bims-mecosi 2024-09-01 papers

Issue of 2024‒09‒01
seven papers selected by
Verena Kohler, Umeå University

Curr Top Membr. 2024 ;pii: S1063-5823(24)00020-6. [Epub ahead of print]93 85-116

Lysosomal membrane contact sites: Integrative hubs for cellular communication and homeostasis.

Sumit Bandyopadhyay, Daniel Adebayo, Eseiwi Obaseki, Hanaa Hariri.

Lysosomes are more than just cellular recycling bins; they play a crucial role in regulating key cellular functions. Proper lysosomal function is essential for growth pathway regulation, cell proliferation, and metabolic homeostasis. Impaired lysosomal function is associated with lipid storage disorders and neurodegenerative diseases. Lysosomes form extensive and dynamic close contacts with the membranes of other organelles, including the endoplasmic reticulum, mitochondria, peroxisomes, and lipid droplets. These membrane contacts sites (MCSs) are vital for many lysosomal functions. In this chapter, we will explore lysosomal MCSs focusing on the machinery that mediates these contacts, how they are regulated, and their functional implications on physiology and pathology.

Keywords: Lipid homeostasis; Lysosomes; Membrane contact sites; Nutrient sensing; Organelles communication

DOI: https://doi.org/10.1016/bs.ctm.2024.07.001

Cells. 2024 Aug 06. pii: 1313. [Epub ahead of print]13(16):

RILP Induces Cholesterol Accumulation in Lysosomes by Inhibiting Endoplasmic Reticulum-Endolysosome Interactions.

Yang Han, Xiaoqing Liu, Liju Xu, Ziheng Wei, Yueting Gu, Yandan Ren, Wenyi Hua, Yongtao Zhang, Xiaoxi Liu, Cong Jiang, Ruijuan Zhuang, Wanjin Hong, Tuanlao Wang.

Endoplasmic reticulum (ER)-endolysosome interactions regulate cholesterol exchange between the ER and the endolysosome. ER-endolysosome membrane contact sites mediate the ER-endolysosome interaction. VAP-ORP1L (vesicle-associated membrane protein-associated protein- OSBP-related protein 1L) interaction forms the major contact site between the ER and the lysosome, which is regulated by Rab7. RILP (Rab7-interacting lysosomal protein) is the downstream effector of Rab7, but its role in the organelle interaction between the ER and the lysosome is not clear. In this study, we found RILP interacts with ORP1L to competitively inhibit the formation of the VAP-ORP1L contact site. Immunofluorescence microscopy revealed that RILP induces late endosome/lysosome clustering, which reduces the contact of endolysosomes with the ER, interfering with the ER-endolysosome interaction. Further examination demonstrated that over-expression of RILP results in the accumulation of cholesterol in the clustered endolysosomes, which triggers cellular autophagy depending on RILP. Our results suggest that RILP interferes with the ER-endolysosome interaction to inhibit cholesterol flow from the endolysosome to the ER, which feedbacks to trigger autophagy.

Keywords: RILP; Rab7; autophagy; cholesterol transport; organelle interaction

DOI: https://doi.org/10.3390/cells13161313

bioRxiv. 2024 Aug 15. pii: 2024.08.15.608087. [Epub ahead of print]

Calcium tunneling through the ER and transfer to other organelles for optimal signaling in Toxoplasma gondii.

Zhu-Hong Li, Beejan Asady, Le Chang, Miryam Andrea Hortua Triana, Catherine Li, Isabelle Coppens, Silvia N J Moreno.

