|Cardiac mitochondrial acetylome after chronic TBI
|Published: Open access to everyone
|DATA SHARING POLICY
|CC-Attribution Non-Commercial Share Alike
|Dr. Omid Azimzadeh
|SIZE OF COHORT
|RADONORM RESEARCH PRIORITY
|Identification of specific metabolic pathways and tissue biomarkers related to radiation specific tissue responses.
|INTERNAL OR EXTERNAL EXPOSURE
|TYPE OF EXTERNAL EXPOSURE
|TYPE OF INTERNAL EXPOSURE
|AGE AT EXPOSURE
|BIOLOGICAL SAMPLE AVAILABLE
Epidemiological studies show that irradiation increases the risk of cardiovascular disease decades after the exposure. Alteration in cardiac energy metabolism has been suggested to contribute to radiation-induced heart pathology. A hallmark of this radiation-associated metabolic impairment is mitochondrial dysfunction and deactivation of the transcription factor PPAR alpha.
The goal of this study was to investigate the role of acetylation in heart mitochondria in the long-term response to chronic radiation. ApoE-deficient (ApoE-/-) C57Bl/6J mice were continuously exposed to low-dose-rate (20 mGy/day) gamma radiation for 300 days, resulting in a cumulative total body dose of 6.0 Gy. Heart mitochondria from irradiated and sham-irradiated control mice were analysed using label-free proteomics. Radiation-induced proteome and acetylome alterations were further validated using immunoblotting, activity assay and ELISA.
In total, 72 proteins showed a changed acetylation status, of which a great majority (96%) were hyperacetylated. These proteins were involved in the mitochondrial energy metabolism, and sirtuin pathway. The elevated acetylation was associated with reduced activity of mitochondrial sirtuins (Sirt3 and 4) and increased amount of Acetyl-CoA. Mitochondrial acetylation has an inhibitory effect on the PPAR alpha-PGC1 regulatory network of metabolism in irradiated hearts.
These data highlight for the first time the role of mitochondrial acetylation in the radiation-induced cardiac injury and suggest a novel mechanism for the late heart damage following irradiation.
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