bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022‒04‒03
seventeen papers selected by
Avinash N. Mukkala
University of Toronto
  1. Proteomic profiling shows mitochondrial nucleoids are autophagy cargo in neurons: implications for neuron maintenance and neurodegenerative disease.
  2. Starting the engine of the powerhouse: mitochondrial transcription and beyond.
  3. Sirtuin 3 and mitochondrial permeability transition pore (mPTP): a systematic review.
  4. Regulatory networks controlling mitochondrial quality control in skeletal muscle.
  5. Mechanisms underlying ubiquitin-driven selective mitochondrial and bacterial autophagy.
  6. IL-33 regulates M1/M2 chemokine expression via mitochondrial redox-related mitophagy in human monocytes.
  7. Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling.
  8. Mitochondrial Quality Control: the Role in Cardiac Injury.
  9. Transient changes to metabolic homeostasis initiate mitochondrial adaptation to endurance exercise.
  10. Mitochondrial DNA replication and repair defects: Clinical phenotypes and therapeutic interventions.
  11. Quantitative metabolic fluxes regulated by trans-omic networks.
  12. Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies.
  13. Redox Activation of Mitochondrial DAMPs and the Metabolic Consequences for Development of Autoimmunity.
  14. An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model.
  15. Intrinsically disordered N-terminal domain (NTD) of p53 interacts with mitochondrial PTP regulator Cyclophilin D.
  16. ER-mitochondria communication is involved in NLRP3 inflammasome activation under stress conditions in the innate immune system.
  17. Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis.
  1. Autophagy. 2022 Mar 29. 1-3
    Proteomic profiling shows mitochondrial nucleoids are autophagy cargo in neurons: implications for neuron maintenance and neurodegenerative disease.
    Juliet Goldsmith, Erika L F Holzbaur.
      Neurons depend on macroautophagy/autophagy to maintain cellular homeostasis, and loss of autophagy leads to neurodegeneration. To better understand the role of basal autophagy in neurons, we enriched autophagic vesicles from healthy adult mouse brain and performed mass spectrometry to identify cargos cleared by autophagy. We found that synaptic and mitochondrial proteins comprise nearly half of the unique AV cargos identified in brain. Similarly, synaptic and mitochondrial proteins are major cargos for basal autophagy in neurons. Strikingly, we noted a specific enrichment of mitochondrial nucleoids within neuronal autophagosomes, which occurs through a mechanism distinct from damage-associated mitophagy. Here, we discuss the implications of these findings for our understanding of homeostatic mechanisms in neurons and how the age-dependent decline of autophagy in neurons may contribute to the onset or progression of neurodegenerative disease.
    Keywords:  DNM1L; SYN1; TFAM; macroautophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis
    DOI:  https://doi.org/10.1080/15548627.2022.2056865
  2. Biol Chem. 2022 Mar 31.
    Starting the engine of the powerhouse: mitochondrial transcription and beyond.
    Maria Miranda, Nina A Bonekamp, Inge Kühl.
      Mitochondria are central hubs for cellular metabolism, coordinating a variety of metabolic reactions crucial for human health. Mitochondria provide most of the cellular energy via their oxidative phosphorylation (OXPHOS) system, which requires the coordinated expression of genes encoded by both the nuclear (nDNA) and mitochondrial genomes (mtDNA). Transcription of mtDNA is not only essential for the biogenesis of the OXPHOS system, but also generates RNA primers necessary to initiate mtDNA replication. Like the prokaryotic system, mitochondria have no membrane-based compartmentalization to separate the different steps of mtDNA maintenance and expression and depend entirely on nDNA-encoded factors imported into the organelle. Our understanding of mitochondrial transcription in mammalian cells has largely progressed, but the mechanisms regulating mtDNA gene expression are still poorly understood despite their profound importance for human disease. Here, we review mechanisms of mitochondrial gene expression with a focus on the recent findings in the field of mammalian mtDNA transcription and disease phenotypes caused by defects in proteins involved in this process.
