The Influence of Diet-Induced Obesity and N-3 Fatty Acids on the Cardiac Mitochondrial Phospholipidome and Respiratory Activity
Robison, E. Madison
Cardiac mitochondrial phospholipids, notably cardiolipin (CL), regulate inner mitochondrial membrane (IMM) organization and protein function, particularly the enzymes associated with respiration. In a range of metabolic diseases, CL and other phospholipids undergo acyl chain remodeling, which would presumably impair respiratory activity. In diet-induced obesity, the influence of cardiac remodeling on respiratory enzyme activity and mitochondrial respiration is poorly studied. Thus, we first established the effect of diet-induced obesity on the mitochondrial phospholipidome and subsequent influences on mitochondrial function using two different dietary models. Surprisingly, the high fat diet and western diet remodeled the phospholipidome, but both obesogenic diets had no influence on cardiac mitochondrial supercomplex formation, respiratory enzyme activities, or respiration. Therefore, we next investigated how extremely remodeling with dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) in the context of obesity, would influence the mitochondrial phospholipidome and thereby respiration. The rationale for focusing on n-3 PUFAs was that these fatty acids are generally considered cardioprotective but paradoxically are elevated in several metabolic diseases. Dietary supplementation with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) extensively remodeled the phospholipidome. Particularly, CL acyl chains were remodeled to include DHA at the loss of linoleic acid, which is incorporated into 90% of CL species. Strikingly, supplementation with DHA reduced the activities of several respiratory enzymes, although overall respiration was not affected. We tested the hypothesis that the reduction in enzymatic activity with DHA was driven by the replacement of linoleic acid with DHA in CL species. Indeed, fusion of linoleic acid to mitochondria isolated from DHA-fed mice, rescued the impairments in the CL lipidome and thereby several respiratory complex activities. These results suggest that increased DHA in the myocardium in differing diseases may be targeting enzymatic activity. Taken together, the data establish that obesity by itself in mice does not disrupt respiratory enzyme activity despite remodeling of CL acyl chains. However, extensive remodeling with n-3 PUFAs has a strong influence. Finally, this study has implications for future nutritional studies on the balance between linoleic acid and n-3 PUFAs in the heart, which is an area of ongoing debate.
Robison, E. Madison. (August 2017). The Influence of Diet-Induced Obesity and N-3 Fatty Acids on the Cardiac Mitochondrial Phospholipidome and Respiratory Activity (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/6507.)
Robison, E. Madison. The Influence of Diet-Induced Obesity and N-3 Fatty Acids on the Cardiac Mitochondrial Phospholipidome and Respiratory Activity. Doctoral Dissertation. East Carolina University, August 2017. The Scholarship. http://hdl.handle.net/10342/6507. October 27, 2020.
Robison, E. Madison, “The Influence of Diet-Induced Obesity and N-3 Fatty Acids on the Cardiac Mitochondrial Phospholipidome and Respiratory Activity” (Doctoral Dissertation., East Carolina University, August 2017).
Robison, E. Madison. The Influence of Diet-Induced Obesity and N-3 Fatty Acids on the Cardiac Mitochondrial Phospholipidome and Respiratory Activity [Doctoral Dissertation]. Greenville, NC: East Carolina University; August 2017.
East Carolina University