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.

Keywords: beta-oxidation; energetics; lipid droplet; palmitoyl CoA; perilipin; reactive oxygen species; redox environment.

Figure 1

Triglyceride synthesis, storage in lipid droplets, and FA oxidation in cardiomyocyte mitochondria. A detailed explanation of the processes depicted in this figure will be found in sections Lipid Droplets and TAG Metabolism and Fatty Acids and Mitochondrial Function of the main text. LDs can be intercalated with mitochondria or surrounded by them as shown schematically at the right bottom. When mitochondria and LD interact in close contact the scheme suggests that FA degradation and activation occur at the contact sites between both organelles. FA precursors of β-oxidation will be subsequently metabolically channeled to the matrix, and likely β-oxidation, through known pathways (see section Metabolic Channeling of Lipid Utilization From Close Contacts Between Mitochondria and Lipid Droplets: A Hypothetical-Qualitative Model in the text for more details).

Figure 2

Redox-Optimized ROS Balance and the effect of oxidative stress on mitochondrial respiration, H₂O₂ emission, and the RE. R-ORB postulates that ROS levels (as the net result of production and scavenging) depend on the intra-cellular and -mitochondrial redox environment (RE). It also proposes that there is a minimum level of ROS emission when mitochondria maximize their energetic output. Under high energy demand, and despite large respiratory rates, ROS emission levels will be kept to a minimum by ROS scavenging systems (Stanley et al., ; Aon et al., 2012). Oxidative stress can happen at either extreme of RE, either highly reduced or highly oxidized, but governed by different mechanisms (Aon et al., ; Kembro et al., 2014). The plot displays schematically the summary of the response of respiration (black traces) and ROS emission in stressed mitochondria (gray traces) plus further addition of the uncoupler FCCP (dashed-dotted line). Continuous lines correspond to the absence of stress whereas dashed lines belong to mitochondria under stressed conditions (Cortassa et al., 2014). Black arrows indicate the direction of change in VO₂ and ROS elicited by stress. Notice the shift toward more oxidized RE in the curves corresponding to stressful conditions. The thick gray arrow pointing to the left denotes pathological conditions arising, e.g., from chronic diseases, where severe stress will affect both energetic (e.g., ΔΨ_m, ADP consumption) and redox [e.g., NAD(P)H, GSH, Trx] functions thus increased mitochondrial ROS emission and higher cytoplasmic ROS levels. Reprinted from Cortassa et al. (2014).