bims-mecosi 2024-06-30 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2024–06–30
eight papers selected by
Verena Kohler, Umeå University

Dialogue between mitochondria and endoplasmic reticulum-potential therapeutic targets for age-related cardiovascular diseases.
A-Syn(ful) MAM: A Fresh Perspective on a Converging Domain in Parkinson's Disease.
Calcium channel signalling at neuronal endoplasmic reticulum-plasma membrane junctions.
Role of mitochondria-associated membranes in the hippocampus in the pathogenesis of depression.
Endoplasmic reticulum and mitochondrial calcium handling dynamically shape slow afterhyperpolarizations in vasopressin magnocellular neurons.
Metabolic channeling of lipids via the contact zones between different organelles.
Mitochondria and Lipid Droplets: Focus on the Molecular Structure of Contact Sites in the Pathogenesis of Metabolic Syndrome.
Pathological Functions of Lysosomal Ion Channels in the Central Nervous System.

Front Pharmacol. 2024 ;15 1389202

Dialogue between mitochondria and endoplasmic reticulum-potential therapeutic targets for age-related cardiovascular diseases.

Chen Chen, Xueyan Dong, Wang Zhang, Xing Chang, Wulin Gao.

  Mitochondria-associated endoplasmic reticulum membranes (MAMs) act as physical membrane contact sites facilitating material exchange and signal transmission between mitochondria and endoplasmic reticulum (ER), thereby regulating processes such as Ca2+/lipid transport, mitochondrial dynamics, autophagy, ER stress, inflammation, and apoptosis, among other pathological mechanisms. Emerging evidence underscores the pivotal role of MAMs in cardiovascular diseases (CVDs), particularly in aging-related pathologies. Aging significantly influences the structure and function of the heart and the arterial system, possibly due to the accumulation of reactive oxygen species (ROS) resulting from reduced antioxidant capacity and the age-related decline in organelle function, including mitochondria. Therefore, this paper begins by describing the composition, structure, and function of MAMs, followed by an exploration of the degenerative changes in MAMs and the cardiovascular system during aging. Subsequently, it discusses the regulatory pathways and approaches targeting MAMs in aging-related CVDs, to provide novel treatment strategies for managing CVDs in aging populations.

Keywords:  aging; calcium homeostasis; cardiovascular diseases; mitochondria-associated endoplasmic reticulum membranes; mitochondrial bioenergetics

DOI:  https://doi.org/10.3389/fphar.2024.1389202
Int J Mol Sci. 2024 Jun 13. pii: 6525. [Epub ahead of print]25(12):

A-Syn(ful) MAM: A Fresh Perspective on a Converging Domain in Parkinson's Disease.

Peter A Barbuti.

  Parkinson's disease (PD) is a disease of an unknown origin. Despite that, decades of research have provided considerable evidence that alpha-synuclein (αSyn) is central to the pathogenesis of disease. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are functional domains formed at contact sites between the ER and mitochondria, with a well-established function of MAMs being the control of lipid homeostasis within the cell. Additionally, there are numerous proteins localized or enriched at MAMs that have regulatory roles in several different molecular signaling pathways required for cellular homeostasis, such as autophagy and neuroinflammation. Alterations in several of these signaling pathways that are functionally associated with MAMs are found in PD. Taken together with studies that find αSyn localized at MAMs, this has implicated MAM (dys)function as a converging domain relevant to PD. This review will highlight the many functions of MAMs and provide an overview of the literature that finds αSyn, in addition to several other PD-related proteins, localized there. This review will also detail the direct interaction of αSyn and αSyn-interacting partners with specific MAM-resident proteins. In addition, recent studies exploring new methods to investigate MAMs will be discussed, along with some of the controversies regarding αSyn, including its several conformations and subcellular localizations. The goal of this review is to highlight and provide insight on a domain that is incompletely understood and, from a PD perspective, highlight those complex interactions that may hold the key to understanding the pathomechanisms underlying PD, which may lead to the targeted development of new therapeutic strategies.

Keywords:  Parkinson’s disease (PD); alpha-synuclein (αSyn); mitochondrial-associated ER membranes (MAMs)

DOI:  https://doi.org/10.3390/ijms25126525
Biochem Soc Trans. 2024 Jun 27. pii: BST20230819. [Epub ahead of print]

Calcium channel signalling at neuronal endoplasmic reticulum-plasma membrane junctions.

Filip Maciąg, Arun Chhikara, Martin Heine.

