bims-nenemi 2023-07-16 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2023–07–16
thirteen papers selected by
Marco Tigano, Thomas Jefferson University

Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression.
Loss of STING in parkin mutant flies suppresses muscle defects and mitochondria damage.
Mitochondria as intracellular signalling organelles. An update.
Immunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction.
Shedding light on mitochondrial outer-membrane permeabilization and membrane potential: State of the art methods and biosensors.
Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.
IF1 ablation prevents ATP synthase oligomerization, enhances mitochondrial ATP turnover and promotes an adenosine-mediated pro-inflammatory phenotype.
CRAT links cholesterol metabolism to innate immune responses in the heart.
Local coordination of mRNA storage and degradation near mitochondria modulates C. elegans ageing.
Fumarate hydratase inhibition activates innate immunity via mitochondrial nucleic acid release.
Urban aerosol particulate matter promotes mitochondrial oxidative stress-induced cellular senescence in human retinal pigment epithelial ARPE-19 cells.
Identification of mitochondrial related signature associated with immune microenvironment in Alzheimer's disease.
Three-dimensional images reveal the impact of the endosymbiont Midichloria mitochondrii on the host mitochondria.

EMBO J. 2023 Jul 13. e113256

Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression.

Nils Grotehans, Lynn McGarry, Hendrik Nolte, Vanessa Xavier, Moritz Kroker, Álvaro Jesús Narbona-Pérez, Soni Deshwal, Patrick Giavalisco, Thomas Langer, Thomas MacVicar.

  Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises the mitochondrial genome, but also affects its transcription. Here, we report that a mitochondrial nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides that are necessary for the transcription of mitochondrial genes. Loss of NME6 function leads to the depletion of mitochondrial transcripts, as well as destabilisation of the electron transport chain and impaired oxidative phosphorylation. These deficiencies are rescued by an exogenous supply of pyrimidine ribonucleosides. Moreover, NME6 is required for the maintenance of mitochondrial DNA when the access to cytosolic pyrimidine deoxyribonucleotides is limited. Our results therefore reveal an important role for ribonucleotide salvage in mitochondrial gene expression.

Keywords:  NME6; mitochondria; mitochondrial DNA; mitochondrial transcription; nucleotide metabolism

DOI:  https://doi.org/10.15252/embj.2022113256
PLoS Genet. 2023 Jul 13. 19(7): e1010828

Loss of STING in parkin mutant flies suppresses muscle defects and mitochondria damage.

Andrew T Moehlman, Gil Kanfer, Richard J Youle.

The early pathogenesis and underlying molecular causes of motor neuron degeneration in Parkinson's Disease (PD) remains unresolved. In the model organism Drosophila melanogaster, loss of the early-onset PD gene parkin (the ortholog of human PRKN) results in impaired climbing ability, damage to the indirect flight muscles, and mitochondrial fragmentation with swelling. These stressed mitochondria have been proposed to activate innate immune pathways through release of damage associated molecular patterns (DAMPs). Parkin-mediated mitophagy is hypothesized to suppress mitochondrial damage and subsequent activation of the cGAS/STING innate immunity pathway, but the relevance of this interaction in the fly remains unresolved. Using a combination of genetics, immunoassays, and RNA sequencing, we investigated a potential role for STING in the onset of parkin-null phenotypes. Our findings demonstrate that loss of Drosophila STING in flies rescues the thorax muscle defects and the climbing ability of parkin-/- mutants. Loss of STING also suppresses the disrupted mitochondrial morphology in parkin-/- flight muscles, suggesting unexpected feedback of STING on mitochondria integrity or activation of a compensatory mitochondrial pathway. In the animals lacking both parkin and sting, PINK1 is activated and cell death pathways are suppressed. These findings support a unique, non-canonical role for Drosophila STING in the cellular and organismal response to mitochondria stress.

DOI: https://doi.org/10.1371/journal.pgen.1010828
Cell Signal. 2023 Jul 06. pii: S0898-6568(23)00208-5. [Epub ahead of print]109 110794

Mitochondria as intracellular signalling organelles. An update.

Lucia-Doina Popov.