    Keywords:   inhibitor of mitochondrial transcription; PPR proteins; mitochondria; mitochondrial disease; mitochondrial gene expression; mitochondrial transcription
    DOI:  https://doi.org/10.1515/hsz-2021-0416
  3. Mitochondrion. 2022 Mar 25. pii: S1567-7249(22)00024-1. [Epub ahead of print]
    Sirtuin 3 and mitochondrial permeability transition pore (mPTP): a systematic review.
    Yaping Yang, Weiping Wang, Ye Tian, Jiong Shi.
      Mitochondrial permeability transition pore (mPTP) is a channel that opens at the inner mitochondrial membrane under conditions of stress. Sirtuin 3 (Sirt3) is a mitochondrial deacetylase known to play a major role in stress resistance and a regulatory role in cell death. This systematic review aims to elucidate the role of Sirt3 in mPTP inhibition. Electronic databases, including PubMed, EMBASE, Web of Science and Cochrane Library were searched up to May 2020. Original studies that investigated the relationship between Sirt3 and mPTP were included. Two reviewers independently extracted data on study characteristics, methods and outcomes. A total of 194 articles were found. Twenty-nine articles, which met criteria were included in the systematic review. Twenty-three studies provided evidence of the inhibitory effect of Sirt3 on the mPTP aperture. This review summarizes up-to-date evidence of the protective and inhibitory role of Sirt3 through deacetylating Cyclophilin D (CypD) on the mPTP aperture. Furthermore, we discuss the implications of this effect in disease.
    Keywords:  Cyclophilin D; Sirtuin3; deacetylase; mPTP; mitochondria
    DOI:  https://doi.org/10.1016/j.mito.2022.03.004
  4. Am J Physiol Cell Physiol. 2022 Mar 30.
    Regulatory networks controlling mitochondrial quality control in skeletal muscle.
    Mikhaela B Slavin, Jonathan M Memme, Ashley N Oliveira, Neushaw Moradi, David A Hood.
      The adaptive plasticity of mitochondria within skeletal muscle is regulated by signals converging on a myriad of regulatory networks that operate during conditions of increased (i.e. exercise) and decreased (inactivity, disuse) energy requirements. Notably, some of the initial signals that induce adaptive responses are common to both conditions, differing in their magnitude and temporal pattern, to produce vastly opposing mitochondrial phenotypes. In response to exercise, signaling to PGC-1α and other regulators ultimately produces an abundance of high quality mitochondria, leading to reduced mitophagy and a higher mitochondrial content. This is accompanied by the presence of an enhanced protein quality control system that consists of the protein import machinery as well chaperones and proteases termed the UPRmt. The UPRmt monitors intra-organelle proteostasis, and strives to maintain a mito-nuclear balance between nuclear- and mtDNA-derived gene products via retrograde signaling from the organelle to the nucleus. In addition, antioxidant capacity is improved, affording greater protection against oxidative stress. In contrast, chronic disuse conditions produce similar signaling but result in decrements in mitochondrial quality and content. Thus, the interactive cross-talk of the regulatory networks that control organelle turnover during wide variations in muscle use and disuse remain incompletely understood, despite our improving knowledge of the traditional regulators of organelle content and function. This brief review acknowledges existing regulatory networks and summarizes recent discoveries of novel biological pathways involved in determining organelle biogenesis, dynamics, mitophagy, protein quality control and antioxidant capacity, identifying ample protein targets for therapeutic intervention that determine muscle and mitochondrial health.
    DOI:  https://doi.org/10.1152/ajpcell.00065.2022
  5. Mol Cell. 2022 Mar 29. pii: S1097-2765(22)00221-0. [Epub ahead of print]
    Mechanisms underlying ubiquitin-driven selective mitochondrial and bacterial autophagy.
    Ellen A Goodall, Felix Kraus, J Wade Harper.
      Selective autophagy specifically eliminates damaged or superfluous organelles, maintaining cellular health. In this process, a double membrane structure termed an autophagosome captures target organelles or proteins and delivers this cargo to the lysosome for degradation. The attachment of the small protein ubiquitin to cargo has emerged as a common mechanism for initiating organelle or protein capture by the autophagy machinery. In this process, a suite of ubiquitin-binding cargo receptors function to initiate autophagosome assembly in situ on the target cargo, thereby providing selectivity in cargo capture. Here, we review recent efforts to understand the biochemical mechanisms and principles by which cargo are marked with ubiquitin and how ubiquitin-binding cargo receptors use conserved structural modules to recruit the autophagosome initiation machinery, with a particular focus on mitochondria and intracellular bacteria as cargo. These emerging mechanisms provide answers to long-standing questions in the field concerning how selectivity in cargo degradation is achieved.
