bims-mecosi 2023-12-24 papers

Issue of 2023‒12‒24
four papers selected by
Verena Kohler, Umeå University

Redox Biol. 2023 Dec 09. pii: S2213-2317(23)00390-7. [Epub ahead of print]69 102989

LncRNA H19 inhibition impairs endoplasmic reticulum-mitochondria contact in hepatic cells and augments gluconeogenesis by increasing VDAC1 levels.

Arun Nandwani, Shalu Rathore, Malabika Datta.

Inspite of exerting independent cellular functions, the endoplasmic-reticulum (ER) and the mitochondria also physically connect at specific sites termed mitochondria-associated ER membranes (MAMs) and these sites consist of several tethering proteins that play varied roles in diverse cellular processes. However, the regulation of these tethering proteins within the cell is relatively less studied. Here, we show that several MAM proteins are significantly altered in the liver during diabetes and among these, the lncRNA, H19 regulates the levels of VDAC1. Inhibition of H19 expression using H19 specific siRNA altered VDAC1, mitochondrial Ca2+ and oxygen consumption rate, ATP and ROS levels and enhanced ER and mitochondria coupling in Hepa 1-6 cells. While H19 inhibition did not impact lipid accumulation, levels of gluconeogenic genes were significantly increased. JNK-phosphorylation and IRS1-Ser307-phosphorylation were increased by H19 inhibition and this was associated with abrogation of insulin-stimulated AKT (Ser-473) phosphorylation and glucose uptake in Hepa 1-6 cells. While inhibition of VDAC1 expression using siRNAs and with metformin significantly rescued the effects of H19 inhibition, VDAC1 overexpression alone exerted effects similar to H19 inhibition, suggesting that VDAC1 increase mediates the adverse effects of H19. In-vivo H19 inhibition using specific siRNAs increased hepatic VDAC1, pJNK and pIRS1 (Ser307) levels and decreased AKT (Ser-473) phosphorylation in mice. These suggest an important role of the H19-VDAC1 axis in ER-mitochondria coupling and regulation of gluconeogenesis in the liver during diabetes.

Keywords: Ca(2+); Diabetes; ER-Mitochondria communication; Gluconeogenesis; JNK; Liver; ROS; lncRNA

DOI: https://doi.org/10.1016/j.redox.2023.102989

Int J Mol Sci. 2023 Dec 06. pii: 17177. [Epub ahead of print]24(24):

Rab18 Drift in Lipid Droplet and Endoplasmic Reticulum Interactions of Adipocytes under Obesogenic Conditions.

Jaime López-Alcalá, M Carmen Soler-Vázquez, Carmen Tercero-Alcázar, Julia Sánchez-Ceinos, Rocío Guzmán-Ruiz, María M Malagón, Ana Gordon.

The adipose tissue stores excess energy in the form of neutral lipids within adipocyte lipid droplets (LDs). The correct function of LDs requires the interaction with other organelles, such as the endoplasmic reticulum (ER) as well as with LD coat-associated proteins, including Rab18, a mediator of intracellular lipid trafficking and ER-LD interaction. Although perturbations of the inter-organelle contact sites have been linked to several diseases, such as cancer, no information regarding ER-LD contact sites in dysfunctional adipocytes from the obese adipose tissue has been published to date. Herein, the ER-LD connection and Rab18 distribution at ER-LD contact sites are examined in adipocytes challenged with fibrosis and inflammatory conditions, which represent known hallmarks of the adipose tissue in obesity. Our results show that adipocytes differentiated in fibrotic conditions caused ER fragmentation, the expansion of ER-LD contact sites, and modified Rab18 dynamics. Likewise, adipocytes exposed to inflammatory conditions favored ER-LD contact, Rab18 accumulation in the ER, and Rab18 redistribution to large LDs. Finally, our studies in human adipocytes supported the suggestion that Rab18 transitions to the LD coat from the ER. Taken together, our results suggest that obesity-related pathogenic processes alter the maintenance of ER-LD interactions and interfere with Rab18 trafficking through these contact sites.

Keywords: Rab18; adipocyte; endoplasmic reticulum; fibrosis; inflammation; lipid droplet

DOI: https://doi.org/10.3390/ijms242417177

Front Plant Sci. 2023 ;14 1293906

Membrane contacts with the endoplasmic reticulum modulate plastid morphology and behaviour.

Jaideep Mathur, Thomas Kadanthottu Kunjumon, Alena Mammone, Neeta Mathur.

Plastid behaviour often occurs in tandem with endoplasmic reticulum (ER) dynamics. In order to understand the underlying basis for such linked behaviour we have used time-lapse imaging-based analysis of plastid movement and pleomorphy, including the extension and retraction of stromules. Stable transgenic plants that simultaneously express fluorescent fusion proteins targeted to the plastid stroma, and the ER along with BnCLIP1-eGFP, an independent plastid envelope localized membrane contact site (MCS) marker were utilized. Our experiments strongly suggest that transient MCS formed between the plastid envelope and the ER are responsible for their concomitant behaviour.

Keywords: BnCLIP1; chloroplasts; endoplasmic reticulum; lipases; membrane-contact-sites; stromules

DOI: https://doi.org/10.3389/fpls.2023.1293906

Cancer Commun (Lond). 2023 Dec 22.

Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites.

Ji Eon Kim, So-Young Park, Chulhwan Kwak, Yoonji Lee, Dae-Geun Song, Jae Woo Jung, Haesong Lee, Eun-Ae Shin, Yangie Pinanga, Kyung-Hee Pyo, Eun Hae Lee, Wonsik Kim, Soyeon Kim, Chang-Duck Jun, Jeanho Yun, Sun Choi, Hyun-Woo Rhee, Kwang-Hyeon Liu, Jung Weon Lee.

BACKGROUND: Transmembrane 4 L six family member 5 (TM4SF5) translocates subcellularly and functions metabolically, although it is unclear how intracellular TM4SF5 translocation is linked to metabolic contexts. It is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of metabolisms.METHODS: Here, we explored the metabolic significance of TM4SF5 localization at mitochondria-lysosome contact sites (MLCSs), using in vitro cells and in vivo animal systems, via approaches by immunofluorescence, proximity labelling based proteomics analysis, organelle reconstitution etc. RESULTS: Upon extracellular glucose repletion following depletion, TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506-binding protein 8 (FKBP8) and lysosomal TM4SF5. Proximity labeling showed molecular clustering of phospho-dynamic-related protein I (DRP1) and certain mitophagy receptors at TM4SF5-enriched MLCSs, leading to mitochondrial fission and autophagy. TM4SF5 bound NPC intracellular cholesterol transporter 1 (NPC1) and free cholesterol, and mediated export of lysosomal cholesterol to mitochondria, leading to impaired oxidative phosphorylation but intact tricarboxylic acid (TCA) cycle and β-oxidation. In mouse models, hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria, both with positive relations to liver malignancy.
CONCLUSIONS: Our findings suggested that TM4SF5-enriched MLCSs regulate glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming, presumably while hepatocellular carcinogenesis, recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial reprogramming to support biomolecule synthesis in addition to glycolytic energetics.

Keywords: cholesterol; fluorescent imaging; glucose catabolism; hepatocellular carcinogenesis; membrane contact sites; mitochondria function; mitophagy; oxidative phosphorylation; protein-protein interaction; tetraspanin

DOI: https://doi.org/10.1002/cac2.12510