Ca2+ signaling in cells begins with the opening of Ca2+ channels in either the plasma membrane (PM) or the endoplasmic reticulum (ER) and results in a dramatic increase in the physiologically low (<100 nM) cytosolic Ca2+ level. The temporal and spatial Ca2+ levels are well regulated to enable precise and specific activation of critical biological processes. Ca2+ signaling regulates pathogenic features of apicomplexan parasites like Toxoplasma gondii which infects approximately one-third of the world's population. T. gondii relies on Ca2+ signals to stimulate traits of its infection cycle and several Ca2+ signaling elements play essential roles in its parasitic cycle. Active egress, an essential step for the infection cycle of T. gondii is preceded by a large increase in cytosolic Ca2+ most likely by release from intracellular stores. Intracellular parasites take up Ca2+ from the host cell during host Ca2+ signaling events to replenish intracellular stores. In this work, we investigated the mechanism by which intracellular stores are replenished with Ca2+ and demonstrated a central role for the SERCA-Ca2+-ATPase to keep not only the ER filled with Ca2+ but also acidic stores. We also show mitochondrial Ca2+ uptake, by transfer of Ca2+ from the ER most likely through membrane contact sites. We propose a central role for the ER in tunneling of calcium from the extracellular milieu through the ER to other organelles.

Keywords: Calcium; SERCA-Ca2+-ATPase; Toxoplasma gondii; calcium tunneling; endoplasmic reticulum; membrane contact sites

DOI: https://doi.org/10.1101/2024.08.15.608087

Res Sq. 2024 Aug 16. pii: rs.3.rs-4720604. [Epub ahead of print]

INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement.

Cara R Schiavon, Yuning Wang, Jasmine W Feng, Stephanie Garrett, Tsung-Chang Sung, Yelena Dayn, Chunxin Wang, Richard J Youle, Omar A Quintero-Carmona, Gerald S Shadel, Uri Manor.

Proper regulation of organelle dynamics and inter-organelle contacts is critical for cellular health and function. Both the endoplasmic reticulum (ER) and actin cytoskeleton are known to regulate organelle dynamics, but how, when, and where these two subcellular components are coordinated to control organelle dynamics remains unclear. Here, we show that ER-associated actin consistently marks mitochondrial, endosomal, and lysosomal fission sites. We also show that actin polymerization by the ER-anchored isoform of the formin protein INF2 is a key regulator of the morphology and mobility of these organelles. Together, our findings establish a mechanism by which INF2-mediated polymerization of ER-associated actin at ER-organelle contacts regulates organelle dynamics.

DOI: https://doi.org/10.21203/rs.3.rs-4720604/v1

Phytomedicine. 2024 Aug 18. pii: S0944-7113(24)00610-X. [Epub ahead of print]134 155952

Phillyrin promotes autophagosome formation in A53T-αSyn-induced Parkinson's disease model via modulation of REEP1.

Li-Feng-Rong Qi, Yuci Liu, Shuai Liu, Lin Xiang, Zhiyuan Liu, Qingling Liu, Jin-Quan Zhao, Xiaojun Xu.

BACKGROUND: The preservation of autophagosome formation presents a promising strategy for tackling neurological disorders, such as Parkinson's disease (PD). Mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) serve not only as a focal point linked to various neurological disorders but also play a crucial role in supporting the biogenesis of autophagosomes.PURPOSE: This investigation aimed to elucidate the neuroprotective properties of phillyrin against PD and its underlying mechanisms in promoting autophagosome formation.
METHODS: ER and mitochondria co-localization was assessed via fluorescent staining. Annexin V-fluorescein isothiocyanate (FITC) fluorescence was employed to quantify accessible cardiolipin (CL) on mitochondrial surfaces. The levels of CL within the MAM fraction of SH-SY5Y cells were evaluated using a CL probe assay kit. Monodansylcadaverine staining was utilized to detect autophagosome formation in SH-SY5Y cells. In an A53T-alpha-synuclein (αSyn)-induced PD mouse model, the anti-PD properties of phillyrin were assessed using open field, pole climbing, and rotarod tests, as well as immunohistochemistry staining of TH+ neurons in the brain sections.
RESULTS: In A53T-αSyn-treated SH-SY5Y cells, phillyrin facilitated autophagosome formation by suppressing CL externalization and restoring MAM integrity. Phillyrin enhanced the localization of receptor expression-enhancing protein 1 (REEP1) within MAM and mitochondria, bolstering MAM formation. Increased REEP1 levels in mitochondria, attributed to phillyrin, enhanced the interaction between REEP1 and NDPK-D, thereby reducing CL externalization. Furthermore, phillyrin exhibited a dose-dependent enhancement of motor function in mice, accompanied by an increase in the abundance of dopaminergic neurons within the substantia nigra.
CONCLUSIONS: These findings illuminate phillyrin's ability to enhance MAM formation through upregulation of REEP1 expression within MAM, while concurrently attenuating CL externalization via the REEP1-NDPK-D interaction. These mechanisms bolster autophagosome biogenesis, offering resilience against A53T-αSyn-induced PD. Thus, our study advances the understanding of phillyrin's complex mechanisms and underscores its potential as a therapeutic approach for PD, opening new avenues in natural product pharmacology.

