bims-mecosi 2023-08-27 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2023–08–27
seven papers selected by
Verena Kohler, University of Graz

Role of Mitochondria-ER Contact Sites in Mitophagy.
Ca2+ signalling: A common language for organelles crosstalk in Parkinson's disease.
PtdSer as a signaling lipid determined by privileged localization of ORP5 and ORP8 at ER/PM junctional foci to determine PM and ER PtdSer/PI(4)P ratio and cell function.
LC3 conjugation to lipid droplets.
Menthol causes mitochondrial Ca2+-influx, affects structure-function relationship and cools mitochondria.
Mechanisms of Modulation of Mitochondrial Architecture.
Three-Dimensional Mitochondria Reconstructions of Murine Cardiac Muscle Changes in Size Across Aging.

Biomolecules. 2023 Jul 31. pii: 1198. [Epub ahead of print]13(8):

Role of Mitochondria-ER Contact Sites in Mitophagy.

Alina Rühmkorf, Angelika Bettina Harbauer.

  Mitochondria are often referred to as the "powerhouse" of the cell. However, this organelle has many more functions than simply satisfying the cells' metabolic needs. Mitochondria are involved in calcium homeostasis and lipid metabolism, and they also regulate apoptotic processes. Many of these functions require contact with the ER, which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria-ER contact sites (MERCS). Upon damage, mitochondria produce reactive oxygen species (ROS) that can harm the surrounding cell. To circumvent toxicity and to maintain a functional pool of healthy organelles, damaged and excess mitochondria can be targeted for degradation via mitophagy, a form of selective autophagy. Defects in mitochondria-ER tethers and the accumulation of damaged mitochondria are found in several neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, which argues that the interplay between the two organelles is vital for neuronal health. This review provides an overview of the different mechanisms of mitochondrial quality control that are implicated with the different mitochondria-ER tether proteins, and also provides a novel perspective on how MERCS are involved in mediating mitophagy upon mitochondrial damage.

Keywords:  mitochondria; mitophagy; organellar contact sites

DOI:  https://doi.org/10.3390/biom13081198
Cell Calcium. 2023 Jul 27. pii: S0143-4160(23)00094-5. [Epub ahead of print]115 102783

Ca2+ signalling: A common language for organelles crosstalk in Parkinson's disease.

Caterina Peggion, Lucia Barazzuol, Elena Poggio, Tito Calì, Marisa Brini.

  Parkinson's disease (PD) is a neurodegenerative disease caused by multifactorial pathogenic mechanisms. Familial PD is linked with genetic mutations in genes whose products are either associated with mitochondrial function or endo-lysosomal pathways. Of note, mitochondria are essential to sustain high energy demanding synaptic activity of neurons and alterations in mitochondrial Ca2+ signaling have been proposed as causal events for neurodegenerative process, although the mechanisms responsible for the selective loss of specific neuronal populations in the different neurodegenerative diseases is still not clear. Here, we specifically discuss the importance of a correct mitochondrial communication with the other organelles occurring at regions where their membranes become in close contact. We discuss the nature and the role of contact sites that mitochondria establish with ER, lysosomes, and peroxisomes, and how PD related proteins participate in the regulation/dysregulation of the tethering complexes. Unravelling molecular details of mitochondria tethering could contribute to identify specific therapeutic targets and develop new strategies to counteract the progression of the disease.

Keywords:  Calcium signalling; Mitochondria; Organelles contact sites; Parkinson's disease

DOI:  https://doi.org/10.1016/j.ceca.2023.102783
Proc Natl Acad Sci U S A. 2023 Aug 29. 120(35): e2301410120

PtdSer as a signaling lipid determined by privileged localization of ORP5 and ORP8 at ER/PM junctional foci to determine PM and ER PtdSer/PI(4)P ratio and cell function.

Woo Young Chung, Malini Ahuja, Beth A McNally, Spencer R Leibow, Henry K E Ohman, Ava Movahed Abtahi, Shmuel Muallem.

  The membrane contact site ER/PM junctions are hubs for signaling pathways, including Ca2+ signaling. Phosphatidylserine (PtdSer) mediates various physiological functions; however, junctional PtdSer composition and the role of PtdSer in Ca2+ signaling and Ca2+-dependent gene regulation are not understood. Here, we show that STIM1-formed junctions are required for PI(4)P/PtdSer exchange by ORP5 and ORP8, which have reciprocal lipid exchange modes and function as a rheostat that sets the junctional PtdSer/PI(4)P ratio. Targeting the ORP5 and ORP8 and their lipid transfer ORD domains to PM subdomains revealed that ORP5 sets low and ORP8 high junctional PI(4)P/PtdSer ratio that controls STIM1-STIM1 and STIM1-Orai1 interaction and the activity of the SERCA pump to determine the pattern of receptor-evoked Ca2+ oscillations, and consequently translocation of NFAT to the nucleus. Significantly, targeting the ORP5 and ORP8 ORDs to the STIM1 ER subdomain reversed their function. Notably, changing PI(4)P/PtdSer ratio by hydrolysis of PM or ER PtdSer with targeted PtdSer-specific PLA1a1 reproduced the ORPs function. The function of the ORPs is determined both by their differential lipid exchange modes and by privileged localization at the ER/PM subdomains. These findings reveal a role of PtdSer as a signaling lipid that controls the available PM PI(4)P, the unappreciated role of ER PtdSer in cell function, and the diversity of the ER/PM junctions. The effect of PtdSer on the junctional PI(4)P level should have multiple implications in cellular signaling and functions.