  Neurons are highly specialised cells that need to relay information over long distances and integrate signals from thousands of synaptic inputs. The complexity of neuronal function is evident in the morphology of their plasma membrane (PM), by far the most intricate of all cell types. Yet, within the neuron lies an organelle whose architecture adds another level to this morphological sophistication - the endoplasmic reticulum (ER). Neuronal ER is abundant in the cell body and extends to distant axonal terminals and postsynaptic dendritic spines. It also adopts specialised structures like the spine apparatus in the postsynapse and the cisternal organelle in the axon initial segment. At membrane contact sites (MCSs) between the ER and the PM, the two membranes come in close proximity to create hubs of lipid exchange and Ca2+ signalling called ER-PM junctions. The development of electron and light microscopy techniques extended our knowledge on the physiological relevance of ER-PM MCSs. Equally important was the identification of ER and PM partners that interact in these junctions, most notably the STIM-ORAI and VAP-Kv2.1 pairs. The physiological functions of ER-PM junctions in neurons are being increasingly explored, but their molecular composition and the role in the dynamics of Ca2+ signalling are less clear. This review aims to outline the current state of research on the topic of neuronal ER-PM contacts. Specifically, we will summarise the involvement of different classes of Ca2+ channels in these junctions, discuss their role in neuronal development and neuropathology and propose directions for further research.

Keywords:  ER-PM junctions; ORAI; STIM; endoplasmic reticulum; membrane contact sites; store-operated calcium entry

DOI:  https://doi.org/10.1042/BST20230819
J Affect Disord. 2024 Jun 22. pii: S0165-0327(24)01008-5. [Epub ahead of print]

Role of mitochondria-associated membranes in the hippocampus in the pathogenesis of depression.

Jia-Rui Zhang, Shi-Yu Shen, Zu-Qi Shen, Shu-Yuan Yin, Ke Ye, Wei Li, Hao-Yuan Li, Ling-Feng Liang, Yan-Qing Wang, Xiao-Yun Guo, Jin Yu.

   BACKGROUND: Pathological changes, such as microglia activation in the hippocampus frequently occur in individuals with animal models of depression; however, they may share a common cellular mechanism, such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction. Mitochondria associated membranes (MAMs) are communication platforms between ER and mitochondria. This study aimed to investigate the role of intracellular stress responses, especially structural and functional changes of MAMs in depression.
METHODS: We used chronic social defeat stress (CSDS) to mimic depression in C57 mice to investigate the pathophysiological changes in the hippocampus associated with depression and assess the antidepressant effect of electroacupuncture (EA). Molecular, histological, and electron microscopic techniques were utilized to study intracellular stress responses, including the ER stress pathway reaction, mitochondrial damage, and structural and functional changes in MAMs in the hippocampus after CSDS. Proteomics technology was employed to explore protein-level changes in MAMs caused by CSDS.
RESULTS: CSDS caused mitochondrial dysfunction, ER stress, closer contact between ER and mitochondria, and enrichment of functional protein clusters at MAMs in hippocampus along with depressive-like behaviors. Also, EA showed beneficial effects on intracellular stress responses and depressive-like behaviors in CSDS mice.
LIMITATION: The cellular specificity of MAMs related protein changes in CSDS mice was not explored.
CONCLUSIONS: In the hippocampus, ER stress and mitochondrial damage occur, along with enriched mitochondria-ER interactions and MAM-related protein enrichment, which may contribute to depression's pathophysiology. EA may improve depression by regulating intracellular stress responses.

Keywords:  Cellular stress responses; Depression; ER stress; Electroacupuncture; MAMs; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.jad.2024.06.076
J Neurosci. 2024 Jun 27. pii: e0003242024. [Epub ahead of print]

Endoplasmic reticulum and mitochondrial calcium handling dynamically shape slow afterhyperpolarizations in vasopressin magnocellular neurons.

Matthew K Kirchner, Ferdinand Althammer, Elba Campos-Lira, Juliana Montanez, Javier E Stern.

Many neurons including vasopressin (VP) magnocellular neurosecretory cells (MNCs) of the hypothalamic supraoptic nucleus (SON) generate afterhyperpolarizations (AHPs) during spiking to slow firing, a phenomenon known as spike frequency adaptation. The AHP is underlain by Ca2+-activated K+ currents, and while slow component (sAHP) features are well described, its mechanism remains poorly understood. Previous work demonstrated that Ca2+ influx through N-type Ca2+ channels is the primary source of sAHP activation in SON oxytocin neurons, but no obvious channel coupling was described for VP neurons. Given this, we tested the possibility of an intracellular source of sAHP activation, namely the Ca2+-handling organelles endoplasmic reticulum (ER) and mitochondria in male and female wistar rats. We demonstrate that ER Ca2+ depletion greatly inhibits sAHPs without a corresponding decrease in Ca2+ signal. Caffeine sensitized AHP activation by Ca2+ In contrast to ER, disabling mitochondria with CCCP or blocking mitochondria Ca2+ uniporter (MCU) enhanced sAHP amplitude and duration, implicating mitochondria as a vital buffer for sAHP-activating Ca2+ Block of mitochondria Na+-dependent Ca2+ release via triphenylphosphonium (TPP+) failed to affect sAHPs, indicating that mitochondria Ca2+ doesn't contribute to sAHP activation. Together, our results support that ER Ca2+-induced Ca2+ release activates sAHPs and mitochondria shape the spatiotemporal trajectory of the sAHP via Ca2+ buffering in VP neurons. Overall, this implicates organelle Ca2+, and specifically ER-mitochondria associated membrane contacts, as an important site of Ca2+ microdomain activity that regulates sAHP signaling pathways. Thus, this site plays a major role in influencing VP firing activity and systemic hormonal release.Significance Statement The slow afterhyperpolarization (sAHP) is mediated by a Ca2+-dependent K+ current. Despite its critical role in regulating neuronal spiking, the Ca2+-dependent mechanisms leading to its activation and spatiotemporal shape remains poorly understood. Here we show that in vasopressin (VP) neurons, dynamic interactions in Ca2+ handling between endoplasmic reticulum (ER) and mitochondria play a significant role in sAHP initiation (via ER Ca2+ release) and its spatiotemporal waveform (via mitochondrial Ca2+ uptake). Our results suggest that contact sites between ER and mitochondria represent Ca2+ microdomains critically involved in initiating the first steps of sAHP generation in VP neurons. Given that changes in the sAHP have been linked to abnormal firing activity in various diseases, our results have both wide-range physiological and pathological implications.

