Docosahexaenoic acid lowers cardiac mitochondrial enzyme activity by replacing linoleic acid in the phospholipidome
Sullivan EM, Pennington ER, Sparagna GC, Torres MJ, Neufer PD, Harris M, Washington J, Anderson EJ, Zeczycki TN, Brown DA, Shaikh SR
The Journal of biological chemistry · 49 citas
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Cómo se estudió
- Diseño
- Estudio en animales (clasificado por nuestro filtro de IA)
- Estudiado en
- Personas, más trabajo en animales o laboratorio
- Resultado principal
- Solo mecanismos
Quién lo pagó
- Financiación
- Financiación independiente
- Gobierno
- National Institutes of Health
- Gobierno
- National Heart, Lung, and Blood Institute
- Gobierno
- National Institute of Diabetes and Digestive and Kidney Diseases
- Gobierno
- National Center for Complementary and Integrative Health
- Gobierno
- NHLBI NIH HHS
- Gobierno
- NCCIH NIH HHS
- Gobierno
- NIDDK NIH HHS
- Subvenciones
- National Heart, Lung, and Blood Institute (R01 HL123647); National Heart, Lung, and Blood Institute (R01 HL122863); National Institute of Diabetes and Digestive and Kidney Diseases (P30DK-056350); National Center for Complementary and Integrative Health (R01 AT008375); National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK110656); National Institutes of Health (P30-DK056350); National Institutes of Health (R01DK110656); National Institutes of Health (R01HL123647); National Institutes of Health (R01AT008375); National Institutes of Health (R01HL122863)
Según 7 financiadores declarados.
Publicación
- Publicado
- 2017-11-21 · J Biol Chem · vol. 293 · número 2 · págs. 466–483
- Editorial
- Elsevier BV
- Citado
- 54 citas · más que el 93% de estudios similares · 3.4× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 89 trabajos
- Acceso
- Acceso abierto (revista híbrida) · CC-BY
- Áreas de investigación
- Fatty Acid Research and Health · Lipid metabolism and biosynthesis · Metabolomics and Mass Spectrometry Studies
- Palabras clave
- Docosahexaenoic acid, Phospholipid, Biochemistry, Phosphatidylethanolamine, Enzyme, Linoleic acid, Cardiolipin, Biology, Mitochondrion, Phosphatidylcholine, Polyunsaturated fatty acid, Respiratory chain, Fatty acid, Chemistry, Membrane
- MeSH
- myocardium, heart, mitochondria, heart, humans, docosahexaenoic acids, eicosapentaenoic acid, fatty acids, unsaturated, linoleic acid, phospholipids, phosphatidylcholines, phosphatidylethanolamines, cardiolipins, mass spectrometry
11 autores
- E. Madison Sullivan🇺🇸East Carolina University
- Edward Ross Pennington🇺🇸University of North Carolina at Chapel Hill; East Carolina University
- Genevieve C. Sparagna🇺🇸University of Colorado Anschutz; University of Colorado Denver
- Maria J. Torres🇺🇸East Carolina University
- Peter Darrell Neufer🇺🇸East Carolina University
- Mitchel Harris🇺🇸East Carolina University
- James Washington🇺🇸East Carolina University
- Ethan J. Anderson🇺🇸University of Iowa; Fraternal Order of Eagles
- Tonya N. Zeczycki🇺🇸East Carolina University
- David A. Brown🇺🇸Virginia Tech
- Saame Raza Shaikh🇺🇸 · autor de correspondenciaUniversity of North Carolina at Chapel Hill; East Carolina University
Resumen
El texto original del estudio, en el idioma en que se publicó.
Cardiac mitochondrial phospholipid acyl chains regulate respiratory enzymatic activity. In several diseases, the rodent cardiac phospholipidome is extensively rearranged; however, whether specific acyl chains impair respiratory enzyme function is unknown. One unique remodeling event in the myocardium of obese and diabetic rodents is an increase in docosahexaenoic acid (DHA) levels. Here, we first confirmed that cardiac DHA levels are elevated in diabetic humans relative to controls. We then used dietary supplementation of a Western diet with DHA as a tool to promote cardiac acyl chain remodeling and to study its influence on respiratory enzyme function. DHA extensively remodeled the acyl chains of cardiolipin (CL), mono-lyso CL, phosphatidylcholine, and phosphatidylethanolamine. Moreover, DHA lowered enzyme activities of respiratory complexes I, IV, V, and I+III. Mechanistically, the reduction in enzymatic activities were not driven by a dramatic reduction in the abundance of supercomplexes. Instead, replacement of tetralinoleoyl-CL with tetradocosahexaenoyl-CL in biomimetic membranes prevented formation of phospholipid domains that regulate enzyme activity. Tetradocosahexaenoyl-CL inhibited domain organization due to favorable Gibbs free energy of phospholipid mixing. Furthermore, in vitro substitution of tetralinoleoyl-CL with tetradocosahexaenoyl-CL blocked complex-IV binding. Finally, reintroduction of linoleic acid, via fusion of phospholipid vesicles to mitochondria isolated from DHA-fed mice, rescued the major losses in the mitochondrial phospholipidome and complexes I, IV, and V activities. Altogether, our results show that replacing linoleic acid with DHA lowers select cardiac enzyme activities by potentially targeting domain organization and phospholipid-protein binding, which has implications for the ongoing debate about polyunsaturated fatty acids and cardiac health.
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