Keywords: Autophagosome; Cardiolipin; Mitochondria-associated ER membranes; NDPK-D; Parkinson's disease; REEP1; phillyrin

DOI: https://doi.org/10.1016/j.phymed.2024.155952

Biomed Pharmacother. 2024 Aug 24. pii: S0753-3322(24)01227-7. [Epub ahead of print]179 117342

13-Methylpalmatine improves myocardial infarction injury by inhibiting CHOP-mediated cross-talk between endoplasmic reticulum and mitochondria.

Zefeng Jiang, Xiaowei Wen, Qin Mao, Gang Wang, Zhuo Wang, Yu Yan, Shan Gao, Xiaoqian Sun, Miao Zhang, Jiajing Liu, Rong Zhang, Baofeng Yang.

Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide, and endoplasmic reticulum stress (ERS) and mitochondrial Ca2+ overload have been involved in apoptotic cardiomyocyte death during MI. 13-Methylpalmatine (13-Me-PLT) is a natural isoquinoline alkaloid isolated from Coptis chinensis and has not been systematically studied for their potential pharmacological effects in cardiovascular diseases. We conducted the present study to elucidate whether 13-Me-PLT modulates MI pathology in animal MI and cellular hypoxic models, employing state-of-the-art molecular techniques. The results demonstrated that 13-Me-PLT preserved post-ischemic cardiac function and alleviated cardiomyocyte apoptosis. 13-Me-PLT decreased ERS and the communication between ER and mitochondria, which serves as a protective mechanism against mitochondrial Ca2+ overload and structural and functional injuries to mitochondria. Our data revealed mitigating mitochondrial Ca2+ overload and apoptosis by inhibiting CHOP-mediated Ca2+ transfer between inositol 1,4,5-trisphosphate receptor (IP3R) in ER and VDAC1 in mitochondria as an underlying mechanism for 13-Me-PLT action. Furthermore, 13-Me-PLT produced superior effects in alleviating cardiac dysfunction and apoptosis post-MI to diltiazem and palmatine. Collectively, our research suggests that the CHOP/IP3R/VDAC1 signaling pathway mediates ER-mitochondrial Ca2+ transfer and 13-Me-PLT activates this axis to maintain cellular and organellar Ca2+ homeostasis, protecting against ischemic myocardial injury. These findings may offer an opportunity to develop new agents for the therapy of ischemic heart disease.

Keywords: 13-Methylpalmatine; CHOP; Endoplasmic reticulum stress; Mitochondrial Ca(2+) overload; Myocardial infarction

DOI: https://doi.org/10.1016/j.biopha.2024.117342

Aging Cell. 2024 Aug 26. e14296

Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?

Antentor O Hinton, Zer Vue, Estevão Scudese, Kit Neikirk, Annet Kirabo, Monty Montano.

The hallmarks of aging have been influential in guiding the biology of aging research, with more recent and growing recognition of the interdependence of these hallmarks on age-related health outcomes. However, a current challenge is personalizing aging trajectories to promote healthy aging, given the diversity of genotypes and lived experience. We suggest that incorporating heterogeneity-including intrinsic (e.g., genetic and structural) and extrinsic (e.g., environmental and exposome) factors and their interdependence of hallmarks-may move the dial. This editorial perspective will focus on one hallmark, namely mitochondrial dysfunction, to exemplify how consideration of heterogeneity and interdependence or crosstalk may reveal new perspectives and opportunities for personalizing aging research. To this end, we highlight heterogeneity within mitochondria as a model.

Keywords: aging; mitochondria; organelle contacts; protein targeting; structure

DOI: https://doi.org/10.1111/acel.14296