Keywords:  Ca2+ signaling; ER/PM junctions; Orai1; STIM1; phosphatidylserine

DOI:  https://doi.org/10.1073/pnas.2301410120
Autophagy. 2023 Aug 23. 1-3

LC3 conjugation to lipid droplets.

Mohyeddine Omrane, Thomas J Melia, Abdou Rachid Thiam.

  Macroautophagy/autophagy and lipid droplet (LD) biology are intricately linked, with autophagosome-dependent degradation of LDs in response to different signals. LDs play crucial roles in forming autophagosomes possibly by providing essential lipids and serving as a supportive autophagosome assembly platform at the endoplasmic reticulum (ER)-LD interface. LDs and autophagosomes share common proteins, such as VPS13, ATG2, ZFYVE1/DFCP1, and ATG14, but their dual functions remain poorly understood. In our recent study, we found that prolonged starvation leads to ATG3 localizing to large LDs and lipidating LC3B, revealing a non-canonical autophagic role on LDs. In vitro, ATG3 associates with purified and artificial LDs, and conjugated Atg8-family proteins. In long-term starved cells, only LC3B is found on the specific large LDs, positioned near LC3B-positive membranes that undergo lysosome-mediated acidification. This implies that LD-lipidated LC3B acts as a tethering factor, connecting phagophores to LDs and promoting degradation. Our data also support the notion that certain LD surfaces may function as lipidation stations for LC3B, which may move to nearby sites of autophagosome formation. Overall, our study unveils an unknown non-canonical implication of LDs in autophagy processes.Abbreviation: ATG: autophagy-related enzyme, ATP: adenosine triphosphate, E2 enzyme: ubiquitin-conjugating enzyme, ER: endoplasmic reticulum, LD: lipid droplet, LIR motif: LC3-interacting region, MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta, PE: phosphatidylethanolamine, PLIN1: perilipin 1, PNPLA2/ATGL: patatin-like phospholipase domain containing 2, SQSTM1/p62: sequestosome 1, VSP13: vacuolar protein sorting 13, ZFYVE1/DFCP1: zinc finger, FYVE domain containing 1.

Keywords:  ATG3; LC3B; lipid droplets; membrane contact sites; noncanonical autophagy; prolonged starvation

DOI:  https://doi.org/10.1080/15548627.2023.2249390
Life Sci. 2023 Aug 19. pii: S0024-3205(23)00667-7. [Epub ahead of print] 122032

Menthol causes mitochondrial Ca2+-influx, affects structure-function relationship and cools mitochondria.

Shamit Kumar, Tusar Kanta Acharya, Ramizur Rahaman Halder, Parnasree Mahapatra, Young-Tae Chang, Chandan Goswami.

  Menthol is a small bioactive compound able to cause several physiological changes and has multiple molecular targets. Therefore, cellular response against menthol is complex, and still poorly understood. In this work, we used a human osteosarcoma cell line (Saos-2) and analysed the effect of menthol, especially in terms of cellular, subcellular and molecular aspects. We demonstrate that menthol causes increased mitochondrial Ca2+ in a complex manner, which is mainly contributed by intracellular sources, including ER. Menthol also changes the Ca2+-load of individual mitochondrial particles in different conditions. Menthol increases ER-mito contact points, causes mitochondrial morphological changes, and increases mitochondrial ATP, cardiolipin, mitochondrial ROS and reduces mitochondrial membrane potential (ΔΨm). Menthol also prevents the mitochondrial quality damaged by sub-lethal and lethal doses of CCCP. In addition, menthol lowers the mitochondrial temperature within cell and also serves as a cooling agent for the isolated mitochondria in a cell free system too. Notably, menthol-induced reduction of mitochondrial temperature is observed in diverse types of cells, including neuronal, immune and cancer cells. As the higher mitochondrial temperature is a hallmark of several inflammatory, metabolic, disease and age-related disorders, we propose that menthol can serve as an active anti-aging compound against all these disorders. These findings may have relevance in case of several pharmacological and clinical applications of menthol. SIGNIFICANCE STATEMENT: Menthol is a plant-derived bioactive compound that is widely used for several physiological, behavioural, addictive, and medicinal purposes. It is a well-established "cooling and analgesic agent". However, the exact cellular and sub-cellular responses of menthol is poorly understood. In this work, we have characterized the effects of menthol on mitochondrial metabolism. Menthol regulates mitochondrial Ca2+, ATP, superoxides, cardiolipin, membrane-potential, and ER-mito contact sites. Moreover, the cooling agent menthol also cools down mitochondria and protects mitochondrial damage by certain toxins. These findings may promote use of menthol as a useful supplementary agent for anti-aging, anti-cancer, anti-inflammatory purposes where higher mitochondrial temperature is prevalent.

