Introduction
- Brown D.A.
- Perry J.B.
- Allen M.E.
- Sabbah H.N.
- Stauffer B.L.
- Shaikh S.R.
- Cleland J.G.
- Colucci W.S.
- Butler J.
- Voors A.A.
- Anker S.D.
- Pitt B.
- Pieske B.
- Filippatos G.
- Greene S.J.
- Gheorghiade M.
- Gonzalvez F.
- D'Aurelio M.
- Boutant M.
- Moustapha A.
- Puech J.P.
- Landes T.
- Arnauné-Pelloquin L.
- Vial G.
- Taleux N.
- Slomianny C.
- Wanders R.J.
- Houtkooper R.H.
- Bellenguer P.
- Møller I.M.
- Gottlieb E.
- et al.
Results
Cardiac DHA levels are elevated in human diabetics


Murine cardiac mitochondrial CL and monolyso-CL acyl chains are dramatically remodeled in response to Western diets in the absence and presence of EPA and DHA

Murine cardiac mitochondrial PC and PE acyl chains are remodeled in response to a Western diet in the absence and presence of EPA and DHA

Cardiac mitochondrial respiratory enzyme activities are decreased with the EPA- and DHA-enriched Western diets

EPA and DHA do not robustly suppress formation of the major supercomplexes
Replacement of (18:2)4CL with (22:6)4CL prevents the formation of lipid domains by influencing the Gibbs free energy of lipid–lipid mixing

Replacement of (18:2)4CL with (22:6)4CL diminishes interactions with complex IV

Constant | (18:2)4CL | (22:6)4CL |
---|---|---|
kon | 500 ± 10 m−1 s−1 | ND |
koff | 7.6 ± 0.2 (×10−4) s−1 | ND |
Kd | 1.8 ± 0.6 μm | ND |
(18:2)4CL rescues the major remodeling in the cardiolipin lipidome induced by long-term intake of DHA

Cardiac mitochondrial complex I, IV, and V activities are rescued upon introduction of (18:2)4CL into the mitochondria of mice consuming DHA

Discussion
- Gonzalvez F.
- D'Aurelio M.
- Boutant M.
- Moustapha A.
- Puech J.P.
- Landes T.
- Arnauné-Pelloquin L.
- Vial G.
- Taleux N.
- Slomianny C.
- Wanders R.J.
- Houtkooper R.H.
- Bellenguer P.
- Møller I.M.
- Gottlieb E.
- et al.
- Aoun M.
- Feillet-Coudray C.
- Fouret G.
- Chabi B.
- Crouzier D.
- Ferreri C.
- Chatgilialoglu C.
- Wrutniak-Cabello C.
- Cristol J.P.
- Carbonneau M.A.
- Coudray C.
DHA potentially lowers cardiac mitochondrial enzyme activities by influencing domain organization and protein–lipid binding
Paradox on DHA
Role of linoleic acid in the myocardium
- Harris W.S.
- Mozaffarian D.
- Rimm E.
- Kris-Etherton P.
- Rudel L.L.
- Appel L.J.
- Engler M.M.
- Engler M.B.
- Sacks F.
- Ramsden C.E.
- Zamora D.
- Leelarthaepin B.
- Majchrzak-Hong S.F.
- Faurot K.R.
- Suchindran C.M.
- Ringel A.
- Davis J.M.
- Hibbeln J.R.
- Chowdhury R.
- Warnakula S.
- Kunutsor S.
- Crowe F.
- Ward H.A.
- Johnson L.
- Franco O.H.
- Butterworth A.S.
- Forouhi N.G.
- Thompson S.G.
- Khaw K.T.
- Mozaffarian D.
- Danesh J.
- Di Angelantonio E.
Conclusions
Experimental procedures
Human subjects
Human atrial appendage biopsy, tissue processing, and fatty acid analyses
Animals and diets
Metabolic profiling
- Kosaraju R.
- Guesdon W.
- Crouch M.J.
- Teague H.L.
- Sullivan E.M.
- Karlsson E.A.
- Schultz-Cherry S.
- Gowdy K.
- Bridges L.C.
- Reese L.R.
- Neufer P.D.
- Armstrong M.
- Reisdorph N.
- Milner J.J.
- Beck M.
- Shaikh S.R.
Isolation of mitochondria
Electrospray ionization mass spectrometry
Small unilamellar vesicle formation and fusion with mitochondria
Blue-native PAGE for quantifying supercomplex formation
Construction of biomimetic mitochondrial giant unilamellar vesicles (GUVs) to quantify domain organization
Confocal microscopy and image analysis
Quantification of the Gibbs free energy of lipid mixing
Synthesis of LUVs
SPR
Mitochondrial kinetic assays
Statistical analyses
Author contributions
Supplementary Material
Author Profile
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Footnotes
This work was supported by National Institutes of Health Grants R01HL123647 (to S. R. S. and D. A. B.), R01AT008375 (to S. R. S.), P30DK056350 (to S. R. S.), R01HL122863 (E. J. A.), and R01DK110656 (to P. D. N). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This article contains Figs. S1–S4 and Tables S1 and S2.
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