Lipid Droplets Guard Mitochondria during Autophagy

In this issue of Developmental Cell, Nguyen et al., 2017Nguyen T.B. Louie S.M. Daniele J.R. Tran Q. Dillin A. Zoncu R. Nomura D.K. Olzmann J.A. Dev. Cell. 2017; 42 (this issue): 9-21Scopus (250) Google Scholar show that lipid droplets serve a dual purpose during starvation. First, they act as an energy source by supplying fatty acids for mitochondrial β oxidation. Second, they sequester toxic lipids that arise during autophagic degradation of membranous organelles, thereby protecting mitochondria. In this issue of Developmental Cell, Nguyen et al., 2017Nguyen T.B. Louie S.M. Daniele J.R. Tran Q. Dillin A. Zoncu R. Nomura D.K. Olzmann J.A. Dev. Cell. 2017; 42 (this issue): 9-21Scopus (250) Google Scholar show that lipid droplets serve a dual purpose during starvation. First, they act as an energy source by supplying fatty acids for mitochondrial β oxidation. Second, they sequester toxic lipids that arise during autophagic degradation of membranous organelles, thereby protecting mitochondria. Life depends on a constant supply of free energy, which is provided by metabolic degradation of nutrients. However, cells frequently endure periods of starvation when external energy sources are scarce. Thus, mechanisms evolved that help to maintain essential cellular functions before cells starve to death. Among these is the ability of cells to gain energy by degrading dispensable organelles and other cellular components. This process of cellular self-eating, or autophagy, includes the formation of autophagosomes, double-membrane bounded structures that engulf cytoplasmic cargo (Figure 1). Autophagosomes subsequently fuse with the lysosome, where the cargo is dismantled into its molecular building blocks, mostly amino acids and fatty acids (FAs). These are either recycled or utilized for energy generation (Kaur and Debnath, 2015Kaur J. Debnath J. Nat. Rev. Mol. Cell Biol. 2015; 16: 461-472Crossref PubMed Scopus (658) Google Scholar). Furthermore, cells prepare for starvation by synthesizing lipids as energy-rich storage compounds under conditions of ample nutrient supply. These can be stocked within specialized organelles, lipid droplets (LDs), which consist of a core of storage lipids encased by a phospholipid monolayer. Upon nutrient depletion, cells survive by converting these internal energy supplies into FAs, which are used for ATP production by β oxidation in mitochondria (Walther and Farese, 2012Walther T.C. Farese Jr., R.V. Annu. Rev. Biochem. 2012; 81: 687-714Crossref PubMed Scopus (975) Google Scholar). In this issue of Developmental Cell, Nguyen et al., 2017Nguyen T.B. Louie S.M. Daniele J.R. Tran Q. Dillin A. Zoncu R. Nomura D.K. Olzmann J.A. Dev. Cell. 2017; 42 (this issue): 9-21Scopus (250) Google Scholar report that LDs not only fuel mitochondrial energy generation during starvation but also protect mitochondria by sequestering excess FAs that are released by autophagy and might damage organellar membranes. The cellular starvation response shifts the cell's metabolism toward mitochondrial FA oxidation and shuts down most energy-consuming anabolic processes. Therefore, it was surprising to find that mouse embryonic fibroblasts (MEFs) exhibit a marked increase in the amount and size of LDs during starvation (Rambold et al., 2015Rambold A.S. Cohen S. Lippincott-Schwartz J. Dev. Cell. 2015; 32: 678-692Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar). Nguyen et al., 2017Nguyen T.B. Louie S.M. Daniele J.R. Tran Q. Dillin A. Zoncu R. Nomura D.K. Olzmann J.A. Dev. Cell. 2017; 42 (this issue): 9-21Scopus (250) Google Scholar now show that the ER-residing enzyme diacylglycerol acyltransferase 1 (DGAT1) is a key mediator of starvation-induced LD biosynthesis. They report that during nutrient depletion, DGAT1 catalyzes the formation of storage lipids, triacylglycerols (TAGs), from FAs that are released during autophagic degradation of organellar membranes (Figure 1). Their results also explain why starvation-induced LD biogenesis was previously found to depend on autophagy and why fluorescently labeled lipids initially accumulate in LDs in starved MEFs (Rambold et al., 2015Rambold A.S. Cohen S. Lippincott-Schwartz J. Dev. Cell. 2015; 32: 678-692Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar). At first glance it seems counterintuitive that the amount of cellular storage lipids increases while the cells suffer from nutrient deprivation. Indeed, TAGs serve as an important cellular energy source during starvation and are lipolytically broken down into FAs, which are imported into mitochondria and consumed by β oxidation to produce ATP. This has been visualized by tracking the transfer of fluorescently labeled FAs from LDs to mitochondria under nutrient deprivation (Rambold et al., 2015Rambold A.S. Cohen S. Lippincott-Schwartz J. Dev. Cell. 2015; 32: 678-692Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar). Nguyen et al., 2017Nguyen T.B. Louie S.M. Daniele J.R. Tran Q. Dillin A. Zoncu R. Nomura D.K. Olzmann J.A. Dev. Cell. 2017; 42 (this issue): 9-21Scopus (250) Google Scholar now report that TAGs from pre-existing and newly formed LDs are subjected to lipolytic breakdown during starvation. Following the fate of isotopically labeled palmitate, the authors observed that inhibition of DGAT1 activity causes a massive re-routing of FAs into lipid species other than TAGs, including a strong increase of acylcarnitines, intermediates of mitochondrial FA import (Figure 1). This indicates that the LD conduit is not mandatory for efficient FA transport from autophagosomes to mitochondria. So why do cells convert autophagy-released FAs first into TAGs, which in turn have to be broken down into FAs for energy generation? FAs are known to be precarious molecules because they damage cellular membranes when present in excess amounts. Thus, when cells remobilize FAs from TAG stores or scavenge them during autophagy, they have to avoid the release of excess FAs into the cytosol to avert cytotoxicity. LDs have been assigned an important protective role against different types of lipotoxicity (Walther and Farese, 2012Walther T.C. Farese Jr., R.V. Annu. Rev. Biochem. 2012; 81: 687-714Crossref PubMed Scopus (975) Google Scholar, Listenberger et al., 2003Listenberger L.L. Han X. Lewis S.E. Cases S. Farese Jr., R.V. Ory D.S. Schaffer J.E. Proc. Natl. Acad. Sci. USA. 2003; 100: 3077-3082Crossref PubMed Scopus (1394) Google Scholar). Nguyen et al., 2017Nguyen T.B. Louie S.M. Daniele J.R. Tran Q. Dillin A. Zoncu R. Nomura D.K. Olzmann J.A. Dev. Cell. 2017; 42 (this issue): 9-21Scopus (250) Google Scholar now report that inhibition of DGAT1 prevents starvation-induced LD biosynthesis and causes mitochondrial damage and dysfunction. They tracked this toxic effect down to the accumulation of acylcarnitines and conclude that LDs guard mitochondria during starvation by sequestering potentially lipotoxic FAs and storing them as non-cytotoxic TAGs. Thus, LDs balance intracellular FA concentrations by storage or release, depending on cellular demands. Additionally, storage of autophagically produced FAs as TAGs in LDs may serve to regulate energy generation by mitochondrial FA oxidation. Autophagic degradation of organellar membranes presumably releases FAs in amounts that far exceed the immediate cellular need as energy source. When uncontrolled, this could produce significant bursts of energy that might interfere with the cellular starvation response. To avert this scenario, LDs might function as a buffer that allows fine-tuning of TAG lipolysis and FA