bims-nenemi 2021-11-07 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2021‒11‒07
twenty papers selected by
Marco Tigano
Thomas Jefferson University

Mitochondrial dysfunction, UPRmt signaling, and targeted therapy in metastasis tumor.
Implications of mitochondrial DNA mutations in human induced pluripotent stem cells.
Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells.
PERK, Beyond an Unfolded Protein Response Sensor in Estrogen-induced Apoptosis in Endocrine-Resistant Breast Cancer.
Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2.
5-Hydroxymethylfurfural Enhances the Antiviral Immune Response in Macrophages through the Modulation of RIG-I-Mediated Interferon Production and the JAK/STAT Signaling Pathway.
β2-adrenergic receptor regulates ER-mitochondria contacts.
Paradoxical implication of BAX/BAK in the persistence of tetraploid cells.
PERK signaling through C/EBPδ contributes to ER stress-induced expression of immunomodulatory and tumor promoting chemokines by cancer cells.
BAX inhibitor-1 regulates autophagy by controlling the IRE1α branch of the unfolded protein response.
Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner.
Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation.
High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy.
PELI1 promotes radiotherapy sensitivity by inhibiting noncanonical NF-κB in esophageal squamous cancer.
Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease.
Alteration of Mitochondrial Function in Oxidative Stress in Parkinsonian Neurodegeneration: A Cross-Sectional Study.
The loss of enzymatic activity of the PHARC associated lipase ABHD12 results in increased phagocytosis that causes neuroinflammation.
Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.
Cynaropicrin Induces Cell Cycle Arrest and Apoptosis by Inhibiting PKM2 to Cause DNA Damage and Mitochondrial Fission in A549 Cells.
A gene toolbox for monitoring autophagy transcription.

Cell Biosci. 2021 Oct 30. 11(1): 186

Mitochondrial dysfunction, UPRmt signaling, and targeted therapy in metastasis tumor.

Rajendiran Keerthiga, De-Sheng Pei, Ailing Fu.

  In modern research, mitochondria are considered a more crucial energy plant in cells. Mitochondrial dysfunction, including mitochondrial DNA (mtDNA) mutation and denatured protein accumulation, is a common feature of tumors. The dysfunctional mitochondria reprogram molecular metabolism and allow tumor cells to proliferate in the hostile microenvironment. One of the crucial signaling pathways of the mitochondrial dysfunction activation in the tumor cells is the retrograde signaling of mitochondria-nucleus interaction, mitochondrial unfolded protein response (UPRmt), which is initiated by accumulation of denatured protein and excess ROS production. In the process of UPRmt, various components are activitated to enhance the mitochondria-nucleus retrograde signaling to promote carcinoma progression, including hypoxia-inducible factor (HIF), activating transcription factor ATF-4, ATF-5, CHOP, AKT, AMPK. The retrograde signaling molecules of overexpression ATF-5, SIRT3, CREB, SOD1, SOD2, early growth response protein 1 (EGR1), ATF2, CCAAT/enhancer-binding protein-d, and CHOP also involved in the process. Targeted blockage of the UPRmt pathway could obviously inhibit tumor proliferation and metastasis. This review indicates the UPRmt pathways and its crucial role in targeted therapy of metastasis tumors.

Keywords:  Cytosolic heat shock response (HSR); Hypoxia-inducible factor (HIF); Integrated stress response (ISR); Mitochondrial unfolded protein response UPRmt; Mitohormesis; Retrograde signaling

DOI:  https://doi.org/10.1186/s13578-021-00696-0
Nat Rev Genet. 2021 Nov 02.

Implications of mitochondrial DNA mutations in human induced pluripotent stem cells.

Valerio Carelli, Michio Hirano, José Antonio Enríquez, Patrick F Chinnery.

DOI: https://doi.org/10.1038/s41576-021-00430-z
Elife. 2021 Nov 02. pii: e65109. [Epub ahead of print]10

Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells.

Michael C Kiritsy, Katelyn McCann, Daniel Mott, Stephen M Holland, Samuel M Behar, Christopher M Sassetti, Andrew J Olive.

  The immunological synapse allows antigen presenting cells (APC) to convey a wide array of functionally distinct signals to T cells, which ultimately shape the immune response. The relative effect of stimulatory and inhibitory signals is influenced by the activation state of the APC, which is determined by an interplay between signal transduction and metabolic pathways. While pathways downstream of toll-like receptors rely on glycolytic metabolism for the proper expression of inflammatory mediators, little is known about the metabolic dependencies of other critical signals such as interferon gamma (IFNg). Using CRISPR-Cas9, we performed a series of genome-wide knockout screens in murine macrophages to identify the regulators of IFNg-inducible T cell stimulatory or inhibitory proteins MHCII, CD40, and PD-L1. Our multi-screen approach enabled us to identify novel pathways that control these functionally distinct markers. Further integration of these screening data implicated complex I of the mitochondrial respiratory chain in the expression of all three markers, and by extension the IFNg signaling pathway. We report that the IFNg response requires mitochondrial respiration, and APCs are unable to activate T cells upon genetic or chemical inhibition of complex I. These findings suggest a dichotomous metabolic dependency between IFNg and toll-like receptor signaling, implicating mitochondrial function as a fulcrum of innate immunity.

