Targeting of reactive isolevuglandins in mitochondrial dysfunction and inflammation

Abstract

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.

Metabolic properties of murine kidney mitochondria

“…Furthermore, our findings highlight the critical role of succinate and long-chain fatty acids in kidney energy metabolism. We recently showed that 58% of glutamate-driven respiration was complex IIdependent [19]. Kidney mitochondria adapt to the high energy demands by diverting the mitochondrial metabolite flux to succinate to feed the Complex II-mediated respiration.…”

“…Oxygen Monitor [12,14]. The respiration rates of kidney mitochondria were measured using Fluorescence Lifetime Micro Oxygen Monitoring System (Instech Laboratories, Inc.) [19].…”

“…Another critical reason why fatty acids are essential as a source of energy is that glucose cannot provide fast rates of ATP production because the NADH dehydrogenase of the respiratory complex I limits the overall transport of electrons in the respiratory chain of mitochondria [25]. Glutamate and pyruvate cannot be regarded as the rigid substrates for the complex I because, in the brain, heart, and kidney, these substrates, to a large degree, undergo transamination with the formation of succinate, which has a much faster rate of oxidation and can drive the reverse electron transport [14,19].…”

Cellular mechanisms and molecular pathways linking bitter taste receptor signalling to cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases

“…Ngwenyama et al ( 2021 ) showed that myocardial oxidative stress triggers the generation of reactive isolevuglandin molecules that act as cardiac antigens to stimulate the T cell receptor (Ngwenyama et al 2021 ) to promote the development of heart failure (May-Zhang et al 2018 ), cardiac senescence, atherosclerotic and hypertensive heart disorders (Aschner et al 2021 ), including high salt-induced heart disease (Ruggeri Barbaro et al 2021 ). Data from both animal and human research (Ruggeri Barbaro et al 2021 ) have revealed that reactive isolevuglandin formation due to high salt diet (Ruggeri Barbaro et al 2021 ), myocardial oxidative stress (Ngwenyama et al 2021 ), pressure overload (Shang et al 2019 ), and lipopolysaccharide (LPS)-induced inflammation in mice (Mayorov et al 2019 ) can initiate the activation of monocytes, dendritic cell, and secretion of the proinflammatory cytokines TNF-α, IL-1β, IL-6, IL-17A (Dikalova et al 2020 ; Ruggeri Barbaro et al 2021 ), and reactive species (superoxide anions, and reactive nitrogen species) (Dikalova et al 2020 ). Thus, isolevuglandin may serve as a therapeutic target in the treatment of certain heart diseases.…”

Cardioprotective Role of Melatonin in Acute Myocardial Infarction

“…As organelles with important functions in eukaryotic cells, mitochondria mainly generate ATP, moderating apoptosis and oxidative stress reactions and exhibit dynamic changes. Their development and degradation, fusion and fission, and their quantity and morphology are precisely regulated and controlled based on changes in the environment where the cells are located (Zhou et al, 2017a,f;Chen S. et al, 2019;Mayorov et al, 2019;Simula et al, 2019). Mitochondrial dynamics include mitochondrial fission, fusion and mitophagy.…”