degradation. Consistent with this, Nguyen et al., 2017Nguyen T.B. Louie S.M. Daniele J.R. Tran Q. Dillin A. Zoncu R. Nomura D.K. Olzmann J.A. Dev. Cell. 2017; 42 (this issue): 9-21Scopus (250) Google Scholar observed that two of the major regulators of cellular energy balance, mTORC1 and AMPK, regulate LD dynamics during nutrient deprivation. However, we are only beginning to understand how cells orchestrate multiple signaling pathways to balance lipolysis and TAG biogenesis to maintain optimal cellular energy levels and to avoid the accumulation of lipotoxic FAs. How FAs are transported specifically to mitochondria after their release from LDs remains unknown. LDs are found in close proximity to mitochondria in different cell types (Goodman, 2008Goodman J.M. J. Biol. Chem. 2008; 283: 28005-28009Crossref PubMed Scopus (198) Google Scholar). Intriguingly, these intimate contacts are increasingly formed under starvation conditions (Herms et al., 2015Herms A. Bosch M. Reddy B.J. Schieber N.L. Fajardo A. Rupérez C. Fernández-Vidal A. Ferguson C. Rentero C. Tebar F. et al.Nat. Commun. 2015; 6: 7176Crossref PubMed Scopus (156) Google Scholar, Rambold et al., 2015Rambold A.S. Cohen S. Lippincott-Schwartz J. Dev. Cell. 2015; 32: 678-692Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar, Nguyen et al., 2017Nguyen T.B. Louie S.M. Daniele J.R. Tran Q. Dillin A. Zoncu R. Nomura D.K. Olzmann J.A. Dev. Cell. 2017; 42 (this issue): 9-21Scopus (250) Google Scholar). Such junctions could enable a direct, vesicle-free lipid transport between both organelles, as it has been observed between other organelles, e.g., mitochondria and the ER (Klecker et al., 2014Klecker T. Böckler S. Westermann B. Trends Cell Biol. 2014; 24: 537-545Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). Thus, close juxtaposition of LDs and mitochondria could facilitate FA transport, thereby preventing a systemic rise of cytosolic FA levels. However, this hypothetical model awaits experimental validation. To date, the only identified candidate molecular constituent of the LD-mitochondria contact site is the LD-associated protein PLIN5 (Gao and Goodman, 2015Gao Q. Goodman J.M. Front. Cell Dev. Biol. 2015; 3: 49Crossref PubMed Scopus (159) Google Scholar). Expression of this protein has been reported to recruit mitochondria to the surface of LDs (Wang et al., 2011Wang H. Sreenivasan U. Hu H. Saladino A. Polster B.M. Lund L.M. Gong D.W. Stanley W.C. Sztalryd C. J. Lipid Res. 2011; 52: 2159-2168Crossref PubMed Scopus (284) Google Scholar). Of interest, PLIN5 also negatively regulates TAG lipolysis on LDs (Gao and Goodman, 2015Gao Q. Goodman J.M. Front. Cell Dev. Biol. 2015; 3: 49Crossref PubMed Scopus (159) Google Scholar), revealing a potential interconnection and co-regulation between FA remobilization from LDs and the establishment of LD-mitochondria contact sites. However, a PLIN5 binding partner on the mitochondrial surface remains to be identified. It will be interesting to see in the future how further studies will complete our understanding of how autophagy, LD biosynthesis, lipolysis, mitochondrial FA import, lipotoxicity, and β oxidation are entangled and orchestrated to cope with the challenge of nutrient deprivation in starving cells. DGAT1-Dependent Lipid Droplet Biogenesis Protects Mitochondrial Function during Starvation-Induced AutophagyNguyen et al.Developmental CellJuly 10, 2017In BriefNguyen et al. demonstrate that lipid droplet biogenesis is a general, protective cellular response during periods of high autophagic flux. Under these conditions, lipid droplets prevent lipotoxicity by sequestering FAs released during the autophagic breakdown of organelles. In the absence of lipid droplets, acylcarnitines accumulate and cause mitochondrial uncoupling. Full-Text PDF Open Archive