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<a href="http://doi.org/10.1074/mcp.RA118.000961" target="_blank" rel="noreferrer noopener">http://doi.org/10.1074/mcp.RA118.000961</a>
Pages
2371–2386
Issue
12
Volume
17
Dublin Core
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Title
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Hepatic Mitochondrial Defects in a Nonalcoholic Fatty Liver Disease Mouse Model Are Associated with Increased Degradation of Oxidative Phosphorylation Subunits.
Publisher
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Molecular & cellular proteomics : MCP
Date
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2018
2018-12
Subject
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Energy metabolism; heavy water; Mass Spectrometry; metabolic labeling; Mitochondria function or biology; oxidative phosphorylation; Oxidative stress; Protein Degradation; Protein Turnover
Creator
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Lee Kwangwon; Haddad Andrew; Osme Abdullah; Kim Chunki; Borzou Ahmad; Ilchenko Sergei; Allende Daniela; Dasarathy Srinivasan; McCullough Arthur; Sadygov Rovshan G; Kasumov Takhar
Description
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Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic mitochondrial dysfunction characterized by reduced ATP synthesis. We applied the (2)H2O-metabolic labeling approach to test the hypothesis that the reduced stability of oxidative phosphorylation proteins contributes to mitochondrial dysfunction in a diet-induced mouse model of NAFLD. A high fat diet containing cholesterol (a so-called Western diet (WD)) led to hepatic oxidative stress, steatosis, inflammation and mild fibrosis, all markers of NAFLD, in low density cholesterol (LDL) receptor deficient (LDLR(-/-)) mice. In addition, compared with controls (LDLR(-/-) mice on normal diet), livers from NAFLD mice had reduced citrate synthase activity and ATP content, suggesting mitochondrial impairment. Proteome dynamics study revealed that mitochondrial defects are associated with reduced average half-lives of mitochondrial proteins in NAFLD mice (5.41 +/- 0.46 versus 5.15 +/- 0.49 day, p \textless 0.05). In particular, the WD reduced stability of oxidative phosphorylation subunits, including cytochrome b-c1 complex subunit 1 (5.9 +/- 0.1 versus 3.4 +/- 0.8 day), ATP synthase subunit alpha (6.3 +/- 0.4 versus 5.5 +/- 0.4 day) and ATP synthase F(0) complex subunit B1 of complex V (8.5 +/- 0.6 versus 6.5 +/- 0.2 day) (p \textless 0.05). These changes were associated with impaired complex III and F0F1-ATP synthase activities. Markers of mitophagy were increased, but proteasomal degradation activity were reduced in NAFLD mice liver, suggesting that ATP deficiency because of reduced stability of oxidative phosphorylation complex subunits contributed to inhibition of ubiquitin-proteasome and activation of mitophagy. In conclusion, the (2)H2O-metabolic labeling approach shows that increased degradation of hepatic oxidative phosphorylation subunits contributed to mitochondrial impairment in NAFLD mice.
Identifier
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<a href="http://doi.org/10.1074/mcp.RA118.000961" target="_blank" rel="noreferrer noopener">10.1074/mcp.RA118.000961</a>
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
2018
Allende Daniela
Borzou Ahmad
Dasarathy Srinivasan
Department of Pharmaceutical Sciences
Energy Metabolism
Haddad Andrew
Heavy water
Ilchenko Sergei
Kasumov Takhar
Kim Chunki
Lee Kwangwon
Mass spectrometry
McCullough Arthur
metabolic labeling
Mitochondria function or biology
Molecular & cellular proteomics : MCP
NEOMED College of Pharmacy
Osme Abdullah
oxidative phosphorylation
Oxidative Stress
Protein Degradation
Protein Turnover
Sadygov Rovshan G