DOI: https://doi.org/10.1523/JNEUROSCI.0003-24.2024
Bioessays. 2024 Jun 27. e2400045

Metabolic channeling of lipids via the contact zones between different organelles.

Kentaro Hanada.

  Various lipid transfer proteins (LTPs) mediate the inter-organelle transport of lipids. By working at membrane contact zones between donor and acceptor organelles, LTPs achieve rapid and accurate inter-organelle transfer of lipids. This article will describe the emerging paradigm that the action of LTPs at organelle contact zones generates metabolic channeling events in lipid metabolism, mainly referring to how ceramide synthesized in the endoplasmic reticulum is preferentially metabolized to sphingomyelin in the distal Golgi region, how cholesterol and phospholipids receive specific metabolic reactions in mitochondria, and how the hijacking of host LTPs by intracellular pathogens may generate new channeling-like events. In addition, the article will discuss how the function of LTPs is regulated, exemplified by a few representative LTP systems, and will briefly touch on experiments that will be necessary to establish the paradigm that LTP-mediated inter-organelle transport of lipids is one of the mechanisms of compartmentalization-based metabolic channeling events.

Keywords:  cholesterol; compartmentalization; lipid transfer proteins; metabolic channeling; organelle contact; sphingolipids

DOI:  https://doi.org/10.1002/bies.202400045
Curr Med Chem. 2024 Jun 26.

Mitochondria and Lipid Droplets: Focus on the Molecular Structure of Contact Sites in the Pathogenesis of Metabolic Syndrome.

Larisa Litvinova, Maria Vulf, Kristina Yurova, Olga Khaziakhmatova, Vladimir Malashchenko, Maria Bograya, Ivan Kozlov, Natalia Todosenko.

  Metabolic syndrome (MetS) is a complex of serious pathologies with a high prevalence worldwide. Disruption of mitochondrial biogenesis and its interaction with other cell organelles plays an important role in the development of MetS. Studies have revealed the phenotypic and functional heterogeneity of mitochondria that exist within a single cell and can regulate metabolic signaling pathways, influencing the development of metabolic diseases. Excessive intake of fatty acids leads to changes in fatty acid metabolism that affect the biology of important cell organelles - the lipid droplets, whose specific biology is not fully understood. Perhaps targeted molecular genetic stimulation aimed at regulating the contact between mitochondria and lipids can break the vicious cycle of inflammation in MetS and restore normal cell function, reducing the risk of developing concomitant pathologies. The review describes potential (promising) therapeutic molecular targets associated with mitochondria and lipid droplets, focusing on the proteins involved in their contact and emphasizing their role in the pathogenesis of MetS.

Keywords:  Metabolic syndrome; fatty; insulin resistance; lipid droplet; liver disease.; mitochondria

DOI:  https://doi.org/10.2174/0109298673309247240610050423
Int J Mol Sci. 2024 Jun 14. pii: 6565. [Epub ahead of print]25(12):

Pathological Functions of Lysosomal Ion Channels in the Central Nervous System.

Jianke Cen, Nan Hu, Jiawen Shen, Yongjing Gao, Huanjun Lu.

  Lysosomes are highly dynamic organelles that maintain cellular homeostasis and regulate fundamental cellular processes by integrating multiple metabolic pathways. Lysosomal ion channels such as TRPML1-3, TPC1/2, ClC6/7, CLN7, and TMEM175 mediate the flux of Ca2+, Cl-, Na+, H+, and K+ across lysosomal membranes in response to osmotic stimulus, nutrient-dependent signals, and cellular stresses. These ion channels serve as the crucial transducers of cell signals and are essential for the regulation of lysosomal biogenesis, motility, membrane contact site formation, and lysosomal homeostasis. In terms of pathophysiology, genetic variations in these channel genes have been associated with the development of lysosomal storage diseases, neurodegenerative diseases, inflammation, and cancer. This review aims to discuss the current understanding of the role of these ion channels in the central nervous system and to assess their potential as drug targets.

Keywords:  central nervous system; disease; immune inflammation; ion channel; lysosomes

DOI:  https://doi.org/10.3390/ijms25126565