bims-mecosi 2024-10-27 papers

Issue of 2024–10–27
five papers selected by
Verena Kohler, Umeå University

J Cell Sci. 2024 Oct 15. pii: jcs262020. [Epub ahead of print]137(20):

Imaging interorganelle contacts at a glance.

Maria Clara Zanellati, Chih-Hsuan Hsu, Sarah Cohen.

Eukaryotic cells are compartmentalized into membrane-bound organelles that must coordinate their responses to stimuli. One way that organelles communicate is via membrane contact sites (MCSs), sites of close apposition between organelles used for the exchange of ions, lipids and information. In this Cell Science at a Glance article and the accompanying poster, we describe an explosion of new methods that have led to exciting progress in this area and discuss key examples of how these methods have advanced our understanding of MCSs. We discuss how diffraction-limited and super-resolution fluorescence imaging approaches have provided important insight into the biology of interorganelle communication. We also describe how the development of multiple proximity-based methods has enabled the detection of MCSs with high accuracy and precision. Finally, we assess how recent advances in electron microscopy (EM), considered the gold standard for detecting MCSs, have allowed the visualization of MCSs and associated proteins in 3D at ever greater resolution.

Keywords: Biosensors; Electron microscopy; Light microscopy; Membrane contact sites; Organelles; Super-resolution microscopy

DOI: https://doi.org/10.1242/jcs.262020

Mol Neurobiol. 2024 Oct 23.

Connexin43 Contributes to Alzheimer's Disease by Promoting the Mitochondria-Associated Membrane-Related Autophagy Inhibition.

Weiwei Yu, Yunong Li, Yao Li, Jun Hu, Jun Wu, Xuhui Chen, Yining Huang, Xin Shi.

The perturbed structure and function of mitochondria-associated membranes (MAM), instead of the amyloid cascade, have been gradually proposed to play a basic role in the pathogenesis of Alzheimer's disease (AD). Notably, autophagy inhibition is one of the main mechanisms of MAM dysfunction and plays an important role in neuronal injury. However, the upstream molecular mechanism underlying the MAM dysfunctions remains elusive. Here, we defined an unexpected and critical role of connexin43 (Cx43) in regulating the MAM structure. The expression levels of Cx43 and mitofusin-2 (MFN2, the MAM biomarker) increase significantly in 9-month-old APPswe/PS1dE9 double-transgenic AD model mice, and there is an obvious colocalization relationship. Moreover, both AD mice and cells lacking Cx43 exhibit an evident reduction in the MAM contact sites, which subsequently promotes the conversion from microtubule-associated protein 1 light-chain 3B I (LC3B-I) to LC3B-II via inhibition mTOR-dependent pathway and then initiates the generation of autophagosomes. Autophagosome formation ultimately promotes β-amyloid (Aβ) clearance and attenuates Aβ-associated pathological changes in AD, mainly including astrogliosis and neuronal apoptosis. Our findings not only reveal a previously unrecognized effect of Cx43 on MAM upregulation but also highlight the major player of MAM-induced autophagy inhibition in Cx43-facilitated AD pathogenesis, providing a novel insight into the alternative therapeutic strategies for the early treatment of AD.

Keywords: Alzheimer’s disease; Autophagy; Connexin43; Mitochondria-associated membranes; β-Amyloid

DOI: https://doi.org/10.1007/s12035-024-04536-3

Trends Cell Biol. 2024 Oct 21. pii: S0962-8924(24)00208-3. [Epub ahead of print]

ERMCS Ca2+ transmission fuels cell division.

Muniswamy Madesh, Neelanjan Vishnu, Dhanendra Tomar.

Mitosis is a cellular process that demands high energy, but it was previously unclear how this process is linked with mitochondrial ATP production. Zhao et al. describe how during mitosis, the lamin B receptor migrates to the ER membrane to enhance ER-mitochondria contact sites, coordinating Ca2+ surges that increase ATP production necessary for cell division.

