bims-mecosi 2022-03-20 papers

Issue of 2022‒03‒20
four papers selected by
Verena Kohler

Front Cell Dev Biol. 2022 ;10 852021

Touch and Go: Membrane Contact Sites Between Lipid Droplets and Other Organelles.

Pin-Chao Liao, Emily J Yang, Taylor Borgman, Istvan R Boldogh, Cierra N Sing, Theresa C Swayne, Liza A Pon.

Lipid droplets (LDs) have emerged not just as storage sites for lipids but as central regulators of metabolism and organelle quality control. These critical functions are achieved, in part, at membrane contact sites (MCS) between LDs and other organelles. MCS are sites of transfer of cellular constituents to or from LDs for energy mobilization in response to nutrient limitations, as well as LD biogenesis, expansion and autophagy. Here, we describe recent findings on the mechanisms underlying the formation and function of MCS between LDs and mitochondria, ER and lysosomes/vacuoles and the role of the cytoskeleton in promoting LD MCS through its function in LD movement and distribution in response to environmental cues.

Keywords: cytoskeleton; endoplasmic reticulum; lipid droplets; lipophagy; lysosome; membrane contact sites; mitochondria; vacuole

DOI: https://doi.org/10.3389/fcell.2022.852021

Front Cell Dev Biol. 2022 ;10 834962

Calcium Signaling Regulated by Cellular Membrane Systems and Calcium Homeostasis Perturbed in Alzheimer's Disease.

Dong-Xu Huang, Xin Yu, Wen-Jun Yu, Xin-Min Zhang, Chang Liu, Hong-Ping Liu, Yue Sun, Zi-Ping Jiang.

Although anything that changes spatiotemporally could be a signal, cells, particularly neurons, precisely manipulate calcium ion (Ca2+) to transmit information. Ca2+ homeostasis is indispensable for neuronal functions and survival. The cytosolic Ca2+ concentration ([Ca2+]CYT) is regulated by channels, pumps, and exchangers on cellular membrane systems. Under physiological conditions, both endoplasmic reticulum (ER) and mitochondria function as intracellular Ca2+ buffers. Furthermore, efficient and effective Ca2+ flux is observed at the ER-mitochondria membrane contact site (ERMCS), an intracellular membrane juxtaposition, where Ca2+ is released from the ER followed by mitochondrial Ca2+ uptake in sequence. Hence, the ER intraluminal Ca2+ concentration ([Ca2+]ER), the mitochondrial matrix Ca2+ concentration ([Ca2+]MT), and the [Ca2+]CYT are related to each other. Ca2+ signaling dysregulation and Ca2+ dyshomeostasis are associated with Alzheimer's disease (AD), an irreversible neurodegenerative disease. The present review summarizes the cellular and molecular mechanism underlying Ca2+ signaling regulation and Ca2+ homeostasis maintenance at ER and mitochondria levels, focusing on AD. Integrating the amyloid hypothesis and the calcium hypothesis of AD may further our understanding of pathogenesis in neurodegeneration, provide therapeutic targets for chronic neurodegenerative disease in the central nervous system.

Keywords: Alzheimer’s disease; calcium homeostasis; calcium signaling; endoplasmic reticulum; membrane contact site; mitochondria

DOI: https://doi.org/10.3389/fcell.2022.834962

Cell Stress Chaperones. 2022 Mar 16.

Endoplasmic reticulum-unfolded protein response pathway modulates the cellular response to mitochondrial proteotoxic stress.

Rajasri Sarkar, Kannan Boosi Narayana Rao, Mainak Pratim Jha, Koyeli Mapa.

Mitochondria and endoplasmic reticulum (ER) remain closely tethered by contact sites to maintain unhindered biosynthetic, metabolic, and signalling functions. Apart from its constituent proteins, contact sites localize ER-unfolded protein response (UPR) sensors like Ire1 and PERK, indicating the importance of ER-mitochondria communication during stress. In the mitochondrial sub-compartment-specific proteotoxic model of yeast, Saccharomyces cerevisiae, we show that an intact ER-UPR pathway is important in stress tolerance of mitochondrial intermembrane space (IMS) proteotoxic stress, while disrupting the pathway is beneficial during matrix stress. Deletion of IRE1 and HAC1 leads to accumulation of misfolding-prone proteins in mitochondrial IMS indicating the importance of intact ER-UPR pathway in enduring mitochondrial IMS proteotoxic stresses. Although localized proteotoxic stress within mitochondrial IMS does not induce ER-UPR, its artificial activation helps cells to better withstand the IMS proteotoxicity. Furthermore, overexpression of individual components of ER-mitochondria contact sites is found to be beneficial for general mitochondrial proteotoxic stress, in an Ire1-Hac1-independent manner.

Keywords: ER stress; ER-mitochondria contact sites; Mito-UPR; Protein homeostasis; Proteotoxic stress; Unfolded protein response

DOI: https://doi.org/10.1007/s12192-022-01264-2

Front Cell Dev Biol. 2022 ;10 848214

Mitochondrial Dynamics, Mitophagy, and Mitochondria-Endoplasmic Reticulum Contact Sites Crosstalk Under Hypoxia.

Shuying Wang, Jin Tan, Yuyang Miao, Qiang Zhang.

Mitochondria are double membrane organelles within eukaryotic cells, which act as cellular power houses, depending on the continuous availability of oxygen. Nevertheless, under hypoxia, metabolic disorders disturb the steady-state of mitochondrial network, which leads to dysfunction of mitochondria, producing a large amount of reactive oxygen species that cause further damage to cells. Compelling evidence suggests that the dysfunction of mitochondria under hypoxia is linked to a wide spectrum of human diseases, including obstructive sleep apnea, diabetes, cancer and cardiovascular disorders. The functional dichotomy of mitochondria instructs the necessity of a quality-control mechanism to ensure a requisite number of functional mitochondria that are present to fit cell needs. Mitochondrial dynamics plays a central role in monitoring the condition of mitochondrial quality. The fission-fusion cycle is regulated to attain a dynamic equilibrium under normal conditions, however, it is disrupted under hypoxia, resulting in mitochondrial fission and selective removal of impaired mitochondria by mitophagy. Current researches suggest that the molecular machinery underlying these well-orchestrated processes are coordinated at mitochondria-endoplasmic reticulum contact sites. Here, we establish a holistic understanding of how mitochondrial dynamics and mitophagy are regulated at mitochondria-endoplasmic reticulum contact sites under hypoxia.

Keywords: hypoxia; mitochondria; mitochondria-endoplasmic reticulum contact sites; mitochondrial dynamics; mitophagy

DOI: https://doi.org/10.3389/fcell.2022.848214