    Keywords:  cargo receptor; mitophagy; selective autophagy; ubiquitin; xenophagy
    DOI:  https://doi.org/10.1016/j.molcel.2022.03.012
  6. Chem Biol Interact. 2022 Mar 23. pii: S0009-2797(22)00120-X. [Epub ahead of print] 109915
    IL-33 regulates M1/M2 chemokine expression via mitochondrial redox-related mitophagy in human monocytes.
    Yi-Ching Lin, Yu-Chih Lin, Mei-Lan Tsai, Yi-Giien Tsai, Chao-Hung Kuo, Chih-Hsing Hung.
      Interleukin (IL)-33 is an epithelial-derived cytokine that enhances T helper (Th) 2 responses. Allergens and other agents induce IL-33 in asthma. Excessive production of reactive oxygen species (ROS) leads to airway inflammation. Mitophagy is the selective degradation of mitochondria by autophagy and often occurs in defective mitochondria, followed by ROS production. In the present study, we examined the effects of IL-33 on ROS production and mitophagy in human monocytes, and the detailed mechanisms were investigated. Human monocyte cell line THP-1 was pretreated with different concentrations of IL-33. ROS production was measured by flow cytometry. Mitochondrial involvement and the mitophagy and intercellular pathway activation were evaluated by quantitative real-time PCR, western blotting, and confocal microscopy, and cytokine/chemokine concentrations were detected by ELISA. The data showed that IL-33 alone could induce ROS expression in THP-1 cells. The expression of complex II and V mRNA was increased in the presence of IL-33. The mitophagy-related proteins PINK1, Parkin, and LC3 were regulated by IL-33 through the AMPK pathway. IL-33 significantly decreased M1-related cytokines CXCL-10 and TNF-α production and significantly increased M2-related cytokine CCL-22 production. In conclusion, IL-33 induces ROS production and subsequently influences mitophagy through AMPK activation, altering the macrophage-polarization phenotype of monocytes.
    Keywords:  Cytokine; Interleukin (IL)-33; Mitophagy; Monocytes; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.cbi.2022.109915
  7. Proc Natl Acad Sci U S A. 2022 Apr 05. 119(14): e2121946119
    Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling.
    Latika Nagpal, Michael D Kornberg, Solomon H Snyder.
      SignificanceInositol pyrophosphates are versatile messenger molecules containing the energetic pyrophosphate bond. One of the principal enzymes generating the inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate) is inositol hexakisphosphate kinase 2 (IP6K2). Previous work has shown that IP6K2 is neuroprotective and maintains mitochondrial respiration. We now report that loss of IP6K2 leads to increased mitochondrial fission and mitophagy. Regulation of mitochondrial dynamics by IP6K2 depends on the protein PINK1 and, interestingly, is independent of IP6K2 enzymatic activity. These findings provide mechanistic insight into the regulation of mitochondrial function by IP6K2, which has implications for neuroprotection and mitochondrial physiology more generally.
    Keywords:  PINK1; inositol phosphate; mitochondrial biogenesis; mitophagy; neuroprotection
    DOI:  https://doi.org/10.1073/pnas.2121946119
  8. Front Biosci (Landmark Ed). 2022 Mar 09. 27(3): 96
    Mitochondrial Quality Control: the Role in Cardiac Injury.
    Grażyna Sygitowicz, Dariusz Sitkiewicz.
