Targeting of reactive isolevuglandins in mitochondrial dysfunction and inflammation, 2019, Dikalov et al

Andy · Aug 23, 2019

Highlights
• Isolevuglandins and their adducts inhibit mitochondrial respiration and attenuates Complex I activity.
• 2-Hydroxybenzylamine conjugated to triphenylphosphonium, mito2HOBA, accumulates in mitochondria.
• Mito2HOBA in drinking water improves complex I-mediated respiration in LPS model of sepsis.
• Mitochondria-targeted scavenger of isolevuglandins mito2HOBA reduces mortality in LPS model.

Abstract
Inflammation is a major cause of morbidity and mortality in Western societies. Despite use of multiple drugs, both chronic and acute inflammation still represent major health burdens. Inflammation produces highly reactive dicarbonyl lipid peroxidation products such as isolevuglandins which covalently modify and cross-link proteins via lysine residues. 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 (0.1 g/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. 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.
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Open access, https://www.sciencedirect.com/science/article/pii/S221323171930480X

Jaybee00 · Aug 23, 2019

Where to get Mito2HOBA water? Looks like they aren’t marketing it yet.

Jaybee00 · Aug 23, 2019

Maybe we need to develop a Mito2HOBA water home brew kit....

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Targeting of reactive isolevuglandins in mitochondrial dysfunction and inflammation, 2019, Dikalov et al

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Targeting of reactive isolevuglandins in mitochondrial dysfunction and inflammation, 2019, Dikalov et al

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