PMID- 31619261 OWN - NLM STAT- MEDLINE DCOM- 20200713 LR - 20200713 IS - 1478-811X (Electronic) IS - 1478-811X (Linking) VI - 17 IP - 1 DP - 2019 Oct 16 TI - Linoleic acid improves assembly of the CII subunit and CIII2/CIV complex of the mitochondrial oxidative phosphorylation system in heart failure. PG - 128 LID - 10.1186/s12964-019-0445-0 [doi] LID - 128 AB - 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/CIII(2)/CIV complex), as well as assembly of CII subunits and the CIII(2)/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. FAU - Maekawa, Satoshi AU - Maekawa S AD - Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. FAU - Takada, Shingo AU - Takada S AUID- ORCID: 0000-0002-7781-9482 AD - Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. s-takada@hotmail.co.jp. AD - Department of Molecular Biology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. s-takada@hotmail.co.jp. AD - Faculty of Lifelong Sport, Department of Sports Education, Hokusho University, Ebetsu, Japan. s-takada@hotmail.co.jp. FAU - Nambu, Hideo AU - Nambu H AD - Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. FAU - Furihata, Takaaki AU - Furihata T AD - Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. FAU - Kakutani, Naoya AU - Kakutani N AD - Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. AD - Research Fellow of the Japan Society for the Promotion of Science, Tokyo, Japan. FAU - Setoyama, Daiki AU - Setoyama D AD - Clinical Laboratories, Kyushu University Hospital, Fukuoka, Japan. FAU - Ueyanagi, Yasushi AU - Ueyanagi Y AD - Clinical Laboratories, Kyushu University Hospital, Fukuoka, Japan. AD - Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Kang, Dongchon AU - Kang D AD - Clinical Laboratories, Kyushu University Hospital, Fukuoka, Japan. AD - Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Sabe, Hisataka AU - Sabe H AD - Department of Molecular Biology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. FAU - Kinugawa, Shintaro AU - Kinugawa S AD - Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. LA - eng PT - Clinical Trial PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20191016 PL - England TA - Cell Commun Signal JT - Cell communication and signaling : CCS JID - 101170464 RN - 0 (Cardiolipins) RN - 0 (Protein Subunits) RN - 9KJL21T0QJ (Linoleic Acid) RN - EC 1.3.5.1 (Electron Transport Complex II) RN - EC 1.9.3.1 (Electron Transport Complex IV) RN - EC 7.1.1.8 (Electron Transport Complex III) SB - IM MH - Aged MH - Animals MH - Cardiolipins/metabolism MH - Electron Transport Complex II/chemistry/*metabolism MH - Electron Transport Complex III/*metabolism MH - Electron Transport Complex IV/*metabolism MH - Female MH - Heart Failure/*metabolism/pathology/physiopathology MH - Humans MH - Linoleic Acid/metabolism/*pharmacology MH - Male MH - Mice MH - Mitochondria, Heart/*drug effects/metabolism MH - Oxidative Phosphorylation/*drug effects MH - Protein Subunits/metabolism PMC - PMC6796462 OTO - NOTNLM OT - Cardiolipin OT - Myocardial infarction OT - Respirasome OT - Succinate dehydrogenase OT - Supercomplex COIS- The authors declare that they have no conflicts of interest associated with this manuscript. EDAT- 2019/10/18 06:00 MHDA- 2020/07/14 06:00 PMCR- 2019/10/16 CRDT- 2019/10/18 06:00 PHST- 2019/05/26 00:00 [received] PHST- 2019/09/24 00:00 [accepted] PHST- 2019/10/18 06:00 [entrez] PHST- 2019/10/18 06:00 [pubmed] PHST- 2020/07/14 06:00 [medline] PHST- 2019/10/16 00:00 [pmc-release] AID - 10.1186/s12964-019-0445-0 [pii] AID - 445 [pii] AID - 10.1186/s12964-019-0445-0 [doi] PST - epublish SO - Cell Commun Signal. 2019 Oct 16;17(1):128. doi: 10.1186/s12964-019-0445-0.