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Targeting of reactive isolevuglandins in mitochondrial dysfunction and inflammation
Author(s) -
Mayorov Vladimir,
Uchakin Peter,
Amarnath Venkataraman,
Dikalova Anna,
Panov Alexander,
Zackert Bill,
Davis Sean,
Dikalov Sergey
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.543.9
Subject(s) - inflammation , mitochondrion , reactive oxygen species , endothelial dysfunction , pathophysiology , biology , pharmacology , medicine , chemistry , immunology , biochemistry
Inflammation is implicated in cardiovascular diseases, acute kidney injury, lung and heart failure, which represent major causes of morbidity and mortality in Western Societies. Despite use of multiple drugs, both chronic and acute inflammation is still remaining a major health burden. Inflammation produces highly reactive dicarbonyl lipid peroxidation products, isolevuglandins (isoLG) which reacting with lysine residues of proteins covalently modify and cross‐link proteins. Mitochondrial dysfunction has been associated with inflammation; however, its pathophysiological role and molecular mechanisms are still obscure. We propose that inflammation‐induced mitochondrial isoLG play a key role in mitochondrial dysfunction and mortality . To test this hypothesis, we have (a) investigated the mitochondrial dysfunction in response to synthetic isoLG and isoLG adducts; (b) developed new mitochondria‐targeted isoLG scavenger mito2HOBA by conjugating the lipophilic cation triphenylphosphonium to 2‐hydroxybenzylamine; (c) tested if mito2HOBA protects from mitochondrial dysfunction and mortality using LPS model of inflammation. Acute isoLG exposure of mitochondria or treatment with low‐molecular isoLG adducts with lysine, ethanolamine or phosphatidylethanolamine inhibits mitochondrial respiration and attenuates Complex I activity while complex II function is much more resistant to isoLG. To test the pathophysiological role of mitochondrial isoLG we have studied therapeutic potential of mito2HOBA. We have confirmed that mito2HOBA vividly accumulates in isolated mitochondria and it is highly reactive with isoLG compared with untargeted 2HOBA. In vivo studies of isoLG‐mediated mitochondrial dysfunction in mouse LPS model showed that mito2HOBA supplementation in drinking water (0.1 g/L) increased animals survival by 3‐fold and improved complex I‐mediated respiration. These data unambiguously support the role of mitochondrial isoLG in mitochondrial dysfunction in inflammation. We conclude that mitochondrial isoLG can be a promising therapeutic target in inflammation and conditions associated with mitochondrial oxidative stress and dysfunction. Support or Funding Information Navicent Health Foundation; NIH/NHLBI 1R01HL124116 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .