bims-mecosi 2022-09-18 papers

Issue of 2022–09–18
five papers selected by
Verena Kohler, University of Graz

FEBS Lett. 2022 Sep 14.

ER exit sites (ERES) and ER-mitochondria encounter structures (ERMES) often localize proximally.

Naini Chakraborty, Bhawik Kumar Jain, Samruddhi Shembekar, Dibyendu Bhattacharyya.

To understand the potential interplay between vesicular trafficking and direct membrane contact sites mediated transport, we selected the endoplasmic reticulum (ER), which participates in both modes of inter-organelle transport. ER-mitochondria encounter structures (ERMES) are direct membrane contact junctions that mediate macromolecule exchange, while the secretory pathway originates at ER exit sites (ERES). Using the budding yeast Pichia pastoris, we documented that ERMES resident proteins are often juxtaposed with ERES markers. We further demonstrated that ERES form de novo almost always near a pre-existing ERMES. Disruption of either ERES or ERMES affects the other. Djp1, a chaperone reported to mediate mitochondrial import of ER-resident proteins, localizes at the ERES-ERMES proximal region. Our results indicate a potential functional link between ERES-ERMES proximity and mitochondrial protein import.

DOI: https://doi.org/10.1002/1873-3468.14497

J Cell Biol. 2022 Oct 03. pii: e202205135. [Epub ahead of print]221(10):

ER as master regulator of membrane trafficking and organelle function.

Eva Maria Wenzel, Liv Anker Elfmark, Harald Stenmark, Camilla Raiborg.

The endoplasmic reticulum (ER), which occupies a large portion of the cytoplasm, is the cell's main site for the biosynthesis of lipids and carbohydrate conjugates, and it is essential for folding, assembly, and biosynthetic transport of secreted proteins and integral membrane proteins. The discovery of abundant membrane contact sites (MCSs) between the ER and other membrane compartments has revealed that, in addition to its biosynthetic and secretory functions, the ER plays key roles in the regulation of organelle dynamics and functions. In this review, we will discuss how the ER regulates endosomes, lysosomes, autophagosomes, mitochondria, peroxisomes, and the Golgi apparatus via MCSs. Such regulation occurs via lipid and Ca2+ transfer and also via control of in trans dephosphorylation reactions and organelle motility, positioning, fusion, and fission. The diverse controls of other organelles via MCSs manifest the ER as master regulator of organelle biology.

DOI: https://doi.org/10.1083/jcb.202205135

Biochem J. 2022 Sep 16. 479(17): 1857-1875

Proteomic mapping and optogenetic manipulation of membrane contact sites.

Gang Lin, Wenyi Shi, Ningxia Zhang, Yi-Tsang Lee, Youjun Wang, Ji Jing.

Membrane contact sites (MCSs) mediate crucial physiological processes in eukaryotic cells, including ion signaling, lipid metabolism, and autophagy. Dysregulation of MCSs is closely related to various diseases, such as type 2 diabetes mellitus (T2DM), neurodegenerative diseases, and cancers. Visualization, proteomic mapping and manipulation of MCSs may help the dissection of the physiology and pathology MCSs. Recent technical advances have enabled better understanding of the dynamics and functions of MCSs. Here we present a summary of currently known functions of MCSs, with a focus on optical approaches to visualize and manipulate MCSs, as well as proteomic mapping within MCSs.

Keywords: inter-organelle communication; membrane contact sites; optogenetics; proximity labelling

DOI: https://doi.org/10.1042/BCJ20220382

Front Cell Dev Biol. 2022 ;10 920228

The Potential of Small Molecules to Modulate the Mitochondria-Endoplasmic Reticulum Interplay in Alzheimer's Disease.

Giacomo Dentoni, Laura Castro-Aldrete, Luana Naia, Maria Ankarcrona.

Alzheimer's disease (AD) is the most common neurodegenerative disease affecting a growing number of elderly individuals. No disease-modifying drugs have yet been identified despite over 30 years of research on the topic, showing the need for further research on this multifactorial disease. In addition to the accumulation of amyloid β-peptide (Aβ) and hyperphosphorylated tau (p-tau), several other alterations have been associated with AD such as calcium (Ca2+) signaling, glucose-, fatty acid-, cholesterol-, and phospholipid metabolism, inflammation, and mitochondrial dysfunction. Interestingly, all these processes have been associated with the mitochondria-endoplasmic reticulum (ER) contact site (MERCS) signaling hub. We and others have hypothesized that the dysregulated MERCS function may be one of the main pathogenic pathways driving AD pathology. Due to the variety of biological processes overseen at the MERCS, we believe that they constitute unique therapeutic targets to boost the neuronal function and recover neuronal homeostasis. Thus, developing molecules with the capacity to correct and/or modulate the MERCS interplay can unleash unique therapeutic opportunities for AD. The potential pharmacological intervention using MERCS modulators in different models of AD is currently under investigation. Here, we survey small molecules with the potential to modulate MERCS structures and functions and restore neuronal homeostasis in AD. We will focus on recently reported examples and provide an overview of the current challenges and future perspectives to develop MERCS modulators in the context of translational research.

Keywords: Alzheimer’s disease; mitochondrial function; mitochondria–endoplasmic reticulum contact sites; neurodegeneration; small molecules

DOI: https://doi.org/10.3389/fcell.2022.920228

Pflugers Arch. 2022 Sep 16.

Human macrophages directly modulate iPSC-derived cardiomyocytes at healthy state and congenital arrhythmia model in vitro.

Arzuhan Koc, Celal Akdeniz, Esra Cagavi.

The electrophysiological regulation of cardiomyocytes (CMs) by the cardiac macrophages (MΦs) has been recently described as an unconventional role of MΦs in the murine heart. Investigating the molecular and physiological modulation of CM by MΦ is critical to understand the novel mechanisms behind cardiac disorders from the systems perspective and to develop new therapeutic approaches. Here, we developed an in vitro direct coculture system to investigate the cellular and functional interaction between human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and monocyte-derived MΦs both in healthy-state and congenital arrhythmia disease model associated with SCN5A ion channel mutations. Congenital arrhythmia patient-derived (P) and healthy individual-derived control (C) monocytes and derived MΦs exhibited distinct M1- and M2-like polarization-related gene expression pattern. The iPSC-CMs and MΦs formed direct membrane contacts in cocultures demonstrated by time-lapse imaging, scanning electron microscopy, and immunolabeling. The intracellular Ca2+ transients were observed in iPSC-CMs and MΦs when in contact with each other. Interestingly, the C-MΦs in direct contact with C-CMs significantly accelerated the contraction rates, demonstrating the positive chronotropic effect of MΦs on healthy cardiac cultures. Furthermore, the MΦs carrying the SCN5A gene mutation significantly enhanced the arrhythmic events in both C-CMs and P-CMs, implying that the sodium channel mutation in the MΦ is important for the CM function. Importantly, when C-MΦs were coupled to tachycardic P-CMs, the contraction frequency drastically decreased, and rhythmicity enhanced implicating the amelioration of the disease phenotype in vitro. Consequently, our results indicated the functional regulatory role of MΦs on human iPSC-CM contractility by membrane contacts in a physiologically relevant in vitro coculture model of both steady-state and arrhythmia. Our findings could serve as a valuable source for the development of effective immunoregulatory therapies for cardiac arrhythmia in the future.

Keywords: Arrhythmia; Cardiomyocytes; Human-induced pluripotent stem cells; Immunocardiology; In vitro disease model; Macrophages

DOI: https://doi.org/10.1007/s00424-022-02743-2