Keywords:  Cardiolipin; ER-Mito contact points; Mitochondrial Ca(2+)-influx; Mitochondrial temperature; Neuro-degeneration; ROS

DOI:  https://doi.org/10.1016/j.lfs.2023.122032
Biomolecules. 2023 Aug 07. pii: 1225. [Epub ahead of print]13(8):

Mechanisms of Modulation of Mitochondrial Architecture.

Juan Pablo Muñoz, Fernanda Luisa Basei, María Laura Rojas, David Galvis, Antonio Zorzano.

  Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can cause the dysfunction of these organelles. In this scenario, mitochondrial dynamics proteins and the phospholipid composition of the mitochondrial membrane are key for fine-tuning the modulation of mitochondrial architecture. In addition, several factors including post-translational modifications such as the phosphorylation, acetylation, SUMOylation, and o-GlcNAcylation of mitochondrial dynamics proteins contribute to shaping the plasticity of this architecture. In this regard, several studies have evidenced that, upon metabolic stress, mitochondrial dynamics proteins are post-translationally modified, leading to the alteration of mitochondrial architecture. Interestingly, several proteins that sustain the mitochondrial lipid composition also modulate mitochondrial morphology and organelle communication. In this context, pharmacological studies have revealed that the modulation of mitochondrial shape and function emerges as a potential therapeutic strategy for metabolic diseases. Here, we review the factors that modulate mitochondrial architecture.

Keywords:  lipids; membrane contact sites (MCSs); metabolic disease; metabolism; mitochondria; mitochondrial dynamics; pharmacology; post-translational modification; tethers

DOI:  https://doi.org/10.3390/biom13081225
Am J Physiol Heart Circ Physiol. 2023 Aug 25.

Three-Dimensional Mitochondria Reconstructions of Murine Cardiac Muscle Changes in Size Across Aging.

Zer Vue, Kit Neikirk, Larry Vang, Edgar Garza-Lopez, Trace A Christensen, Jianqiang Shao, Jacob Lam, Heather K Beasley, Andrea G Marshall, Amber Crabtree, Josephs Anudokem, Benjamin Rodriguez, Benjamin Kirk, Serif Bacevac, Taylor Barongan, Bryanna Shao, Dominique C Stephens, Kinuthia Kabugi, Ho-Jin Koh, Alice Koh, Chantell S Evans, Brittany Taylor, Anilkumar K Reddy, Tyne Miller-Fleming, Ky'Era V Actkins, Elma Zaganjor, Nastaran Daneshgar, Sandra A Murray, Bret C Mobley, Steven Damo, Jennifer A Gaddy, Blake Riggs, Celestine Wanjalla, Annet Kirabo, Melanie McReynolds, Jose A Gomez, Mark A Phillips, Vernat Exil, Dao-Fu Dai, Antentor Hinton.

  With sparse treatment options, cardiac disease remains a significant cause of death among humans. As a person ages, mitochondria break down and the heart becomes less efficient. Heart failure is linked to many mitochondria-associated processes, including endoplasmic reticulum stress, mitochondrial bioenergetics, insulin signaling, autophagy, and oxidative stress. The roles of key mitochondrial complexes that dictate the ultrastructure, such as the mitochondrial contact site and cristae organizing system (MICOS), in aging cardiac muscle are poorly understood. To better understand the cause of age-related alteration in mitochondrial structure in cardiac muscle, we used transmission electron microscopy (TEM) and serial block facing-scanning electron microscopy (SBF-SEM) to quantitatively analyze the 3D networks in cardiac muscle samples of male mice at aging intervals of 3 months, 1 year, and 2 years. Here, we present the loss of cristae morphology, the inner folds of the mitochondria, across age. In conjunction with this, the 3D volume of mitochondria decreased. These findings mimicked observed phenotypes in murine cardiac fibroblasts with CRISPR/Cas9 knockout of Mitofilin, Chchd3, Chchd6 (some members of the MICOS complex), and Opa1, which showed poorer oxidative consumption rate and mitochondria with decreased mitochondrial length and volume. In combination, these data show the need to explore if loss of the MICOS complex in the heart may be involved in age-associated mitochondrial and cristae structural changes.

Keywords:  3D morphometry; Cardiac Muscle; MICOS; Mitochondria; serial block-face SEM

DOI:  https://doi.org/10.1152/ajpheart.00202.2023