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Lipid droplet-mitochondria coupling via perilipin 5 augments respiratory capacity but is dispensable for FA oxidation |
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| Authors: | Benedikt Kien Stephanie Kolleritsch Natalia Kunowska Christoph Heier Gabriel Chalhoub Anna Tilp Heimo Wolinski Ulrich Stelzl Guenter Haemmerle |
| Institution: | 1. Institute of Molecular Biosciences, University of Graz, Graz, Austria;2. Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria;3. BioTechMed-Graz, University of Graz, Graz University of Technology and Medical University of Graz, Graz, Austria;4. Field of Excellence BioHealth, University of Graz, Graz, Austria |
| 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. |
| Keywords: | PLIN5 lipid droplets lipolysis mitochondrial respiration FA oxidation lipid droplet-mitochondria coupling adipose-triglyceride lipase comparative gene identification-58 lipotoxicity cardiovascular disease β-Gal"} {"#name":"keyword" "$":{"id":"kwrd0065"} "$$":[{"#name":"text" "_":"β-galactosidase ASM"} {"#name":"keyword" "$":{"id":"kwrd0075"} "$$":[{"#name":"text" "_":"acid-soluble metabolite ATGL"} {"#name":"keyword" "$":{"id":"kwrd0085"} "$$":[{"#name":"text" "_":"adipose triglyceride lipase BAT"} {"#name":"keyword" "$":{"id":"kwrd0095"} "$$":[{"#name":"text" "_":"brown adipose tissue CGI-58"} {"#name":"keyword" "$":{"id":"kwrd0105"} "$$":[{"#name":"text" "_":"comparative gene identification-58 DR"} {"#name":"keyword" "$":{"id":"kwrd0115"} "$$":[{"#name":"text" "_":"Deep Red ETC"} {"#name":"keyword" "$":{"id":"kwrd0125"} "$$":[{"#name":"text" "_":"electron transport chain EYFP"} {"#name":"keyword" "$":{"id":"kwrd0135"} "$$":[{"#name":"text" "_":"enhanced yellow fluorescent protein IBMX"} {"#name":"keyword" "$":{"id":"kwrd0145"} "$$":[{"#name":"text" "_":"3-isobutyl-1-methylxanthine IP"} {"#name":"keyword" "$":{"id":"kwrd0155"} "$$":[{"#name":"text" "_":"immunoprecipitation LD"} {"#name":"keyword" "$":{"id":"kwrd0165"} "$$":[{"#name":"text" "_":"lipid droplet LDMC"} {"#name":"keyword" "$":{"id":"kwrd0175"} "$$":[{"#name":"text" "_":"LD-mitochondria coupling OA"} {"#name":"keyword" "$":{"id":"kwrd0185"} "$$":[{"#name":"text" "_":"oleic acid OCR"} {"#name":"keyword" "$":{"id":"kwrd0195"} "$$":[{"#name":"text" "_":"oxygen consumption rate OXPHOS"} {"#name":"keyword" "$":{"id":"kwrd0205"} "$$":[{"#name":"text" "_":"oxidative phosphorylation PA"} {"#name":"keyword" "$":{"id":"kwrd0215"} "$$":[{"#name":"text" "_":"palmitic acid PGC-1α"} {"#name":"keyword" "$":{"id":"kwrd0225"} "$$":[{"#name":"text" "_":"peroxisome proliferator-activated receptor γ coactivator 1 alpha PLIN5"} {"#name":"keyword" "$":{"id":"kwrd0235"} "$$":[{"#name":"text" "_":"perilipin 5 PKA"} {"#name":"keyword" "$":{"id":"kwrd0245"} "$$":[{"#name":"text" "_":"protein kinase A TG"} {"#name":"keyword" "$":{"id":"kwrd0255"} "$$":[{"#name":"text" "_":"triacylglycerol |
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