  Traditionally, mitochondria are known as "the powerhouse of the cell," responsible for energy (ATP) generation (by the electron transport chain, oxidative phosphorylation, the tricarboxylic acid cycle, and fatty acid ß-oxidation), and for the regulation of several metabolic processes, including redox homeostasis, calcium signalling, and cellular apoptosis. The extensive studies conducted in the last decades portray mitochondria as multifaceted signalling organelles that ultimately command cells' survival or death. Based on current knowledge, we'll outline the mitochondrial signalling to other intracellular compartments in homeostasis and pathology-related mitochondrial stress conditions here. The following topics are discussed: (i) oxidative stress and mtROS signalling in mitohormesis, (ii) mitochondrial Ca2+ signalling; (iii) the anterograde (nucleus-to-mitochondria) and retrograde (mitochondria-to-nucleus) signal transduction, (iv) the mtDNA role in immunity and inflammation, (v) the induction of mitophagy- and apoptosis - signalling cascades, (vi) the mitochondrial dysfunctions (mitochondriopathies) in cardiovascular, neurodegenerative, and malignant diseases. The novel insights into molecular mechanisms of mitochondria-mediated signalling can explain mitochondria adaptation to metabolic and environmental stresses to achieve cell survival.

Keywords:  Mitochondriopathies; Mitophagy; Oxidative stress; Signal transduction; mtDNA

DOI:  https://doi.org/10.1016/j.cellsig.2023.110794
Nat Commun. 2023 07 11. 14(1): 4092

Immunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction.

Minji Kim, Remigiusz A Serwa, Lukasz Samluk, Ida Suppanz, Agata Kodroń, Tomasz M Stępkowski, Praveenraj Elancheliyan, Biniyam Tsegaye, Silke Oeljeklaus, Michal Wasilewski, Bettina Warscheid, Agnieszka Chacinska.

Perturbed cellular protein homeostasis (proteostasis) and mitochondrial dysfunction play an important role in neurodegenerative diseases, however, the interplay between these two phenomena remains unclear. Mitochondrial dysfunction leads to a delay in mitochondrial protein import, causing accumulation of non-imported mitochondrial proteins in the cytosol and challenging proteostasis. Cells respond by increasing proteasome activity and molecular chaperones in yeast and C. elegans. Here, we demonstrate that in human cells mitochondrial dysfunction leads to the upregulation of a chaperone HSPB1 and, interestingly, an immunoproteasome-specific subunit PSMB9. Moreover, PSMB9 expression is dependent on the translation elongation factor EEF1A2. These mechanisms constitute a defense response to preserve cellular proteostasis under mitochondrial stress. Our findings define a mode of proteasomal activation through the change in proteasome composition driven by EEF1A2 and its spatial regulation, and are useful to formulate therapies to prevent neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41467-023-39642-8
Semin Cell Dev Biol. 2023 Jul 10. pii: S1084-9521(23)00141-6. [Epub ahead of print]

Shedding light on mitochondrial outer-membrane permeabilization and membrane potential: State of the art methods and biosensors.

Nikolay Popgeorgiev, Clara Gil, Kevin Berthenet, Giulia Bertolin, Gabriel Ichim.

  Membrane structural integrity is essential for optimal mitochondrial function. These organelles produce the energy needed for all vital processes, provided their outer and inner membranes are intact. This prevents the release of mitochondrial apoptogenic factors into the cytosol and ensures intact mitochondrial membrane potential (ΔΨm) to sustain ATP production. Cell death by apoptosis is generally triggered by outer mitochondrial membrane permeabilization (MOMP), tightly coupled with loss of ΔΨ m. As these two processes are essential for both mitochondrial function and cell death, researchers have devised various techniques to assess them. Here, we discuss current methods and biosensors available for detecting MOMP and measuring ΔΨ m, focusing on their advantages and limitations and discuss what new imaging tools are needed to improve our knowledge of mitochondrial function.

Keywords:  Biosensor; MOMP; Microscopy; Mitochondrial membrane potential

DOI:  https://doi.org/10.1016/j.semcdb.2023.07.003
Nat Commun. 2023 07 11. 14(1): 4105

Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.

Tianshu Hao, Jianglong Yu, Zhida Wu, Jie Jiang, Longlong Gong, Bingjun Wang, Hanze Guo, Huabin Zhao, Bin Lu, Simone Engelender, He He, Zhiyin Song.

Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism. However, the mode and biological functions of mitochondria-lysosome communication remain largely unknown. Here, we show that hypoxia remodels normal tubular mitochondria into megamitochondria by inducing broad inter-mitochondria contacts and subsequent fusion. Importantly, under hypoxia, mitochondria-lysosome contacts are promoted, and certain lysosomes are engulfed by megamitochondria, in a process we term megamitochondria engulfing lysosome (MMEL). Both megamitochondria and mature lysosomes are required for MMEL. Moreover, the STX17-SNAP29-VAMP7 complex contributes to mitochondria-lysosome contacts and MMEL under hypoxia. Intriguingly, MMEL mediates a mode of mitochondrial degradation, which we termed mitochondrial self-digestion (MSD). Moreover, MSD increases mitochondrial ROS production. Our results reveal a mode of crosstalk between mitochondria and lysosomes and uncover an additional pathway for mitochondrial degradation.

DOI: https://doi.org/10.1038/s41467-023-39811-9
Cell Death Dis. 2023 Jul 12. 14(7): 413

IF1 ablation prevents ATP synthase oligomerization, enhances mitochondrial ATP turnover and promotes an adenosine-mediated pro-inflammatory phenotype.

Sonia Domínguez-Zorita, Inés Romero-Carramiñana, Fulvio Santacatterina, Pau B Esparza-Moltó, Carolina Simó, Araceli Del-Arco, Cristina Núñez de Arenas, Jorge Saiz, Coral Barbas, José M Cuezva.

ATPase Inhibitory Factor 1 (IF1) regulates the activity of mitochondrial ATP synthase. The expression of IF1 in differentiated human and mouse cells is highly variable. In intestinal cells, the overexpression of IF1 protects against colon inflammation. Herein, we have developed a conditional IF1-knockout mouse model in intestinal epithelium to investigate the role of IF1 in mitochondrial function and tissue homeostasis. The results show that IF1-ablated mice have increased ATP synthase/hydrolase activities, leading to profound mitochondrial dysfunction and a pro-inflammatory phenotype that impairs the permeability of the intestinal barrier compromising mouse survival upon inflammation. Deletion of IF1 prevents the formation of oligomeric assemblies of ATP synthase and alters cristae structure and the electron transport chain. Moreover, lack of IF1 promotes an intramitochondrial Ca2+ overload in vivo, minimizing the threshold to Ca2+-induced permeability transition (mPT). Removal of IF1 in cell lines also prevents the formation of oligomeric assemblies of ATP synthase, minimizing the threshold to Ca2+-induced mPT. Metabolomic analyses of mice serum and colon tissue highlight that IF1 ablation promotes the activation of de novo purine and salvage pathways. Mechanistically, lack of IF1 in cell lines increases ATP synthase/hydrolase activities and installs futile ATP hydrolysis in mitochondria, resulting in the activation of purine metabolism and in the accumulation of adenosine, both in culture medium and in mice serum. Adenosine, through ADORA2B receptors, promotes an autoimmune phenotype in mice, stressing the role of the IF1/ATP synthase axis in tissue immune responses. Overall, the results highlight that IF1 is required for ATP synthase oligomerization and that it acts as a brake to prevent ATP hydrolysis under in vivo phosphorylating conditions in intestinal cells.

DOI: https://doi.org/10.1038/s41419-023-05957-z
Nat Metab. 2023 Jul 13.

CRAT links cholesterol metabolism to innate immune responses in the heart.

Hua Mao, Aude Angelini, Shengyu Li, Guangyu Wang, Luge Li, Cam Patterson, Xinchun Pi, Liang Xie.

Chronic inflammation is associated with increased risk and poor prognosis of heart failure; however, the precise mechanism that provokes sustained inflammation in the failing heart remains elusive. Here we report that depletion of carnitine acetyltransferase (CRAT) promotes cholesterol catabolism through bile acid synthesis pathway in cardiomyocytes. Intracellular accumulation of bile acid or intermediate, 7α-hydroxyl-3-oxo-4-cholestenoic acid, induces mitochondrial DNA stress and triggers cGAS-STING-dependent type I interferon responses. Furthermore, type I interferon responses elicited by CRAT deficiency substantially increase AIM2 expression and AIM2-dependent inflammasome activation. Genetic deletion of cardiomyocyte CRAT in mice of both sexes results in myocardial inflammation and dilated cardiomyopathy, which can be reversed by combined depletion of caspase-1, cGAS or AIM2. Collectively, we identify a mechanism by which cardiac energy metabolism, cholesterol homeostasis and cardiomyocyte-intrinsic innate immune responses are interconnected via a CRAT-mediated bile acid synthesis pathway, which contributes to chronic myocardial inflammation and heart failure progression.

