| Abstract |
A number of works from other laboratories have demonstrated that skeletal muscle mitochondria from patients with peripheral arterial disease have abnormal ultrastructure, extensive DNA damage, abnormal enzymatic activity, and evidence of significantly increased oxidative stress. This doctoral thesis includes three consecutive studies investigating the functional significance of these mitochondrial changes and the mechanisms underlying their pathobiology. Our first study documented that these findings from other laboratories appear to be associated with defective mitochondrial function, which is similar to the one in patients with mitochondrial myopathies. Our second study then demonstrated that this mitochondriopathy is potentially reversible with pharmacotherapy. Lastly, our third study demonstrated that these mitochondrial defects appear to be secondary to a problematic function at the level of the electron transport chain. This mitochondrial dysfunction may have two significant negative effects. First, mitochondria from patients with peripheral arterial disease are not capable to produce as much ATP as normal muscle mitochondria do. Therefore, patients with arterial disease are in double jeopardy. Not only their lower extremities receive a decreased amount of nutrients and oxygen because of the diseased arterial tree, but the decreased oxygen and nutrients that get to the
muscle cannot be normally translated to ATP because of diseased mitochondria. Second, these dysfunctional mitochondria are a constant source for abnormally high levels of reactive oxygen species. Those species can be independently detrimental to the mechanisms that maintain normal cellular structure and function. The end result is a significant drop in the energy levels and a significant increase of the detrimental reactive oxygen species in the skeletal muscles of patients with peripheral arterial disease. The combination of these two pathophysiologic mechanisms appears to be of central importance for the production and worsening of all clinical manifestations of peripheral arterial disease, including intermittent claudication and tissue loss/gangrene.
Although we have made substantial progress investigating this mitochondrial abnormality, there are still a lot of significant details in its pathophysiology that need further exploration. Our studies demonstrate that most likely the underlying mechanism for this mitochondrial dysfunction is at the level of the electron transport chain. Additional work is necessary to, not only prove this hypothesis beyond doubt, but also to further investigate and clarify all the involved molecular mechanisms.
Peripheral arterial disease is associated with a significant physical impairment and the available therapeutic options are very limited. The mitochondriopathy we have described appears to be a significant contributor to the functional handicap of these patients. Treatment of this mitochondriopathy along with surgical revascularization could result in significantly enhanced outcomes. Perhaps, even more exciting, is the possibility of an independent therapeutic modality able to produce meaningful improvement in leg function when revascularization is not an option.
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Μιτοχονδριοπάθεια των σκελετικών μυών ασθενών με περιφερική αρτηριακή νόσο
