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Mitochondria‐targeted scavenger of reactive isolevuglandins, mito2HOBA, protects from mitochondrial dysfunction and inflammatory injury
Author(s) -
Mayorov Vladimir,
Uchakin Peter,
Amarnath Venkataraman,
Panov Alexander,
Bridges Christy,
Uzhachenko Roman,
Zackert Bill,
Dikalova Anna,
Moore Christy,
Davies Sean,
Dikalov Sergey
Publication year - 2020
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.2020.34.s1.02987
Subject(s) - mitochondrion , lipopolysaccharide , reactive oxygen species , mitochondrial ros , oxidative stress , inflammation , chemistry , biochemistry , biology , pharmacology , immunology
Hypertension is linked to oxidative stress and inflammation producing highly reactive dicarbonyl lipid peroxidation products, isolevuglandins (IsoLG) which covalently modify and cross‐link proteins via lysine residues and promote end‐organ‐damage. Mitochondrial dysfunction has been associated with inflammation; however, its molecular mechanisms and pathophysiological role are still obscure. We hypothesized that inflammation‐induced isolevuglandins contribute to mitochondrial dysfunction and mortality. To test this hypothesis, we have (a) investigated the mitochondrial dysfunction in response to synthetic 15‐E2‐isolevuglandin (IsoLG) and its adducts; (b) developed a new mitochondria‐targeted scavenger of isolevuglandins by conjugating 2‐hydroxybenzylamine to the lipophilic cation triphenylphosphonium, (4‐(4‐aminomethyl)‐3‐hydroxyphenoxy)butyl)triphenylphosphonium (mito2HOBA); (c) tested if mito2HOBA protects from mitochondrial dysfunction and mortality using a lipopolysaccharide model of inflammation. Acute exposure to either IsoLG or IsoLG adducts with lysine, ethanolamine or phosphatidylethanolamine inhibits mitochondrial respiration and attenuates Complex I activity. Complex II function was much more resistant to IsoLG. We confirmed that mito2HOBA markedly accumulates in isolated mitochondria and it is highly reactive with IsoLGs. To test the role of mitochondrial IsoLGs, we studied the therapeutic potential of mito2HOBA in lipopolysaccharide mouse model of sepsis. Mito2HOBA supplementation in drinking water (0.1g/L) to lipopolysaccharide treated mice increased survival by 3‐fold, improved complex I‐mediated respiration, and histopathological analyses supported mito2HOBA‐mediated protection of renal cortex from cell injury. Depletion of Cyclophilin D partially attenuated IsoLG‐induced mitochondrial dysfunction suggesting that mitochondrial IsoLG can affect both Cyclophilin D and Complex I functions. These data support the role of mitochondrial IsoLG in mitochondrial dysfunction and inflammation. We conclude that reducing mitochondrial IsoLGs may be a promising therapeutic target in inflammation and conditions associated with mitochondrial oxidative stress and dysfunction. Support or Funding Information This work was supported by the National Institutes of Health grants (R01HL124116 and R01HL144943) and Navicent Health Foundation Research & Education Grant.