DOI: https://doi.org/10.1038/s42255-023-00844-5
EMBO J. 2023 Jul 10. e112446

Local coordination of mRNA storage and degradation near mitochondria modulates C. elegans ageing.

Ioanna Daskalaki, Maria Markaki, Ilias Gkikas, Nektarios Tavernarakis.

  Mitochondria are central regulators of healthspan and lifespan, yet the intricate choreography of multiple, tightly controlled steps regulating mitochondrial biogenesis remains poorly understood. Here, we uncover a pivotal role for specific elements of the 5'-3' mRNA degradation pathway in the regulation of mitochondrial abundance and function. We find that the mRNA degradation and the poly-A tail deadenylase CCR4-NOT complexes form distinct foci in somatic Caenorhabditis elegans cells that physically and functionally associate with mitochondria. Components of these two multi-subunit complexes bind transcripts of nuclear-encoded mitochondria-targeted proteins to regulate mitochondrial biogenesis during ageing in an opposite manner. In addition, we show that balanced degradation and storage of mitochondria-targeted protein mRNAs are critical for mitochondrial homeostasis, stress resistance and longevity. Our findings reveal a multifaceted role of mRNA metabolism in mitochondrial biogenesis and show that fine-tuning of mRNA turnover and local translation control mitochondrial abundance and promote longevity in response to stress and during ageing.

Keywords:  ageing; mRNA metabolism; mitochondria; protein synthesis; stress

DOI:  https://doi.org/10.15252/embj.2022112446
MedComm (2020). 2023 Aug;4(4): e314

Fumarate hydratase inhibition activates innate immunity via mitochondrial nucleic acid release.

Xiang Li, Fangfang Zhou, Linghui Zeng.

DOI: https://doi.org/10.1002/mco2.314
Environ Toxicol Pharmacol. 2023 Jul 07. pii: S1382-6689(23)00153-9. [Epub ahead of print] 104211

Urban aerosol particulate matter promotes mitochondrial oxidative stress-induced cellular senescence in human retinal pigment epithelial ARPE-19 cells.

EunJin Bang, Hyun Hwangbo, Min Yeong Kim, Seon Yeong Ji, Da Hye Kim, Jung-Hyun Shim, Sung-Kwon Moon, Gi-Young Kim, Jaehun Cheong, Yung Hyun Choi.

  Environmental exposure to urban particulate matter (UPM) is a serious health concern worldwide. Although several studies have linked UPM to ocular diseases, no study has reported effects of UPM exposure on senescence in retinal cells. Therefore, this study aimed to investigate the effects of UPM on senescence and regulatory signaling in human retinal pigment epithelial ARPE-19 cells. Our study demonstrated that UPM significantly promoted senescence, with increased senescence-associated β-galactosidase activity. Moreover, both mRNA and protein levels of senescence markers (p16 and p21) and the senescence-associated secretory phenotype, including IL-1β, matrix metalloproteinase-1, and -3 were upregulated. Notably, UPM increased mitochondrial reactive oxygen species-dependent nuclear factor-kappa B (NF-κB) activation during senescence. In contrast, use of NF-κB inhibitor Bay 11-7082 reduced the level of senescence markers. Taken together, our results provide the first in vitro preliminary evidence that UPM induces senescence by promoting mitochondrial oxidative stress-mediated NF-κB activation in ARPE-19 cells.

Keywords:  NF-κB; reactive oxygen species; retinal pigment epithelial cells; senescence; urban particulate matter

DOI:  https://doi.org/10.1016/j.etap.2023.104211
J Transl Med. 2023 07 11. 21(1): 458

Identification of mitochondrial related signature associated with immune microenvironment in Alzheimer's disease.

Yaodan Zhang, Yuyang Miao, Jin Tan, Fanglian Chen, Ping Lei, Qiang Zhang.

   BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease. Mitochondrial dysfunction and immune responses are important factors in the pathogenesis of AD, but their crosstalk in AD has not been studied. In this study, the independent role and interaction of mitochondria-related genes and immune cell infiltration in AD were investigated using bioinformatics methods.
METHODS: The datasets of AD were obtained from NCBI Gene Expression Omnibus (GEO), and the data of mitochondrial genes was from MitoCarta3.0 database. Subsequently, differential expression genes (DEGs) screening and GSEA functional enrichment analysis were performed. The intersection of DEGs and mitochondrial related genes was used to obtain MitoDEGs. The MitoDEGs most relevant to AD were determined by Least absolute shrinkage and selection operator and multiple support vector machine recursive feature elimination, as well as protein-protein interactions (PPI) network and random forest. The infiltration of 28 kinds of immune cells in AD was analyzed by ssGSEA, and the relationship between hub MitoDEGs and the proportion of immune infiltration was studied. The expression levels of hub MitoDEGs were verified in cell models and AD mice, and the role of OPA1 in mitochondrial damage and neuronal apoptosis was investigated.
RESULTS: The functions and pathways of DEGs were significantly enriched in AD, including immune response activation, IL1R pathway, mitochondrial metabolism, oxidative damage response and electron transport chain-oxphos system in mitochondria. Hub MitoDEGs closely related to AD were obtained based on PPI network, random forest and two machine learning algorithms. Five hub MitoDEGs associated with neurological disorders were identified by biological function examination. The hub MitoDEGs were found to be correlated with memory B cell, effector memory CD8 T cell, activated dendritic cell, natural killer T cell, type 17 T helper cell, Neutrophil, MDSC, plasmacytoid dendritic cell. These genes can also be used to predict the risk of AD and have good diagnostic efficacy. In addition, the mRNA expression levels of BDH1, TRAP1, OPA1, DLD in cell models and AD mice were consistent with the results of bioinformatics analysis, and expression levels of SPG7 showed a downward trend. Meanwhile, OPA1 overexpression alleviated mitochondrial damage and neuronal apoptosis induced by Aβ1-42.
CONCLUSIONS: Five potential hub MitoDEGs most associated with AD were identified. Their interaction with immune microenvironment may play a crucial role in the occurrence and prognosis of AD, which provides a new insight for studying the potential pathogenesis of AD and exploring new targets.

Keywords:  Alzheimer's disease; Bioinformatics analysis; Immune infiltration; Mitochondria

DOI:  https://doi.org/10.1186/s12967-023-04254-9
Nat Commun. 2023 07 12. 14(1): 4133

Three-dimensional images reveal the impact of the endosymbiont Midichloria mitochondrii on the host mitochondria.

Zerrin Uzum, Dmitry Ershov, Michael J Pavia, Adeline Mallet, Olivier Gorgette, Olivier Plantard, Davide Sassera, Fabrizia Stavru.

The hard tick, Ixodes ricinus, a main Lyme disease vector, harbors an intracellular bacterial endosymbiont. Midichloria mitochondrii is maternally inherited and resides in the mitochondria of I. ricinus oocytes, but the consequences of this endosymbiosis are not well understood. Here, we provide 3D images of wild-type and aposymbiotic I. ricinus oocytes generated with focused ion beam-scanning electron microscopy. Quantitative image analyses of endosymbionts and oocyte mitochondria at different maturation stages show that the populations of both mitochondrion-associated bacteria and bacterium-hosting mitochondria increase upon vitellogenisation, and that mitochondria can host multiple bacteria in later stages. Three-dimensional reconstructions show symbiosis-dependent morphologies of mitochondria and demonstrate complete M. mitochondrii inclusion inside a mitochondrion. Cytoplasmic endosymbiont located close to mitochondria are not oriented towards the mitochondria, suggesting that bacterial recolonization is unlikely. We further demonstrate individual globular-shaped mitochondria in the wild type oocytes, while aposymbiotic oocytes only contain a mitochondrial network. In summary, our study suggests that M. mitochondrii modulates mitochondrial fragmentation in oogenesis possibly affecting organelle function and ensuring its presence over generations.

DOI: https://doi.org/10.1038/s41467-023-39758-x