Huisamen 2015 Abstract MiPschool Cape Town 2015
|The ATM protein and myocardial mitochondria.|
Huisamen B (2015)
Event: MiPschool Cape Town 2015
According to the latest statistics, various cardiovascular diseases accounted for 8.3% of natural deaths in South Africa during 2013, ranking the 6th place as cause of mortality. With the efficiency of therapies aimed at decreasing mortality from heart disease, life expectancy increased. As result of this, the focus of recent research changed towards understanding the energy demands of the heart in order to optimize function. Because of its high energetic needs, the human heart utilizes between 3.5 and 6 kg of ATP per day to function. This is produced by its mitochondrial populations which occupy up to 50% of the volume of a cardiomyocyte. A close link therefore exists between mitochondrial dysfunction and heart disease. In addition, there is growing recognition that inborn errors of metabolism can influence cardiomyocyte dysfunction  and that primary inherited mitochondrial diseases display a full spectrum of cardiac disorders . ATM is a 350kDa serine/threonine protein kinase displaying homologies to the large protein family of PI3-Kinases, although it lacks the ability to phosphorylate lipids . It came under scrutiny because of the disease, Ataxia-telangiectasie (A-T), which is an autosomal, recessive disorder that progressively affects multiple organs. This disease is caused by mutations in the Atm gene, resulting in lack or inactivation of the ATM protein . ATM in the cell can be localized to the nucleus, cytoplasm of mitochondria.
We became interested in myocardial ATM because it was found that skeletal muscle of insulin resistant, obese rats had dramatically reduced levels of the so-called ATM protein, in association with the well-known reduced activation of the insulin/ phosphatidylinositol 3 kinases (PI3- kinase)/PKB/Akt pathway, which is the main mechanism of relaying the metabolic effects of insulin . Foster et al  found structural and functional changes in the hearts of ATM KO mice, using echocardiography and Doppler echocardiography.
The mitochondrial association of ATM protein kinase plays an important role in its integrity and functioning such that ATM deficiency results in defects in mitochondrial respiration . ATM also regulates mitochondrial biogenesis and DNA content . In addition, it was demonstrated that a mitochondria-targeted antioxidant MitoQ, could decrease the features of the metabolic syndrome in ATM+/-ApoE-/- mice . This may be because one of the mechanisms known to activate the ATM protein is increased oxidative stress. Activated ATM initiates an anti-oxidant response based on a metabolic shift while, in fibroblast cell lines, inactivation of ATM is associated with increased ROS levels followed by expression and activation of the transcription factor HIF-1alpha .
Labels: MiParea: Patients, mt-Awareness Pathology: Cardiovascular
Because of the above and in light of scant knowledge with regards to the role and function of ATM in the heart, we hypothesized that low activity of ATM in the heart will compromise myocardial function and mitochondrial potential. Our study involved perfusion of isolated rat hearts with an inhibitor of ATM and measuring myocardial function and mitochondrial oxidative phosphorylation potential. Our results demonstrated that ATM: (i) is down regulated in hearts from obese, insulin resistant rats, (ii) is associated with myocardial mitochondria and (iii) inhibition of ATM enhances coronary flow, increases RPP recovery after ischaemia and results in enhanced oxidative phosphorylation capacity of isolated mitochondria. Contrary to what was expected, inhibition of ATM in our model was beneficial.
Univ Stellenbosch Dept Med Physiol, South Africa. - [email protected]
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