Location: Arkansas Children's Nutrition CenterTitle: Novel molecular interactions of acylcarnitines and fatty acids with myoglobin
|CHINTAPALLI, S - Arkansas Children'S Nutrition Research Center (ACNC)|
|JAYANTHI, S - University Of Arkansas|
|MALLIPEDDI, P - University Of Houston|
|GUNDAMPATI, R - University Of Arkansas|
|SURESH KUMAR, T - University Of Arkansas|
|VAN ROSSUM, D - Pennsylvania State University|
|ANISHKIN, A - University Of Maryland|
Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/7/2016
Publication Date: 11/25/2016
Citation: Chintapalli, S.V., Jayanthi, S., Mallipeddi, P.L., Gundampati, R.K., Suresh Kumar, T.K., Van Rossum, D.B., Anishkin, A., Adams, S.H. 2016. Novel molecular interactions of acylcarnitines and fatty acids with myoglobin. Journal of Biological Chemistry. 291(48):25133-25143. doi:10.1074/jbc.M116.754978.
Interpretive Summary: Exercise and fitness are associated with better overall metabolic health, and so determining the pathways involved in regulating muscle metabolism is important. The oxygen supply for all the living organisms is aided by a protein hemoglobin in the blood. Similar to hemoglobin, myoglobin (the protein that gives muscle its characteristic red color) supplies oxygen to the powerhouses of the cell, mitochondria, in muscle cells where it helps to fuel nutrient combustion to produce energy. Fats are a major source of energy in muscle, but how this fuel is transported inside the cell are not completely known. Although myoglobin has traditionally been considered only as an oxygen delivery protein, recently, we proposed that myoglobin also carries fats. In the present study, we discovered that acylcarnitines (fat derivatives mostly generated by mitochondria as part of oxidative metabolism) also bind to myoglobin when the protein is bound to oxygen. However, myoglobin does not bind to all fat molecules: the minimum chain length for the fat molecule to bind is 12 carbons. As the chain length increases (more added carbons), the binding of these fat molecules to myoglobin gets stronger. Acylcarnitines bind more tightly to myoglobin than fatty acids. Experiments showed that one molecule of myoglobin will bind either to one acylcarnitine or fat molecule at a given time. Together, these studies help explain, for the first time, the likely mechanism by which both fuel and oxygen can be transported within muscle to support energy production and to ensure that excessive build-up of fat derivatives does not occur. This raises the possibility that increases in myoglobin protein in muscle, over time with regular physical activity, could help explain how exercise improves fat burning and muscle health.
Technical Abstract: Previous research has indicated that long-chain fatty acids can bind myoglobin (Mb) in an oxygen dependent manner. This suggests that Oxy-Mb may play an important role in fuel delivery in Mb-rich muscle fibers (e.g., type I fibers and cardiomyocytes), and raises the possibility that Mb also serves as an acylcarnitine binding protein. We report for the first time the putative interaction and affinity characteristics for different chain lengths of both fatty acids and acylcarnitines with Oxy-Mb using molecular dynamic simulations and isothermal titration calorimetry experiments. We found that short- to medium-chain fatty acids or acylcarnitines (ranging from C2:0 to C10:0) fail to achieve a stable conformation with Oxy-Mb. Furthermore, our results indicate that C12:0 is the minimum chain length essential for stable binding of either fatty acids or acylcarnitines with Oxy-Mb. Importantly, the empirical lipid binding studies were consistent with structural modeling. These results reveal that: (i) the lipid binding affinity for Oxy-Mb increases as the chain length increases (i.e., C12:0 to C18:1), (ii) the binding affinities of acylcarnitines are higher when compared to their respective fatty acid counterpart, and (iii) both fatty acids and acylcarnitines bind to Oxy-Mb in 1:1 stoichiometry. Taken together, our results support a model in which Oxy-Mb is a novel regulator of long-chain acylcarnitine and fatty acid pools in Mb-rich tissues. This has important implications for physiological fuel management during exercise, and relevance to pathophysiological conditions (e.g., fatty acid oxidation disorders and cardiac ischemia) where long-chain acylcarnitine accumulation is evident.