Lipotoxicity, fatty acid uncoupling and mitochondrial carrier function

Abstract

Diseases like obesity, diabetes or generalized lipodystrophy cause a chronic elevation of circulating fatty acids that can become cytotoxic, a condition known as lipotoxicity. Fatty acids cause oxidative stress and alterations in mitochondrial structure and function. The uncoupling of the oxidative phosphorylation is one of the most recognized deleterious fatty acid effects and several metabolite transporters are known to mediate in their action. The fatty acid interaction with the carriers leads to membrane depolarization and/or the conversion of the carrier into a pore. The result is the opening of the permeability transition pore and the initiation of apoptosis. Unlike the other members of the mitochondrial carrier superfamily, the eutherian uncoupling protein UCP1 has evolved to achieve its heat-generating capacity in the physiological context provided by the brown adipocyte and therefore it is activated by the low fatty acid concentrations generated by the noradrenaline-stimulated lipolysis.

Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells

“…How is this metabolic remodeling initiated? We hypothesize that the massive influx of cellular FFAs in breast cancer cells delivered by proximal adipocytes induces lipotoxicity and promotes, to counteract this lipotoxicity, the passive mitochondrial uncoupling, as extensively described in other contexts (33). In turn, increased expression of UCP2 (also upregulated by FFA influx), as well as upregulation of IF1, maintains this metabolic remodeling (23,34).…”

<i>Sasa borealis</i> Extract Efficiently Enhanced Swimming Capacity by Improving Energy Metabolism and the Antioxidant Defense System in Mice

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Mitochondria as a pharmacological target: Magnum overview

“…The inhibition of the mitochondrial FAO can result in the accumulation of free fatty acids and triglycerides in the cytoplasm as small vesicles or larger vacuoles. Accumulated fatty acids and their derivatives can have toxic effects on mitochondrial respiration, ATP synthesis, ketone body production, and gluconeogenesis (65). Patients with inhibited mitochondrial b-oxidation may develop liver failure (steatosis).…”