Blood cells from Friedreich ataxia patients harbor frataxin deficiency without a loss of mitochondrial function

Abstract

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by GAA triplet expansions or point mutations in the FXN gene on chromosome 9q13. The gene product called frataxin, a mitochondrial protein that is severely reduced in FRDA patients, leads to mitochondrial iron accumulation, FeS cluster deficiency and oxidative damage. The tissue specificity of this mitochondrial disease is complex and poorly understood. While frataxin is ubiquitously expressed, the cellular phenotype is most severe in neurons and cardiomyocytes. Here, we conducted comprehensive proteomic, metabolic and functional studies to determine whether subclinical abnormalities exist in mitochondria of blood cells from FRDA patients. Frataxin protein levels were significantly decreased in platelets and peripheral blood mononuclear cells from FRDA patients. Furthermore, the most significant differences associated with frataxin deficiency in FRDA blood cell mitochondria were the decrease of two mitochondrial heat shock proteins. We did not observe profound changes in frataxin-targeted mitochondrial proteins or mitochondrial functions or an increase of apoptosis in peripheral blood cells, suggesting that functional defects in these mitochondria are not readily apparent under resting conditions in these cells.

Increased Copy Number Variation of mtDNA in an Array-based Digital PCR Assay Predicts Ulcerative Colitis-associated Colorectal Cancer

“…Copy number variation (CNV) of mtDNA varies between tissues depending on energy requirements. Brain cells contain 2,000 of mtDNA, but there are <100 in white blood cells (16,17). On the other hand, Afshan et al hypothesized that CNV of mtDNA depends on damage and can function as a biomarker of mitochondrial dysfunction in a particular tissue (18).…”

Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock

“…Although platelet counts did not differ between the three septic shock subclasses, group A had a lower total leukocyte count with a greater percentage of lymphocytes and fewer neutrophils. Lymphocytes have a relatively lower mitochondrial content than neutrophils, though how this effects nuclear-encoded mitochondrial gene expression is not clear [65,66], and have been shown to have slightly less gene upregulation in sepsis [67]. However, we have previously shown that whole blood-derived RNA can yield biologically meaningful data, gene expression profiles have revealed similar themes in leukocyte subsets and whole blood [62], and our current data are consistent with mitochondrial gene expression profiles from previous laboratory-and clinical-based studies [17,56,[68][69][70].…”

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases

“…For example the serum iron and haemoglobin levels of FA patients appear to be within the normal physiological range despite that haem synthesis is carried out in mitochondria mainly in the bone marrow and spleen [90] . This suggests that the haemopoietic tissues are not affected or targeted by the toxicity mechanisms related to low levels frataxin and also of other related abnormalities including iron deposition observed in the mitochondria and cytosol of FA patients [97] . Overall, the iron deposition rate in the mitochondria of the tissues affected in FA patients appears to be very slow.…”

“…In general, the clinical problems arising from the abnormalities of frataxin are not equally affecting the FA patients or the various organs with the exception of the heart, the brain and other parts of the nervous system [97] . For example the serum iron and haemoglobin levels of FA patients appear to be within the normal physiological range despite that haem synthesis is carried out in mitochondria mainly in the bone marrow and spleen [90] .…”