Browsing School, Graduate by Subject "mitochondrial permeability transition pore"
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o-3 polyunsaturated fatty acids and cardiac mitochondriaOpening of the mitochondrial permeability transition pore (MPTP) leads to cell death, contributes to progressive left ventricular dysfunction and remodeling and has also been implicated in the development and progression of heart failure. Thus, pharmacological inhibition of the MPTP is a target for cardioprotective therapy. The beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) have long been recognized. However, the precise mechanism(s) underlying their cardioprotective effects are not well-established. Omega-3 PUFAs can affect mitochondrial function and can prevent cardiomyocyte death in certain conditions. We have previously shown that treatment with the omega-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) exerts cardioprotective effects, and suppresses Ca2+-induced opening of MPTP. These effects are associated with a large increase in DHA and a smaller increase EPA, and lower arachidonic acid (ARA) in cardiac phospholipids. This indicates that DHA may play a larger role in membrane-associated modulation of mitochondria. Thus, recommendations for dietary supplementation of both EPA+DHA may be unnecessary or counterproductive, if DHA alone is actually responsible for mediating the beneficial effects. In this doctoral project, we determined the effects of a diet rich in DHA alone or EPA alone when compared to a control diet on MPTP opening and mitochondrial respiratory function, in the healthy and hypertrophied myocardium, as well as elucidated the potential role of ARA. We show that DHA delayed MPTP opening in response to Ca2+. This effect was associated with an increase in DHA and total omega-3 PUFA in cardiac mitochondrial phospholipids and a reduction in the amount of ARA. EPA, on the other hand, had no effect on MPTP opening, despite increasing membrane EPA and moderately reducing ARA. Supplementation with DHA+EPA also increased DHA and delayed MPTP opening, but had a less profound effect on phospholipid DHA and total DHA+EPA content than DHA alone. ARA supplementation delayed Ca2+-induced MPTP opening to approximately the same extent as DHA supplementation, but also increased pro-inflammatory prostaglandin synthesis. Combined DHA+ARA had a sensitizing effect on MPTP opening, decreasing the threshold cumulative Ca2+ load necessary to elicit a response, as well as increasing markers of inflammation. Thus, DHA, but not EPA dramatically alters cardiac mitochondrial phospholipid fatty acid composition and prevents MPTP. This effect is potentially independent from membrane ARA content and linked to membrane unsaturation. Recommendations for dietary supplementation of both EPA+DHA may be unnecessary or counterproductive, if DHA alone is actually responsible for mediating the beneficial effects.