DOI: https://doi.org/10.1016/j.tcb.2024.10.002

Toxicology. 2024 Oct 21. pii: S0300-483X(24)00260-9. [Epub ahead of print]509 153979

Particulate matter induced cognitive impairments via endoplasmic reticulum stress-mediated damage to mitochondria-associated endoplasmic reticulum membranes in immature rats.

Lingman Wang, Jianxiong Gui, Bing Tian, Ran Ding, Wandi Wang, Chunxue Jiang, Shengxuan Zhang, Xiaofang Zhang, Jie Liu, Li Jiang.

Particulate matter (PM) exposure has been increasingly recognized as detrimental to cognitive function and is associated with neurodevelopmental disorders. Mitochondria-associated endoplasmic reticulum membranes (MAMs) form an integrated interface between mitochondria and the endoplasmic reticulum (ER), facilitating crucial cellular functions. Prolonged ER stress (ERS) is implicated in various pathological states in the nervous system. MAMs and ERS may play vital roles in adverse effects of early-life PM exposure on cognitive abilities. This study investigated whether ERS plays a role in PM-induced MAMs dysfunction, leading to neuronal damage and cognitive impairments in early postnatal rats. Using a rat model with PM exposure concentrations of 2 and 10 mg/kg from postnatal Day 3 (PND3) to PND28, we observed that PM exposure resulted in anxiety-like behavior and impaired spatial working memory. The protein levels of ERS markers, including GRP78 and CHOP, were significantly increased in response to PM exposure. Western blot, transmission electron microscopy (TEM), and immunofluorescence analyses revealed decreased MAMs-related proteins and disrupted MAM structure and function caused by PM exposure. Administration of the ERS inhibitor 4-phenylbutyric acid (4-PBA) ameliorated these effects, restoring MAMs integrity and improving cognitive deficits. These findings highlighted the key role of ERS-MAMs dysfunction in PM-induced neurotoxicity and cognitive impairments, providing a new perspective and strategy for the prevention of cognitive deficits in early age with PM exposure.

Keywords: Cognitive behavioral impairments; Endoplasmic reticulum stress; Hippocampus; Mitochondria-associated endoplasmic reticulum membranes; Particulate matter

DOI: https://doi.org/10.1016/j.tox.2024.153979

Adv Sci (Weinh). 2024 Oct 21. e2406760

The MICOS Complex Subunit Mic60 is Hijacked by Intracellular Bacteria to Manipulate Mitochondrial Dynamics and Promote Bacterial Pathogenicity.

Changyong Cheng, Mianmian Chen, Jing Sun, Jiali Xu, Simin Deng, Jing Xia, Yue Han, Xian Zhang, Jing Wang, Lei Lei, Ruidong Zhai, Qin Wu, Weihuan Fang, Houhui Song.

Host mitochondria undergo fission and fusion, which bacteria often exploit for their infections. In this study, the underlying molecular mechanisms are aimed to clarify through which Listeria monocytogenes (L. monocytogenes), a human bacterial pathogen, manipulates mitochondrial dynamics to enhance its pathogenicity. It is demonstrated that L. monocytogenes triggers transient mitochondrial fission through its virulence factor listeriolysin O (LLO), driven by LLO's interaction with Mic60, a core component of the mitochondrial contact site and the cristae organizing system (MICOS). Specifically, Phe251 within LLO is identify as a crucial residue for binding to Mic60, crucial for LLO-induced mitochondrial fragmentation and bacterial pathogenicity. Importantly, it is that Mic60 affect the formation of F-actin tails recruited by L. monocytogenes, thereby contributing to intracellular bacterial infection. Mic60 plays a critical role in mediating changes in mitochondrial morphology, membrane potential, and reactive oxidative species (ROS) production, and L. monocytogenes infection exacerbates these changes by affecting Mic60 expression. These findings unveil a novel mechanism through which intracellular bacteria exploit host mitochondria, shedding light on the complex interplay between hosts and microbes during infections. This knowledge holds promise for developing innovative strategies to combat bacterial infections.

Keywords: MICOS; Mic60; host‐microbe interplay; listeriolysin O (LLO); mitochondrial fragmentation

DOI: https://doi.org/10.1002/advs.202406760