Targeting the mitochondrial inner membrane to improve bioenergetics in the diseased heart
Cardiovascular diseases continue to exact unparalleled economic and humanitarian costs across the globe. Manifestations of cardiovascular diseases include acute coronary syndromes and heart failure, both of which are exacerbated in diabetic patients. Although the underlying cellular culprits responsible for these cardiomyopathies are multi-factorial, aberrant cellular bioenergetics is emerging as a central component. Decrements in mitochondrial function impair cardiac function, and accordingly the development of novel therapies that improve cardiac function by targeting mitochondria has enormous therapeutic potential. In the work presented herein, we studied two diseases where impaired bioenergetics comprises a central component: diabetes, and ischemia/reperfusion injury. In diabetic heart studies, we determined the mechanisms responsible for the decline in mitochondrial bioenergetics of the diabetic heart. Comprehensive mitochondrial functional assays coupled with molecular techniques were employed. Our results showed that mitochondrial respiration and reactive oxygen species buffering capacity were significantly decreased in diabetic hearts. Diabetic mitochondria displayed aberrant mitochondrial calcium handling, post-translational oxidative modification of the adenine nucleotide translocase, increased sensitivity to permeability transition pore opening, and lowered overall expression of proteins involved in the electron transport system. These effects led to inefficient energy supply-demand matching and heightened reperfusion injury in intact heart studies. Treatment with several novel therapies that target the mitochondrial inner membrane reduced the extent of injury and restored mitochondrial function in the diabetic heart. In ischemia/reperfusion studies, we tested the hypothesis that aberrant respiration in the post-ischemic heart was due to impaired molecular organization along the inner mitochondrial membrane. Specifically, we used a novel respiratory substrate-inhibitor titration protocol to determine complex-specific changes, in the electron transport system, that lead to poor respiration. These respiratory studies were coupled with experiments using native gel electrophoresis, allowing us to link changes in respiration to altered expression of native respiratory "supercomplex" clusters. The decrease in mitochondrial respiration after ischemia/reperfusion was observed along several different sites of the electron transport system. These changes were associated with lower supercomplex expression, and altered levels of several native respiratory complexes. Post-ischemic treatment with a mitochondria-targeting peptide restored supercomplex assembly and was associated with improved respiration and a decreased extent of injury. Taken together, the results presented herein provide new insight into the molecular and functional alterations that occur along the mitochondrial inner membrane in diabetic and post-ischemic hearts. These data provide a basis for novel therapies targeting the inner mitochondrial membrane as viable pharmacological approaches to improving bioenergetics in diseased myocardium.
Moukdar, Fatiha. (January 2014). Targeting the mitochondrial inner membrane to improve bioenergetics in the diseased heart (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/4574.)
Moukdar, Fatiha. Targeting the mitochondrial inner membrane to improve bioenergetics in the diseased heart. Doctoral Dissertation. East Carolina University, January 2014. The Scholarship. http://hdl.handle.net/10342/4574. December 11, 2018.
Moukdar, Fatiha, “Targeting the mitochondrial inner membrane to improve bioenergetics in the diseased heart” (Doctoral Dissertation., East Carolina University, January 2014).
Moukdar, Fatiha. Targeting the mitochondrial inner membrane to improve bioenergetics in the diseased heart [Doctoral Dissertation]. Greenville, NC: East Carolina University; January 2014.
East Carolina University