      The heart is a highly energy-dependent organ, and most of its energy is provided by mitochondrial oxidative phosphorylation. Therefore, maintaining a well-functioning mitochondrial population is of paramount importance for cardiac homeostasis, since damaged mitochondria produce less adenosine triphosphate (ATP) and generate higher amounts of reactive oxygen species (ROS). Mitochondrial dysfunction is associated with the development of many diseases, including cardiovascular disorders. In this article, we review the role of mitochondria as key determinants of acute myocardial ischemic/reperfusion injury (IRI) and also diabetic cardiomyopathy. The structure and function of mitochondria are regulated by the mitochondrial quality control (MQC) system. Mitochondrial quality control mechanisms involve a series of adaptive responses that preserve mitochondrial structure and function as well as ensure cardiomyocyte survival and cardiac function after injury. This review summarizes the basic mechanisms of MQC, including mitochondrial dynamics (fusion and fission), mitophagy and mitochondrial biogenesis. Mitochondrial dynamics are mainly controlled by the level of fission and fusion proteins and also by their post-translational modifications. In addition, this review aims to provide a contemporary view of the importance of miRNA molecules in the regulation of mitochondrial dynamics at the post-transcriptional level. Thus, miRNAs play an important role not only in the pathogenesis and prognosis of cardiac diseases, but can also be an important therapeutic target.
    Keywords:  cardiac injury; fusion and fission; miRNAs; mitochondrial biogenesis; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.31083/j.fbl2703096
  9. Semin Cell Dev Biol. 2022 Mar 26. pii: S1084-9521(22)00096-9. [Epub ahead of print]
    Transient changes to metabolic homeostasis initiate mitochondrial adaptation to endurance exercise.
    Jessica R Dent, Ben Stocks, Dean G Campelj, Andrew Philp.
      Endurance exercise is well established to increase mitochondrial content and function in skeletal muscle, a process termed mitochondrial biogenesis. Current understanding is that exercise initiates skeletal muscle mitochondrial remodeling via modulation of cellular nutrient, energetic and contractile stress pathways. These subtle changes in the cellular milieu are sensed by numerous transduction pathways that serve to initiate and coordinate an increase in mitochondrial gene transcription and translation. The result of these acute signaling events is the promotion of growth and assembly of mitochondria, coupled to a greater capacity for aerobic ATP provision in skeletal muscle. The aim of this review is to highlight the acute metabolic events induced by endurance exercise and the subsequent molecular pathways that sense this transient change in cellular homeostasis to drive mitochondrial adaptation and remodeling.
    Keywords:  Adaptation; Exercise; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1016/j.semcdb.2022.03.022
  10. Biochim Biophys Acta Bioenerg. 2022 Mar 24. pii: S0005-2728(22)00023-8. [Epub ahead of print]1863(5): 148554
    Mitochondrial DNA replication and repair defects: Clinical phenotypes and therapeutic interventions.
    Abhipsa Roy, Amoolya Kandettu, Swagat Ray, Sanjiban Chakrabarty.
      Mitochondria is a unique cellular organelle involved in multiple cellular processes and is critical for maintaining cellular homeostasis. This semi-autonomous organelle contains its circular genome - mtDNA (mitochondrial DNA), that undergoes continuous cycles of replication and repair to maintain the mitochondrial genome integrity. The majority of the mitochondrial genes, including mitochondrial replisome and repair genes, are nuclear-encoded. Although the repair machinery of mitochondria is quite efficient, the mitochondrial genome is highly susceptible to oxidative damage and other types of exogenous and endogenous agent-induced DNA damage, due to the absence of protective histones and their proximity to the main ROS production sites. Mutations in replication and repair genes of mitochondria can result in mtDNA depletion and deletions subsequently leading to mitochondrial genome instability. The combined action of mutations and deletions can result in compromised mitochondrial genome maintenance and lead to various mitochondrial disorders. Here, we review the mechanism of mitochondrial DNA replication and repair process, key proteins involved, and their altered function in mitochondrial disorders. The focus of this review will be on the key genes of mitochondrial DNA replication and repair machinery and the clinical phenotypes associated with mutations in these genes.
    Keywords:  Base-excision repair; CPEO; LIG3; POLG; mtDNA replication
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148554
  11. Biochem J. 2022 Mar 31. 479(6): 787-804
    Quantitative metabolic fluxes regulated by trans-omic networks.
    Satoshi Ohno, Saori Uematsu, Shinya Kuroda.
