Proteomics

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Hepatic mitochondrial proteome dynamics in NAFLD mice


ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic mitochondrial dysfunction characterized by reduced ATP synthesis. We applied the 2H2O-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 LDLR-/- mice. In addition, compared to controls, livers from NAFLD mice had reduced citrate synthase activity and ATP content, suggesting reduced mitochondrial oxidative capacity. Proteome dynamics analysis revealed that mitochondrial dysfunction is associated with reduced average half-lives of mitochondrial proteins in NAFLD mice (5.41±0.46 vs. 5.15±0.49 day, P<0.05). In particular, the WD reduced stability of oxidative phosphorylation subunits, including cytochrome c oxidase subunit 4 isoform 1 of complex III (5.9 ± 0.1 vs 3.4 ± 0.8 day), ATP synthase subunit α (6.3±0.4 vs. 5.5±0.4 day) and ATP synthase F(0) complex subunit B1 of complex V (8.5±0.6 vs. 6.5±0.2 day) (P<0.05). These changes were associated with impaired complex III and F0F1-ATP synthase activities, suggesting that increased degradation of mitochondrial proteins contributed to hepatic mitochondrial dysfunction in NAFLD mice. Autophagy, but not proteasomal degradation, contributed to increased clearance of hepatic mitochondrial proteins in NAFLD mice. In conclusion, the proteome dynamics approach suggests that alterations in mitochondrial proteome dynamics is involved in hepatic mitochondrial dysfunction in NAFLD.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

DISEASE(S): Nonalchoholic Fatty Liver Disease 1

SUBMITTER: Kwangwon Lee  

LAB HEAD: Takhar Kasumov

PROVIDER: PXD008766 | Pride | 2018-11-21

REPOSITORIES: Pride

Dataset's files

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Ctrl_Liver-1.dat Other
Ctrl_Liver-1.raw Raw
Ctrl_Liver-2.dat Other
Ctrl_Liver-2.raw Raw
Ctrl_Liver-3.dat Other
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Publications

Hepatic Mitochondrial Defects in a Nonalcoholic Fatty Liver Disease Mouse Model Are Associated with Increased Degradation of Oxidative Phosphorylation Subunits.

Lee Kwangwon K   Haddad Andrew A   Osme Abdullah A   Kim Chunki C   Borzou Ahmad A   Ilchenko Sergei S   Allende Daniela D   Dasarathy Srinivasan S   McCullough Arthur A   Sadygov Rovshan G RG   Kasumov Takhar T  

Molecular & cellular proteomics : MCP 20180831 12


Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic mitochondrial dysfunction characterized by reduced ATP synthesis. We applied the <sup>2</sup>H<sub>2</sub>O-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  ...[more]

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