Linoleic acid improves assembly of the CII subunit and CIII2/CIV complex of the mitochondrial oxidative phosphorylation system in heart failure.
BACKGROUND
Linoleic acid is the major fatty acid moiety of cardiolipin, which is central to the assembly of components involved in mitochondrial oxidative phosphorylation (OXPHOS). Although linoleic acid is an essential nutrient, its excess intake is harmful to health. On the other hand, linoleic acid has been shown to prevent the reduction in cardiolipin content and to improve mitochondrial function in aged rats with spontaneous hypertensive heart failure (HF). In this study, we found that lower dietary intake of linoleic acid in HF patients statistically correlates with greater severity of HF, and we investigated the mechanisms therein involved.


METHODS
HF patients, who were classified as New York Heart Association (NYHA) functional class I (n = 45), II (n = 93), and III (n = 15), were analyzed regarding their dietary intakes of different fatty acids during the one month prior to the study. Then, using a mouse model of HF, we confirmed reduced cardiolipin levels in their cardiac myocytes, and then analyzed the mechanisms by which dietary supplementation of linoleic acid improves cardiac malfunction of mitochondria.


RESULTS
The dietary intake of linoleic acid was significantly lower in NYHA III patients, as compared to NYHA II patients. In HF model mice, both CI-based and CII-based OXPHOS activities were affected together with reduced cardiolipin levels. Silencing of CRLS1, which encodes cardiolipin synthetase, in cultured cardiomyocytes phenocopied these events. Feeding HF mice with linoleic acid improved both CI-based and CII-based respiration as well as left ventricular function, together with an increase in cardiolipin levels. However, although assembly of the respirasome (i.e., CI/CIII2/CIV complex), as well as assembly of CII subunits and the CIII2/CIV complex statistically correlated with cardiolipin levels in cultured cardiomyocytes, respirasome assembly was not notably restored by dietary linoleic acid in HF mice. Therefore, although linoleic acid may significantly improve both CI-based and CII-based respiration of cardiomyocytes, respirasomes impaired by HF were not easily repaired by the dietary intake of linoleic acid.


CONCLUSIONS
Dietary supplement of linoleic acid is beneficial for improving cardiac malfunction in HF, but is unable to completely cure HF.
['Maekawa|Satoshi|S|', 'Takada|Shingo|S|0000-0002-7781-9482', 'Nambu|Hideo|H|', 'Furihata|Takaaki|T|', 'Kakutani|Naoya|N|', 'Setoyama|Daiki|D|', 'Ueyanagi|Yasushi|Y|', 'Kang|Dongchon|D|', 'Sabe|Hisataka|H|', 'Kinugawa|Shintaro|S|']
D000368:Aged D000818:Animals D002308:Cardiolipins D042963:Electron Transport Complex II D014450:Electron Transport Complex III D003576:Electron Transport Complex IV D005260:Female D006333:Heart Failure D006801:Humans D019787:Linoleic Acid D008297:Male D051379:Mice D008929:Mitochondria, Heart D010085:Oxidative Phosphorylation D021122:Protein Subunits
Cardiolipin Respirasome Myocardial infarction Succinate dehydrogenase Supercomplex