Investigating the differential effects of LPS toward cardiac mitochondria in young and aged mice

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OVERVIEW: Aging is a natural process involving the progressive decline in biological systems, such as mitochondrial structure and function. Many exogenous factors over a lifetime can impact mitochondria quality including exposure to environmental toxins like lipopolysaccharide (LPS). It is predicted there is an increased susceptibility to mitochondrial damage with age. However, the effect of chronic stressors on mitochondrial quality and the subsequent impact of aging is unknown. My research has been interested in studying long-chain n-3 and n-6 polyunsaturated fatty acids (PUFA) within the heart. These fatty acids are required components of phospholipid membranes and serve as precursors to a large family of eicosanoids. The metabolism of n-3 and n-6 PUFA occurs through three primary enzymatic systems cyclooxygenases (COX), lipoxygenases (LOX) and cytochrome P450 (CYP) enzymes generating a plethora of bioactive eicosanoids. Many of the eicosanoids are produced in response to inflammation; however, the biological activity of many of these metabolites, notably within the heart, remains largely unexplored and unknown. Our preliminary data suggest LPS triggers increased production CYP-derived metabolites of linoleic acid, which decrease mitochondrial quality.OBJECTIVES: The objective of my NSERC program is to discover novel and fundamental roles for bioactive lipid mediators produced endogenously within the heart. The focus of the current proposal is to explore the effect of low-grade chronic inflammation caused by LPS toward cardiac mitochondrial quality and how this changes in an aged heart. We propose that increased production of detrimental lipid mediators play a critical role in regulating mitochondrial quality contributing to an aged cardiac phenotype. The proposed research will (1) establish the time course and characterization of an eicosanoid profile, mitochondrial quality and cardiac function in young and aged mice exposed to chronic low doses of LPS; (2) evaluate the role of bioactive lipid mediators in regulating mitochondrial quality; and (3) explore the effect of a germ-free environment on cardiac function and mitochondrial during aging. Axenic (germ-free) mice together with a germ-free environment will be utilized to dissect out interactions between the host and LPS. This approach will allow us to explore basic mechanisms of how environmental toxins impact eicosanoid profiles and mitochondrial quality as well some fundamental insight into unique processes of biological aging isolated from microflora.SIGNIFICANCE: This work will increase our knowledge of endogenously produced lipid mediators and identify novel roles they have in regulating mitochondria in young and aged hearts. As well provide insight into understanding how chronic low-grade inflammation will alter eicosanoid profiles and effect mitochondria while investigating the impact of aging.