Frataxin deficiency in Friedreich’s ataxia is associated with reduced levels of HAX-1, a regulator of cardiomyocyte death and survival

Abstract

Frataxin deficiency, responsible for Friedreich’s ataxia (FRDA), is crucial for cell survival since it critically affects viability of neurons, pancreatic beta cells and cardiomyocytes. In FRDA, the heart is frequently affected with typical manifestation of hypertrophic cardiomyopathy, which can progress to heart failure and cause premature death. A microarray analysis performed on FRDA patient’s lymphoblastoid cells stably reconstituted with frataxin, indicated HS-1-associated protein X-1 (HAX-1) as the most significantly upregulated transcript (FC = +2, P < 0.0006). quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) and western blot analysis performed on (I) HEK293 stably transfected with empty vector compared to wild-type frataxin and (II) lymphoblasts from FRDA patients show that low frataxin mRNA and protein expression correspond to reduced levels of HAX-1. Frataxin overexpression and silencing were also performed in the AC16 human cardiomyocyte cell line. HAX-1 protein levels are indeed regulated through frataxin modulation. Moreover, correlation between frataxin and HAX-1 was further evaluated in peripheral blood mononuclear cells (PBMCs) from FRDA patients and from non-related healthy controls. A regression model for frataxin which included HAX-1, group membership and group* HAX-1 interaction revealed that frataxin and HAX-1 are associated both at mRNA and protein levels. Additionally, a linked expression of FXN, HAX-1 and antioxidant defence proteins MnSOD and Nrf2 was observed both in PBMCs and AC16 cardiomyocytes. Our results suggest that HAX-1 could be considered as a potential biomarker of cardiac disease in FRDA and the evaluation of its expression might provide insights into its pathogenesis as well as improving risk stratification strategies.

Cardiac Involvement in Movement Disorders

“…The pathogenesis of cardiomyopathy in FRDA involves a severe reduction of cardiac frataxin levels, failure to clear iron from myocytes, ferroptosis (a recently identified pathway of regulated, iron‐dependent cell death, distinct from apoptosis), lack of oxidative phosphorylation, reduced adenosine triphosphate production, chronic inflammation, and disorganization of intercalated discs (plasma membrane specializations that connect heart fibers end to end and provide mechanical cohesion and ionic coupling) 24,25 . Frataxin is crucial for neuron and cardiomyocyte survival, and its deficiency has been recently linked to low levels of HAX‐1, a regulator of cardiomyocyte death, which could be a potential biomarker of cardiac disease in FRDA 26 . Early clinical indicators of myocardial involvement include elevated serum cardiac troponin I levels 27 and electrocardiographic (ECG) abnormalities, which are present in as many as 93% of patients 9,14 .…”

“…24,25 Frataxin is crucial for neuron and cardiomyocyte survival, and its deficiency has been recently linked to low levels of HAX-1, a regulator of cardiomyocyte death, which could be a potential biomarker of cardiac disease in FRDA. 26 Early clinical indicators of myocardial involvement include elevated serum cardiac troponin I levels 27 and electrocardiographic (ECG) abnormalities, which are present in as many as 93% of patients. 9,14 Twave inversion is the most common ECG abnormality detected, followed by abnormally broad Q waves, signs of left ventricular hypertrophy, a short PR interval, and arrhythmias such as atrial fibrillation or flutter.…”

Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells

“…These antioxidant enzymes are typically induced in the presence of pro-oxidants in order to eliminate superoxide free radicals within the mitochondrial and cytosolic compartments. However, FRDA cells lose the physiological ability of healthy cells to upregulate SODs when exposed to an oxidative insult [ 12 , 20 ] or to maintain protective basal expression levels [ 13 , 58 ].…”

Two RECK Splice Variants (Long and Short) Are Differentially Expressed in Patients with Stable and Unstable Coronary Artery Disease: A Pilot Study

“…We used GAPDH for data normalization and analysis of the results. Data analysis was performed using the comparative threshold cycle (Ct) method quantification as describe in Tiano et al [ 36 ].…”