Journal article
Docosahexaenoic acid lowers cardiac mitochondrial enzyme activity by replacing linoleic acid in the phospholipidome
The Journal of biological chemistry, Vol.293(2), pp.466-483
01/12/2018
DOI: 10.1074/jbc.M117.812834
PMCID: PMC5767854
PMID: 29162722
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), monolyso-CL, phosphatidylcholine, and phosphatidylethanolamine. Moreover, DHA lowered enzyme activities of respiratory complexes I, IV, V, and I + III. Mechanistically, the reduction in enzymatic activities was 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.
Details
- Title: Subtitle
- Docosahexaenoic acid lowers cardiac mitochondrial enzyme activity by replacing linoleic acid in the phospholipidome
- Creators
- E. Madison Sullivan - Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, North Carolina 27834Edward Ross Pennington - Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, North Carolina 27834Genevieve C Sparagna - Department of Medicine, Division of Cardiology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado 80045Maria J Torres - East Carolina Diabetes and Obesity Institute, and East Carolina University, Greenville, North Carolina 27834P. Darrell Neufer - East Carolina Diabetes and Obesity Institute, and East Carolina University, Greenville, North Carolina 27834Mitchel Harris - Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, North Carolina 27834James Washington - Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, North Carolina 27834Ethan J Anderson - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, andTonya N Zeczycki - Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, North Carolina 27834David A Brown - Virginia TechSaame Raza Shaikh - Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, North Carolina 27834
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.293(2), pp.466-483
- DOI
- 10.1074/jbc.M117.812834
- PMID
- 29162722
- PMCID
- PMC5767854
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- R01HL123647 / National Institutes of Health
- Language
- English
- Date published
- 01/12/2018
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center; Health, Sport, and Human Physiology
- Record Identifier
- 9984065312602771
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