Perilipin 5 interacts with Fatp4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport

Miner, Gregory E.; So, Christina M.; Edwards, W. Daniel; Herring, Laura E.; Coleman, Rosalind A.; Klett, Eric L.; Cohen, Sarah

doi:10.1101/2022.02.03.479028

Cited by 12 publications

(23 citation statements)

References 67 publications

(87 reference statements)

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“…As previously reported, the C-terminal (444-463 aa) of Plin5 mediates its mitochondrial localization, and the HepG2 cells with overexpressed full-length (HepG2-Plin5) and C-terminal deleted Plin5 (HepG2-Plin5Δ444-463) were generated (Figure 6B). Consistent with other studies, 16,29 Plin5 promoted the interaction between LDs and mitochondria, mainly located at the contact site between LDs and mitochondria. The results showed that alcohol did indeed increase the localization of Plin5 in mitochondria, which is manifested by increased contact area and number of LDs with mitochondria.…”

Section: The Mitochondrial Localization Of Plin5 Improved the Alcohol...supporting

confidence: 92%

Perilipin 5 protects the mitochondrial oxidative functions and improves the alcoholic liver injury in mice

Gao,

Jian,

Zhang

et al. 2023

Liver International

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Background and AimsAlcohol consumption is a well‐established risk factor for the onset and progression of hepatic steatosis. Perilipin 5 (Plin5), a lipid droplet protein, is an important protective factor against hepatic lipotoxicity induced by excessive lipolysis, but its role and molecular mechanism in alcoholic liver disease (ALD) are not fully elucidated.MethodsThe optimized National Institute on Alcohol Abuse and Alcoholism model was used to construct ALD model mice. Automatic biochemical analyser was used for Biochemical Parameters. The primary hepatocytes and Plin5‐overexpressed HepG2 cells (including full‐length Plin5 and Plin5 deleting 444–464 aa) were used for in vitro experiment. Haematoxylin and Eosin staining, Oil Red O staining, Bodipy 493/503 staining, Periodic Acid‐Schiff staining, immunohistochemistry and JC‐1 staining were used to evaluate cell morphology, lipids, glycogen, inflammation and membrane potential. Commercially kits are used to detect glycolipid metabolites, such as triglycerides, glycogen, glucose, reactive oxygen species, lactic acids, ketone bodies. Fluorescently labelled deoxyglucose, NBDG, was used for glucose intake. An XF96 extracellular flux analyser was used to determinate oxygen consumption rate in hepatocytes. The morphological and structural damage of mitochondria was evaluated by electron microscopy. Classical ultracentrifugation is used to separate the subcellular organelles of tissues and cells. Immunoblotting and qPCR were used to detect changes in mRNA and protein levels of related genes.ResultsOur results showed that the expression of Plin5 in mouse livers was enhanced by alcohol intake, and Plin5 deficiency aggravated the alcohol‐induced liver injury. To clarify the mechanism, we found that Plin5 deficiency significantly elevated the hepatic NADH levels and ketone body production in the alcohol‐treated mice. As NADH elevation could promote the reduction of pyruvate into lactate and then inhibit the gluconeogenesis, alcohol‐treated Plin5‐deficient mice exhibited more lactate production and severer hypoglycemia. These results implied that Plin5 deficiency impaired the mitochondrial oxidative functions in the presence of alcohol. In addition, we demonstrated that Plin5 could be recruited onto mitochondria by alcohol, while Plin5 without mitochondrial targeting sequences lost its mitochondrial protection functions.ConclusionCollectively, this study demonstrated that the mitochondrial Plin5 could protect the alcohol‐induced mitochondrial injury, which provides an important new insight on the roles of Plin5 in highly oxidative tissues.

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Section: The Mitochondrial Localization Of Plin5 Improved the Alcohol...supporting

confidence: 92%

Perilipin 5 protects the mitochondrial oxidative functions and improves the alcoholic liver injury in mice

Gao,

Jian,

Zhang

et al. 2023

Liver International

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“…Interactions between mitochondria and lipid droplets are important, as mitochondria can either consume or produce lipids ( Benador et al, 2018 ), depending on the metabolic needs of the cell ( Boutant et al, 2017 ). The role of MFN2 in tethering mitochondria and lipid droplets has only recently been recognized, with MFN2 shown to interact with lipid droplets perilipin proteins PLIN1 ( Boutant et al, 2017 ) and PLIN5 ( Miner et al, 2022 ). However, there is not much known about how important this interaction is with respect to the pathology of CMT2A.…”

Section: Overview Of Mfn2 Functions Impacted By Mfn2 Variantsmentioning

confidence: 99%

The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology

Zaman

Shutt

2022

Front. Cell Dev. Biol.