      Cells change their metabolism in response to internal and external conditions by regulating the trans-omic network, which is a global biochemical network with multiple omic layers. Metabolic flux is a direct measure of the activity of a metabolic reaction that provides valuable information for understanding complex trans-omic networks. Over the past decades, techniques to determine metabolic fluxes, including 13C-metabolic flux analysis (13C-MFA), flux balance analysis (FBA), and kinetic modeling, have been developed. Recent studies that acquire quantitative metabolic flux and multi-omic data have greatly advanced the quantitative understanding and prediction of metabolism-centric trans-omic networks. In this review, we present an overview of 13C-MFA, FBA, and kinetic modeling as the main techniques to determine quantitative metabolic fluxes, and discuss their advantages and disadvantages. We also introduce case studies with the aim of understanding complex metabolism-centric trans-omic networks based on the determination of metabolic fluxes.
    Keywords:  computational models; metabolic flux; metabolism; trans-omics
    DOI:  https://doi.org/10.1042/BCJ20210596
  12. Geroscience. 2022 Mar 30.
    Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies.
    Charlotte Graham, Rhoda Stefanatos, Angeline E H Yek, Ruth V Spriggs, Samantha H Y Loh, Alejandro Huerta Uribe, Tong Zhang, L Miguel Martins, Oliver D K Maddocks, Filippo Scialo, Alberto Sanz.
      Mitochondrial reactive oxygen species (mtROS) are cellular messengers essential for cellular homeostasis. In response to stress, reverse electron transport (RET) through respiratory complex I generates high levels of mtROS. Suppression of ROS production via RET (ROS-RET) reduces survival under stress, while activation of ROS-RET extends lifespan in basal conditions. Here, we demonstrate that ROS-RET signalling requires increased electron entry and uninterrupted electron flow through the electron transport chain (ETC). We find that in old fruit flies, ROS-RET is abolished when electron flux is decreased and that their mitochondria produce consistently high levels of mtROS. Finally, we demonstrate that in young flies, limiting electron exit, but not entry, from the ETC phenocopies mtROS generation observed in old individuals. Our results elucidate the mechanism by which ROS signalling is lost during ageing.
    Keywords:  Ageing; Complex I; Complex IV; Drosophila; Mitochondria; Reactive oxygen species; Reverse electron transport
    DOI:  https://doi.org/10.1007/s11357-022-00555-x
  13. Antioxid Redox Signal. 2022 Mar;36(7-9): 441-461
    Redox Activation of Mitochondrial DAMPs and the Metabolic Consequences for Development of Autoimmunity.
    Andreas Koenig, Iwona A Buskiewicz-Koenig.
      Significance: Reactive oxygen species (ROS) are well known to promote innate immune responses during and in the absence of microbial infections. However, excessive or prolonged exposure to ROS provokes innate immune signaling dysfunction and contributes to the pathogenesis of many autoimmune diseases. The relatively high basal expression of pattern recognition receptors (PRRs) in innate immune cells renders them prone to activation in response to minor intrinsic or extrinsic ROS misbalances in the absence of pathogens. Critical Issues: A prominent source of ROS are mitochondria, which are also major inter-organelle hubs for innate immunity activation, since most PRRs and downstream receptor molecules are directly located either at mitochondria or at mitochondria-associated membranes. Due to their ancestral bacterial origin, mitochondria can also act as quasi-intrinsic self-microbes that mimic a pathogen invasion and become a source of danger-associated molecular patterns (DAMPs) that triggers innate immunity from within. Recent Advances: The release of mitochondrial DAMPs correlates with mitochondrial metabolism changes and increased generation of ROS, which can lead to the oxidative modification of DAMPs. Recent studies suggest that ROS-modified mitochondrial DAMPs possess increased, persistent immunogenicity. Future Directions: Herein, we discuss how mitochondrial DAMP release and oxidation activates PRRs, changes cellular metabolism, and causes innate immune response dysfunction by promoting systemic inflammation, thereby contributing to the onset or progression of autoimmune diseases. The future goal is to understand what the tipping point for DAMPs is to become oxidized, and whether this is a road without return. Antioxid. Redox Signal. 36, 441-461.
