Mitochondrial dysfunction in rat with nonalcoholic fatty liver

Abstract

Mitochondrial dysfunction and oxidative stress play a central role in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). This study aimed to elucidate the mechanism(s) responsible for mitochondrial dysfunction in nonalcoholic fatty liver. Fatty liver was induced in rats with a choline-deficient (CD) diet for 30 days. We examined the effect of CD diet on various parameters related to mitochondrial function such as complex I activity, oxygen consumption, reactive oxygen species (ROS) generation and cardiolipin content and oxidation. The activity of complex I was reduced by 35% in mitochondria isolated from CD livers compared with the controls. These changes in complex I activity were associated with parallel changes in state 3 respiration. Hydrogen peroxide (H(2)O(2)) generation was significantly increased in mitochondria isolated from CD livers. The mitochondrial content of cardiolipin, a phospholipid required for optimal activity of complex I, decreased by 38% as function of CD diet, while there was a significantly increase in the level of peroxidized cardiolipin. The lower complex I activity in mitochondria from CD livers could be completely restored to the level of control livers by exogenously added cardiolipin. This effect of cardiolipin could not be replaced by other phospholipids nor by peroxidized cardiolipin. It is concluded that CD diet causes mitochondrial complex I dysfunction which can be attributed to ROS-induced cardiolipin oxidation. These findings provide new insights into the alterations underlying mitochondrial dysfunction in NAFLD.

Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction

“…Reduced complex I activity has been found in NAFLD [46], although not consistently [reviewed in 9]. Of note, choline deficient diet-induced steatosis also causes reduced complex I activity [47]. Since impaired complex I activity is found both in NAFLD and in our LPD model, one might speculate that hepatic lipid accumulation is the cause rather than the effect of the reduced complex I activity.…”

Choline and Cystine Deficient Diets in Animal Models with Hepatocellular Injury: Evaluation of Oxidative Stress and Expression of RAGE, TNF-α, and IL-1β

“…It is believed that complex I is one of the major sources of ROS in liver mitochondria and, in case of choline deficiency, the liver mitochondria composition is significantly altered. This could be associated with changes in respiratory chain complex I activity, called NADH: ubiquinone oxidoreductase and this could be modulated in rats fed with choline deficient diet [30, 31]. …”

Mitochondrial Aldehyde Dehydrogenase Activation by Alda‐1 Inhibits Atherosclerosis and Attenuates Hepatic Steatosis in Apolipoprotein E‐Knockout Mice

“…43 The mitochondrial abnormalities associated with NAFLD include ultrastructural lesions, depletion of mtDNA, decreased activity of respiratory chain complexes, and impaired mitochondrial β‐oxidation. 7 Mitochondrial respiratory chain dysfunction can directly lead to the production of ROS.…”