Mitochondrial and cellular mechanisms for managing lipid excess

Abstract

Current scientific debates center on the impact of lipids and mitochondrial function on diverse aspects of human health, nutrition and disease, among them the association of lipotoxicity with the onset of insulin resistance in skeletal muscle, and with heart dysfunction in obesity and diabetes. Mitochondria play a fundamental role in aging and in prevalent acute or chronic diseases. Lipids are main mitochondrial fuels however these molecules can also behave as uncouplers and inhibitors of oxidative phosphorylation. Knowledge about the functional composition of these contradictory effects and their impact on mitochondrial-cellular energetics/redox status is incomplete. Cells store fatty acids (FAs) as triacylglycerol and package them into cytoplasmic lipid droplets (LDs). New emerging data shows the LD as a highly dynamic storage pool of FAs that can be used for energy reserve. Lipid excess packaging into LDs can be seen as an adaptive response to fulfilling energy supply without hindering mitochondrial or cellular redox status and keeping low concentration of lipotoxic intermediates. Herein we review the mechanisms of action and utilization of lipids by mitochondria reported in liver, heart and skeletal muscle under relevant physiological situations, e.g., exercise. We report on perilipins, a family of proteins that associate with LDs in response to loading of cells with lipids. Evidence showing that in addition to physical contact, mitochondria and LDs exhibit metabolic interactions is presented and discussed. A hypothetical model of channeled lipid utilization by mitochondria is proposed. Direct delivery and channeled processing of lipids in mitochondria could represent a reliable and efficient way to maintain reactive oxygen species (ROS) within levels compatible with signaling while ensuring robust and reliable energy supply.

Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promote monocyte adhesion and impair insulin transcytosis

“…In addition, fatty acid metabolites such as diacylglycerol and ceramides can induce perturbations in metabolism and contribute to insulin resistance in metabolic tissues (46). Fatty acids can also be incorporated in other cellular lipids that accumulate in membranes or lipid droplets (2). In contrast to those findings in tissues that actively metabolize fatty acids, we found that HAMEC do not take in or oxidize significant amounts of fatty acids.…”

Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans

“…Decreases in carnitine and increases in acylcarnitines together with elevated 3-hydroxybutyrate, a marker of hepatic b-oxidation, in serum after ozone exposure relative to air suggests changes in fatty acid oxidation that may be attributed to mitochondrial involvement (44). Additionally, increases in dicarboxylic acids in serum after ozone exposure may relate to increased v-oxidation, a nicotinamide adenine dinucleotide phosphate-and cytochrome P-450-dependent process where the omega carbon of a fatty acid is oxidized to an alcohol and then to a carboxylic acid, thereby generating dicarboxylic acid.…”

Arabidopsis Small Rubber Particle Protein Homolog SRPs Play Dual Roles as Positive Factors for Tissue Growth and Development and in Drought Stress Responses

“…Alternatively, SRPs may inhibit the lipolysis of LDs by blocking LD-lipase interaction, thereby influencing LD morphology. Fatty acids, which are formed by the lipolysis of LD, are transported into the mitochondria and used to generate ATP via b-oxidation (Aon et al, 2014). qRT-PCR analysis revealed that the mRNA levels of both cytochrome c oxidase 1 (COX1) and COX2, which encode the rate-limiting enzymes of the mitochondrial respiratory chain (Khalimonchuk and Rödel, 2005;Fontanesi et al, 2008), were correlated with SRP mRNA levels.…”