    Keywords:  ATP; Carbamoyl phosphate synthetase-1 (CPS1); MAVS oligomerization; N-formyl peptides (NFPs); autoimmunity; cardiolipin (CL); cyclic GMP-AMP synthase (cGAS); cytochrome C; damage-associated molecular pattern (DAMP); innate immunity; metabolism; mitochondria; mitochondrial ROS (mtROS); mitochondrial TFAM; mitochondrial antiviral signaling (MAVS) protein; neutrophil extracellular trap (NET); oxidized ATP; oxidized cardiolipin; oxidized mitochondrial DNA (mtDNA); oxidized mitochondrial RNA (mtRNA); reactive oxygen species (ROS); redox; stimulator of interferon genes (STING); succinate; systemic lupus erythematosus (SLE); transcription factor A
    DOI:  https://doi.org/10.1089/ars.2021.0073
  14. J Vis Exp. 2022 Mar 09.
    An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model.
    Andrea Cavaliere, Silvia Marchet, Ivano Di Meo, Valeria Tiranti.
      Deficiency of the mitochondrial respiratory chain complexes that carry out oxidative phosphorylation (OXPHOS) is the biochemical marker of human mitochondrial disorders. From a genetic point of view, the OXPHOS represents a unique example because it results from the complementation of two distinct genetic systems: nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Therefore, OXPHOS defects can be due to mutations affecting nuclear and mitochondrial encoded genes. The groundbreaking work by King and Attardi, published in 1989, showed that human cell lines depleted of mtDNA (named rho0) could be repopulated by exogenous mitochondria to obtain the so-called "transmitochondrial cybrids." Thanks to these cybrids containing mitochondria derived from patients with mitochondrial disorders (MDs) and nuclei from rho0 cells, it is possible to verify whether a defect is mtDNA- or nDNA-related. These cybrids are also a powerful tool to validate the pathogenicity of a mutation and study its impact at a biochemical level. This paper presents a detailed protocol describing cybrid generation, selection, and characterization.
    DOI:  https://doi.org/10.3791/63452
  15. J Mol Biol. 2022 Mar 24. pii: S0022-2836(22)00126-7. [Epub ahead of print] 167552
    Intrinsically disordered N-terminal domain (NTD) of p53 interacts with mitochondrial PTP regulator Cyclophilin D.
    Jing Zhao, Xinyue Liu, Alan Blayney, Yumeng Zhang, Lauren Gandy, Paige Olivia Mirsky, Nathan Smith, Fuming Zhang, Robert J Linhardt, Jianhan Chen, Christopher Baines, Stewart N Loh, Chunyu Wang.
      Mitochondrial permeability transition pore (mPTP) plays crucial roles in cell death in a variety of diseases, including ischemia/reperfusion injury in heart attack and stroke, neurodegenerative conditions, and cancer. To date, cyclophilin D is the only confirmed component of mPTP. Under stress, p53 can translocate into mitochondria and interact with CypD, triggering necrosis and cell growth arrest. However, the molecular details of p53/CypD interaction are still poorly understood. Previously, several studies reported that p53 interacts with CypD through its DNA-binding domain (DBD). However, using surface plasmon resonance (SPR), we found that both NTD-DBD, NTD and NTD (1-70) bind to CypD at ∼μM KD. In solution NMR, NTD binds CypD with μM affinity and mimics the pattern of FLp53 binding in chemical shift perturbation. In contrast, neither solution NMR nor fluorescence anisotropy detected DBD binding to CypD. Thus, instead of DBD, NTD is the major CypD binding site on p53. NMR titration and MD simulation revealed that NTD binds CypD with broad and dynamic interfaces dominated by electrostatic interactions. NTD 20-70 was further identified as the minimal binding region for CypD interaction, and two NTD fragments, D1 (residues 22-44) and D2 (58-70), can each bind CypD with mM affinity. Our detailed biophysical characterization of the dynamic interface between NTD and CypD provides novel insights on the p53-dependent mPTP opening and drug discovery targeting NTD/CypD interface in diseases.
