bims-lypmec 2023-05-07 papers

Front Pharmacol. 2023 ;14 1148611

Berberine stimulates lysosomal AMPK independent of PEN2 and maintains cellular AMPK activity through inhibiting the dephosphorylation regulator UHRF1.

Gang Ren, Yu-Wei Ding, Lu-Lu Wang, Jian-Dong Jiang.

Aim: AMPK is the key regulatory kinase mediating the effect of berberine (BBR) and metformin on metabolic improvement. The present study investigated the mechanism of BBR on AMPK activation at low doses, which was different from that of metformin. Methods: Lysosomes were isolated, and AMPK activity assay was performed. PEN2, AXIN1 and UHRF1 were investigated through gain/loss of function approaches, including overexpression, RNA interfering and CRISPR/Cas9-mediated gene knockout. Immunoprecipitation was utilized for detecting the interaction of UHRF1 and AMPKα1 after BBR treatment. Results: BBR activated lysosomal AMPK, but weaker than metformin. AXIN1 mediated BBR's effect on lysosomal AMPK activation, while PEN2 did not. BBR, but not metformin, decreased UHRF1 expression by promoting its degradation. BBR reduced the interaction between UHRF1 and AMPKα1. And overexpression of UHRF1 abolished the effect of BBR on AMPK activation. Conclusion: BBR activated lysosomal AMPK as dependent on AXIN1, but not PEN2. BBR maintained cellular AMPK activity by reducing UHRF1 expression and its interaction with AMPKα1. The mode of action of BBR was different from that of metformin on AMPK activation.

Keywords: AMPK; AXIN1; UHRF1; berberine; metformin

DOI: https://doi.org/10.3389/fphar.2023.1148611

Nat Commun. 2023 May 04. 14(1): 2573

Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease.

Jialiu Zeng, Rebeca Acin-Perez, Essam A Assali, Andrew Martin, Alexandra J Brownstein, Anton Petcherski, Lucía Fernández-Del-Rio, Ruiqing Xiao, Chih Hung Lo, Michaël Shum, Marc Liesa, Xue Han, Orian S Shirihai, Mark W Grinstaff.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD.

DOI: https://doi.org/10.1038/s41467-023-38165-6

Philos Trans R Soc Lond B Biol Sci. 2023 06 19. 378(1879): 20220170

Timing mechanisms to control heart rhythm and initiate arrhythmias: roles for intracellular organelles, signalling pathways and subsarcolemmal Ca2.

Derek A Terrar.

Rhythms of electrical activity in all regions of the heart can be influenced by a variety of intracellular membrane bound organelles. This is true both for normal pacemaker activity and for abnormal rhythms including those caused by early and delayed afterdepolarizations under pathological conditions. The influence of the sarcoplasmic reticulum (SR) on cardiac electrical activity is widely recognized, but other intracellular organelles including lysosomes and mitochondria also contribute. Intracellular organelles can provide a timing mechanism (such as an SR clock driven by cyclic uptake and release of Ca2+, with an important influence of intraluminal Ca2+), and/or can act as a Ca2+ store involved in signalling mechanisms. Ca2+ plays many diverse roles including carrying electric current, driving electrogenic sodium-calcium exchange (NCX) particularly when Ca2+ is extruded across the surface membrane causing depolarization, and activation of enzymes which target organelles and surface membrane proteins. Heart function is also influenced by Ca2+ mobilizing agents (cADP-ribose, nicotinic acid adenine dinucleotide phosphate and inositol trisphosphate) acting on intracellular organelles. Lysosomal Ca2+ release exerts its effects via calcium/calmodulin-dependent protein kinase II to promote SR Ca2+ uptake, and contributes to arrhythmias resulting from excessive beta-adrenoceptor stimulation. A separate arrhythmogenic mechanism involves lysosomes, mitochondria and SR. Interacting intracellular organelles, therefore, have profound effects on heart rhythms and NCX plays a central role. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Keywords: arrhythmia; calcium; endolysosome; heart rhythm; mitochondria; sarcoplasmic reticulum

DOI: https://doi.org/10.1098/rstb.2022.0170

Nat Cell Biol. 2023 May 01.

Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids.

Katharina Papsdorf, Jason W Miklas, Amir Hosseini, Matias Cabruja, Christopher S Morrow, Marzia Savini, Yong Yu, Carlos G Silva-García, Nicole R Haseley, Luke Meraz Murphy, Pallas Yao, Elisa de Launoit, Scott J Dixon, Michael P Snyder, Meng C Wang, William B Mair, Anne Brunet.

Dietary mono-unsaturated fatty acids (MUFAs) are linked to longevity in several species. But the mechanisms by which MUFAs extend lifespan remain unclear. Here we show that an organelle network involving lipid droplets and peroxisomes is critical for MUFA-induced longevity in Caenorhabditis elegans. MUFAs upregulate the number of lipid droplets in fat storage tissues. Increased lipid droplet number is necessary for MUFA-induced longevity and predicts remaining lifespan. Lipidomics datasets reveal that MUFAs also modify the ratio of membrane lipids and ether lipids-a signature associated with decreased lipid oxidation. In agreement with this, MUFAs decrease lipid oxidation in middle-aged individuals. Intriguingly, MUFAs upregulate not only lipid droplet number but also peroxisome number. A targeted screen identifies genes involved in the co-regulation of lipid droplets and peroxisomes, and reveals that induction of both organelles is optimal for longevity. Our study uncovers an organelle network involved in lipid homeostasis and lifespan regulation, opening new avenues for interventions to delay aging.

DOI: https://doi.org/10.1038/s41556-023-01136-6