Abstract
Disturbances in lipid homeostasis can cause mitochondrial dysfunction and lipotoxicity. Perilipin 5 (PLIN5) decorates intracellular lipid droplets (LDs) in oxidative tissues and controls triacylglycerol (TG) turnover via its interactions with adipose triglyceride lipase and the adipose triglyceride lipase coactivator, comparative gene identification-58. Furthermore, PLIN5 anchors mitochondria to the LD membrane via the outermost part of the carboxyl terminus. However, the role of this LD-mitochondria coupling (LDMC) in cellular energy catabolism is less established. In this study, we investigated the impact of PLIN5-mediated LDMC in comparison to disrupted LDMC on cellular TG homeostasis, FA oxidation, mitochondrial respiration, and protein interaction. To do so, we established PLIN5 mutants deficient in LDMC whilst maintaining normal interactions with key lipolytic players. Radiotracer studies with cell lines stably overexpressing wild-type or truncated PLIN5 revealed that LDMC has no significant impact on FA esterification upon lipid loading or TG catabolism during stimulated lipolysis. Moreover, we demonstrated that LDMC exerts a minor if any role in mitochondrial FA oxidation. In contrast, LDMC significantly improved the mitochondrial respiratory capacity and metabolic flexibility of lipid-challenged cardiomyocytes, which was corroborated by LDMC-dependent interactions of PLIN5 with mitochondrial proteins involved in mitochondrial respiration, dynamics, and cristae organization. Taken together, this study suggests that PLIN5 preserves mitochondrial function by adjusting FA supply via the regulation of TG hydrolysis and that LDMC is a vital part of mitochondrial integrity.
Highlights
Lipid droplets (LD) are highly dynamic organelles found in most eukaryotic cell types and consist of a triacylglycerol (TG)-rich neutral lipid core that is enveloped by a phospholipid monolayer [1]
We observed that lipid droplet-mitochondria coupling (LDMC) persisted upon forskolin/IBMX treatment (Fig. 1B, lower panel), which is in accordance with a recent study demonstrating that fasting or β3-adrenergic stimulation mildly increases LDMC in cardiac tissue of mice [24]
Given the perturbed interaction of Perilipin 5 (PLIN5)(∆461-463) with respiratory complex proteins, we examined the impact of disrupted LDMC on mitochondrial respiratory capacity via Seahorse XF analysis in cells incubated in complete medium or in cells subjected to 24-hour loading with oleic acid (OA) prior to Seahorse analysis
Summary
Lipid droplets (LD) are highly dynamic organelles found in most eukaryotic cell types and consist of a triacylglycerol (TG)-rich neutral lipid core that is enveloped by a phospholipid monolayer [1]. PLIN5 deficiency is associated with increased reactive oxygen species (ROS) formation, impaired mitochondrial function and cardiac myopathy, upon ageing and following myocardial stress [10,11,12,13,14]. PLIN5 has been shown to counteract oxidative stress and lipotoxicity in HepG2 cells and pancreatic β-cells [15, 16]. These findings may in part be explained by the recently described role of PLIN5 in the nucleus, where the protein acts as a transcriptional modulator altering the expression of genes involved in mitochondrial function, ROS defense, inflammation and autophagy [17,18,19]. The cytoprotective effects of PLIN5 may involve other currently unknown functions of PLIN5
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