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The Mitofusin 2 protein (MFN2), encoded by the MFN2 gene, was first described for its role in mediating mitochondrial fusion. However, MFN2 is now recognized to play additional roles in mitochondrial autophagy (mitophagy), mitochondrial motility, lipid transfer, and as a tether to other organelles including the endoplasmic reticulum (ER) and lipid droplets. The tethering role of MFN2 is an important mediator of mitochondrial-ER contact sites (MERCs), which themselves have many important functions that regulate mitochondria, including calcium homeostasis and lipid metabolism. Exemplifying the importance of MFN2, pathogenic variants in MFN2 are established to cause the peripheral neuropathy Charcot-Marie-Tooth Disease Subtype 2A (CMT2A). However, the mechanistic basis for disease is not clear. Moreover, additional pathogenic phenotypes such as lipomatosis, distal myopathy, optic atrophy, and hearing loss, can also sometimes be present in patients with CMT2A. Given these variable patient phenotypes, and the many cellular roles played by MFN2, the mechanistic underpinnings of the cellular impairments by which MFN2 dysfunction leads to disease are likely to be complex. Here, we will review what is known about the various functions of MFN2 that are impaired by pathogenic variants causing CMT2A, with a specific emphasis on the ties between MFN2 variants and MERCs.

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“…One hypothesis we cannot rule out is if exercise changes the function of LD-mitochondria interaction from LD expansion to LD utilization in NAFLD. In cells under starvation, the transfer of fatty acids from LD to mitochondria using a labeled fatty acid has been demonstrated (23,45) . Furthermore, phosphorylation at serine 155 of PLIN5 in the liver induced by the protein kinase A pathway promotes LD-mitochondria interaction and enhances β-oxidation (46).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we showed that oleic acid promotes more LD-mitochondria contacts than palmitic acid, reducing the charge over mitochondrial function in the hepatic cell line HepG2 (21). The LD-associated protein PLIN5 contains a single C-terminal domain not present in the other perilipins, which is necessary to establish contact between LD and mitochondria (22,23). On the other hand, the role of LD-mitochondria interaction may be tissue-specific.…”

Section: Introductionmentioning

confidence: 99%

Effects of Aerobic Exercise in Hepatic Lipid Droplet-Mitochondria interaction in Non-alcoholic Fatty Liver Disease

Bórquez

Díaz-Castro

Fuente

et al. 2023

Preprint

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Lipid Droplets (LD) are highly dynamic storage organelles. In the liver, its accumulation causes non-alcoholic fatty liver (NAFL) that can progress to a more severe disease stage, nonalcoholic steatohepatitis (NASH). In hepatic and non-hepatic tissues LD interacts with mitochondria impacting lipid homeostasis. However, whether exercise modulates this interaction in the liver has not been studied yet. Our objective is to determine whether exercise modifies LD-mitochondria interaction in hepatocytes and if this interaction has an association with the severity of the disease. Two different models of NAFLD, a high fat diet (HFD) to evaluate NAFL and a methionine choline deficient diet (MCD) to evaluate NASH, were used to analyze the effects of aerobic exercise in the liver. Our results in the NAFL model showed that exercise decreased the severity of the disease and improved physical capacity compared to sedentary HFD mice. In this regard, although exercise increased the number of LD in hepatocytes, LD were smaller in size than in the sedentary HFD mice. Notably, while sedentary HFD mice increased hepatic lipid droplet (LD)-mitochondria interaction, in exercised animals, this interaction was decreased. Additionally, exercise decreased the size of the LD bound to mitochondria, and this peridroplet mitochondria (PDM) exhibited higher basal respiration and ATP synthesis capacity than PDM from sedentary HFD mice. Besides, we found a positive correlation that predicts the severity of NAFL between LD-mitochondria interaction in the liver and plasmatic ALT transaminases. This correlation is also positive between hepatic LD-mitochondria interaction and the area under the glucose tolerance test curve in this model. Our results in the NASH model resemble, to a greater extent, what we observed in the NAFL model. In NASH, exercise also reduced collagen accumulation, decreased LD-mitochondria interaction, and reduced the size of LD coupled to mitochondria compared to sedentary MCD mice. In all, our results show that aerobic exercise decreases LD-mitochondria interaction in hepatocytes and this interaction is associated with less severity of NAFL and NASH. We propose that exercise provokes an improvement of NAFLD by reduction of the hepatic LD-mitochondria interaction that in turn increase peridroplet mitochondria activity.

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Perilipin 5 interacts with Fatp4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport

Cited by 12 publications

References 67 publications

Perilipin 5 protects the mitochondrial oxidative functions and improves the alcoholic liver injury in mice

Perilipin 5 protects the mitochondrial oxidative functions and improves the alcoholic liver injury in mice

The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology

Effects of Aerobic Exercise in Hepatic Lipid Droplet-Mitochondria interaction in Non-alcoholic Fatty Liver Disease

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