Differential alterations in mitochondrial function induced by a choline-deficient diet: Understanding fatty liver disease progression

Abstract

a b s t r a c tNon-alcoholic fatty liver disease (NAFLD) is an increasingly reported pathology, characterized by fat accumulation within the hepatocyte. Growing evidences suggest specific effects on mitochondrial metabolism, but it is still unclear the relationship between fatty liver progression and mitochondrial function. In the present work we have investigated the impact of fatty liver on mitochondrial bioenergetic functions and susceptibility to mitochondrial permeability transition (MPT) induction in animals fed a choline-deficient diet (CDD) for 4, 8, 12 or 16 weeks. Mitochondria isolated from CDD animals always exhibited higher state 4 respiration. Mitochondrial membrane potential was decreased in CDD animals at 4 and 16 weeks. At 12 weeks, oxidative phosphorylation was more efficient in CDD animals, suggesting a possible early response trying to revert the deleterious effect of increased triglyceride storage in the liver. However, mitochondrial dysfunction was evident in CDD animals at 16 weeks as indicated by decreased RCR and ADP/O, with a corresponding decrease in respiratory chain enzymes activities. Such loss of respiratory efficiency was associated with accumulation of protein oxidation products, in tissue and mitochondrial fraction. Additionally, although no differences in ATPase activity, the lag phase was increased in mitochondria from CDD animals at 16 weeks, associated with decreased content of the adenine nucleotide translocator. Increased susceptibility to calcium-induced MPT was evident in CDD animals at all time points. These results suggest a dynamic mechanism for the development of NALFD associated with altered mitochondrial function.

Mitochondria Express α7 Nicotinic Acetylcholine Receptors to Regulate Ca2+ Accumulation and Cytochrome c Release: Study on Isolated Mitochondria

“…However, the half-life time of intracellular choline is very short [42], therefore, the mitochondria protection depends on the balance of its intake and degradation. Recent evidence demonstrates the increased susceptibility of mitochondria to calcium-induced permeability transition upon choline deficiency [43] that supports our idea. In contrast, intracellular release of choline upon ischemia [42] obviously has the protective anti-apoptotic effect.…”

Exposure to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin and tetraethyl lead affects lung mitochondria bioenergetics

“…These parameters were all found to be decreased in mitochondria exposed to TCDD. The decrease in mitochondrial membrane potential in the lung mitochondria incubated with TCDD is probably due to an increased proton leak (Chance and Williams 1956;Teodoro et al 2008). The time that elapses from depolarization after ADP addition until all the ADP was phosphorylated-lag phase-is significantly enlarged in mitochondria exposed to TCDD and to tetraethyl lead.…”

Nonalcoholic Fatty Liver Disease, the Gut Microbiome, and Diet

“…Reduced phosphatidylcholine contributes to TG accumulation in the liver and NAFLD (128). Choline-deficient diets disturb the mitochondrial function, resulting in increased hepatic lipid accumulation that contributes to NAFLD pathogenesis (129). Gut bacteria can convert choline to trimethylamine and reduce choline bioavailability, mimicking choline deficiency side effects (130).…”