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

Abstract

Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic mitochondrial dysfunction characterized by reduced ATP synthesis. We applied the HO-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 5.15 ± 0.49 day, < ). In particular, the WD reduced stability of oxidative phosphorylation subunits, including cytochrome b- complex subunit 1 (5.9 ± 0.1 3.4 ± 0.8 day), ATP synthase subunit α (6.3 ± 0.4 5.5 ± 0.4 day) and ATP synthase F(0) complex subunit B1 of complex V (8.5 ± 0.6 6.5 ± 0.2 day) ( < ). 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, theHO-metabolic labeling approach shows that increased degradation of hepatic oxidative phosphorylation subunits contributed to mitochondrial impairment in NAFLD mice.

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

“…The Krebs cycle has a central role in liver metabolism, connecting hepatic fatty acid and glucose-related pathways. Abnormal cellular [20] and circulating [21] Krebs cycle intermediates are closely associated with mitochondrial dysfunction as was demonstrated in numerous studies [22][23][24][25]. Given the decreased activity in respiratory chain complexes in NAFLD [4], perturbations in cellular concentrations of Krebs cycle intermediates are expected.…”

miR-200b regulates cellular senescence and inflammatory responses by targeting ZEB2 in pulmonary emphysema

“…The stressors leading to senescence include telomere shortening due to replicative exhaustion, DNA or chromatin structure and mitochondrial dysfunction [15][16][17][18][19]. Recent reports indicated that mitochondrial dysfunction plays an important role in initiating inflammatory responses and cellular senescence and has significance in the pathogenesis of lung disease [20].…”

Western Diet Causes Obesity-Induced Nonalcoholic Fatty Liver Disease Development by Differentially Compromising the Autophagic Response

“…Mitochondria increase fatty acids (FAs) β-oxidation (mt-FAO) to restrain hepatic fat accumulation [ 12 ]. However, the abolished mt-FAO response in NAFLD can be associated with different mitochondrial alterations, such as reduced oxidative phosphorylation (OXPHOS), diminished ATP production and enhanced sensitivity for mitochondrial permeability transition pore (mPTP) opening [ 12 , 13 , 14 ]. The progression of NAFL towards NASH in a nonreversible manner was reported to involve a prooxidative state and mitochondrial-induced reactive oxygen species (ROS) production, which ultimately alter cellular signaling cascades leading to hepatocellular inflammation and fibrosis [ 15 , 16 , 17 ].…”