    Keywords:  Cyclophilin D; MD simulation; NMR; mitochondrial permeability transition pore; p53
    DOI:  https://doi.org/10.1016/j.jmb.2022.167552
  16. Cell Mol Life Sci. 2022 Mar 28. 79(4): 213
    ER-mitochondria communication is involved in NLRP3 inflammasome activation under stress conditions in the innate immune system.
    Ana Catarina Pereira, Jessica De Pascale, Rosa Resende, Susana Cardoso, Isabel Ferreira, Bruno Miguel Neves, Mylène A Carrascal, Mónica Zuzarte, Nuno Madeira, Sofia Morais, António Macedo, Anália do Carmo, Paula I Moreira, Maria Teresa Cruz, Cláudia F Pereira.
      Endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which are key events in the initiation and/or progression of several diseases, are correlated with alterations at ER-mitochondria contact sites, the so-called "Mitochondria-Associated Membranes" (MAMs). These intracellular structures are also implicated in NLRP3 inflammasome activation which is an important driver of sterile inflammation, however, the underlying molecular basis remains unclear. This work aimed to investigate the role of ER-mitochondria communication during ER stress-induced NLRP3 inflammasome activation in both peripheral and central innate immune systems, by using THP-1 human monocytes and BV2 microglia cells, respectively, as in vitro models. Markers of ER stress, mitochondrial dynamics and mass, as well as NLRP3 inflammasome activation were evaluated by Western Blot, IL-1β secretion was measured by ELISA, and ER-mitochondria contacts were quantified by transmission electron microscopy. Mitochondrial Ca2+ uptake and polarization were analyzed with fluorescent probes, and measurement of aconitase and SOD2 activities monitored mitochondrial ROS accumulation. ER stress was demonstrated to activate the NLRP3 inflammasome in both peripheral and central immune cells. Studies in monocytes indicate that ER stress-induced NLRP3 inflammasome activation occurs by a Ca2+-dependent and ROS-independent mechanism, which is coupled with upregulation of MAMs-resident chaperones, closer ER-mitochondria contacts, as well as mitochondrial depolarization and impaired dynamics. Moreover, enhanced ER stress-induced NLRP3 inflammasome activation in the immune system was found associated with pathological conditions since it was observed in monocytes derived from bipolar disorder (BD) patients, supporting a pro-inflammatory status in BD. In conclusion, by demonstrating that ER-mitochondria communication plays a key role in the response of the innate immune cells to ER stress, this work contributes to elucidate the molecular mechanisms underlying NLRP3 inflammasome activation under stress conditions, and to disclose novel potential therapeutic targets for diseases associated with sterile inflammation.
    Keywords:  Bipolar disorder (BD); Calcium; Endoplasmic reticulum (ER) stress; Mitochondria; Sterile inflammation; Unfolded protein response
    DOI:  https://doi.org/10.1007/s00018-022-04211-7
  17. Mol Metab. 2022 Mar 25. pii: S2212-8778(22)00050-3. [Epub ahead of print] 101481
    Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis.
    Aakriti Jain, Roberto Zoncu.
      Spatial compartmentalization of metabolic pathways within membrane-separated organelles is key to the ability of eukaryotic cells to precisely regulate their biochemical functions. Membrane-bound organelles such as mitochondria, endoplasmic reticulum (ER) and lysosomes enable the concentration of metabolic precursors within optimized chemical environments, greatly accelerating the efficiency of both anabolic and catabolic reactions, enabling division of labor and optimal utilization of resources. However, metabolic compartmentalization also poses a challenge to cells because it creates spatial discontinuities that must be bridged for reaction cascades to be connected and completed. To do so, cells employ different methods to coordinate metabolic fluxes occurring in different organelles, such as membrane-localized transporters to facilitate regulated metabolite exchange between mitochondria and lysosomes, non-vesicular transport pathways via physical contact sites connecting the ER with both mitochondria and lysosomes, as well as localized regulatory signaling processes that coordinately regulate the activity of all these organelles. Effective communication among these systems is essential to cellular health and function, whereas disruption of inter-organelle communication is an emerging driver in a multitude of diseases, from cancer to neurodegeneration.
    Keywords:  Contact sites; Lysosome; Metabolism; Mitochondria; Transporters; mTORC1
    DOI:  https://doi.org/10.1016/j.molmet.2022.101481
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