ATP production in postexercise skeletal muscle in FA patients (6,7).…”

Hydrogen peroxide scavenging rescues frataxin deficiency in a Drosophila model of Friedreich's ataxia

“…cACON activities normalized to the G32/ϩ control (100%) are: UDIR1/G32, 25 Ϯ 6%; mitoCAT/ϩ;UDIR1/G32, 28 Ϯ 5%. ACON activities were compiled from densitometric scans of three separate experiments tection of other iron cofactor enzyme activities important in electron transport and oxidative phosphorylation and improve the noted decrease in ATP production associated with FRDA (47).…”