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 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- Animal study (classified by our AI screen)
- Studied in
- People, plus animal or lab work
- Main outcome
- Mechanisms only
Who paid for it
- Funding
- Independent funding
- Government
- National Institutes of Health
- Government
- National Heart, Lung, and Blood Institute
- Government
- National Institute of Diabetes and Digestive and Kidney Diseases
- Government
- National Center for Complementary and Integrative Health
- Government
- NHLBI NIH HHS
- Government
- NCCIH NIH HHS
- Government
- NIDDK NIH HHS
- Grants
- 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)
Based on 7 listed funder(s).
Publication
- Published
- 2017-11-21 · J Biol Chem · vol. 293 · issue 2 · pp. 466–483
- Publisher
- Elsevier BV
- Cited
- 54 citations · more than 93% of similar papers · 3.4× the field average
- Impact
- Top 10% most cited in its field
- References
- 89 works
- Access
- Open access (hybrid journal) · CC-BY
- Research areas
- Fatty Acid Research and Health · Lipid metabolism and biosynthesis · Metabolomics and Mass Spectrometry Studies
- Keywords
- 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 authors
From US
- E. Madison SullivanEast Carolina University
- Edward Ross PenningtonUniversity of North Carolina at Chapel Hill; East Carolina University
- Genevieve C. SparagnaUniversity of Colorado Anschutz; University of Colorado Denver
- Maria J. TorresEast Carolina University
- Peter Darrell NeuferEast Carolina University
- Mitchel HarrisEast Carolina University
Abstract
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.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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