Keywords:  human; immunology; inflammation; mouse

DOI:  https://doi.org/10.7554/eLife.65109
Mol Cancer Res. 2021 Nov 02. pii: molcanres.0702.2021. [Epub ahead of print]

PERK, Beyond an Unfolded Protein Response Sensor in Estrogen-induced Apoptosis in Endocrine-Resistant Breast Cancer.

Ping Fan, V Craig Jordan.

The discovery of 17β-estradiol (E2)-induced apoptosis has clinical relevance. Mechanistically, E2 over activates nuclear estrogen receptor α (ERα) that results in stress responses. The unfolded protein response (UPR) is initiated by E2 in the endoplasmic reticulum after hours of treatment in endocrine-resistant breast cancer cells, thereby activating three UPR sensors-PRK-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) with different functions. Specifically, PERK plays a critical role in induction of apoptosis while IRE1α and ATF6 are involved in the endoplasmic reticulum stress-associated degradation (ERAD) of PI3K/Akt/mTOR pathways. In addition to attenuating protein translation, PERK increases the DNA-binding activity of nuclear factor-κB (NF-κB) and subsequent tumor necrosis factor α (TNFα) expression. Additionally, PERK communicates with the mitochondria to regulate oxidative stress at mitochondria-associated endoplasmic reticulum membranes (MAMs). Furthermore, PERK is a component enriched in MAMs that interacts with multifunctional MAM-tethering proteins and integrally modulates the exchange of metabolites such as lipids, reactive oxygen species (ROS), and Ca2+ at contact sites. MAMs are also critical sites for the initiation of autophagy to remove defective organelles and misfolded proteins through specific regulatory proteins. Thus, PERK conveys signals from nucleus to these membrane-structured organelles that form an interconnected network to regulate E2-induced apoptosis. Herein, we address the mechanistic progress on how PERK acts as a multifunctional molecule to commit E2 to inducing apoptosis in endocrine-resistant breast cancer.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0702
Cell Death Dis. 2021 Nov 05. 12(11): 1050

Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2.

Chenyang Duan, Lei Kuang, Chen Hong, Xinming Xiang, Jiancang Liu, Qinghui Li, Xiaoyong Peng, Yuanqun Zhou, Hongchen Wang, Liangming Liu, Tao Li.

Mitochondrial mass imbalance is one of the key causes of cardiovascular dysfunction after hypoxia. The activation of dynamin-related protein 1 (Drp1), as well as its mitochondrial translocation, play important roles in the changes of both mitochondrial morphology and mitochondrial functions after hypoxia. However, in addition to mediating mitochondrial fission, whether Drp1 has other regulatory roles in mitochondrial homeostasis after mitochondrial translocation is unknown. In this study, we performed a series of interaction and colocalization assays and found that, after mitochondrial translocation, Drp1 may promote the excessive opening of the mitochondrial permeability transition pore (mPTP) after hypoxia. Firstly, mitochondrial Drp1 maximumly recognizes mPTP channels by binding Bcl-2-associated X protein (BAX) and a phosphate carrier protein (PiC) in the mPTP. Then, leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) is recruited, whose kinase activity is inhibited by direct binding with mitochondrial Drp1 after hypoxia. Subsequently, the mPTP-related protein hexokinase 2 (HK2) is inactivated at Thr-473 and dissociates from the mitochondrial membrane, ultimately causing structural disruption and overopening of mPTP, which aggravates mitochondrial and cellular dysfunction after hypoxia. Thus, our study interprets the dual direct regulation of mitochondrial Drp1 on mitochondrial morphology and functions after hypoxia and proposes a new mitochondrial fission-independent mechanism for the role of Drp1 after its translocation in hypoxic injury.

DOI: https://doi.org/10.1038/s41419-021-04343-x
ACS Omega. 2021 Oct 26. 6(42): 28019-28030

5-Hydroxymethylfurfural Enhances the Antiviral Immune Response in Macrophages through the Modulation of RIG-I-Mediated Interferon Production and the JAK/STAT Signaling Pathway.

Han Zou, Tingyue Wu, Yuan Wang, Yanhua Kang, Qingye Shan, Liqing Xu, Zheyi Jiang, Xiaohan Lin, Xiang-Yang Ye, Tian Xie, Hang Zhang.

5-Hydroxymethylfurfural (5-HMF) exists in a wide range of sugar-rich foods and traditional Chinese medicines. The role of 5-HMF in antiviral innate immunity and its mechanism have not been reported previously. In this study, we reveal for the first time that 5-HMF upregulates the production of retinoic acid-inducible gene I (RIG-I)-mediated type I interferon (IFN) as a response to viral infection. IFN-β and IFN-stimulated chemokine gene expressions induced by the vesicular stomatitis virus (VSV) are upregulated in RAW264.7 cells and primary peritoneal macrophages after treatment with 5-HMF, a natural product that appears to inhibit the efficiency of viral replication. Meanwhile, 5-HMF-pretreated mice show enhanced innate antiviral immunity, increased serum levels of IFN-β, and reduced morbidity and viral loads upon infection with VSV. Thus, 5-HMF can be seen to have a positive effect on enhancing type I IFN production. Mechanistically, 5-HMF upregulates the expression of RIG-I in macrophages, resulting in an acceleration of the RIG-I signaling pathway activation. Additionally, STAT1 and STAT2 phosphorylations, along with the expression of IFN-stimulated chemokine genes induced by IFN-α/β, were also enhanced in macrophages cotreated with 5-HMF. In summary, these findings indicate that 5-HMF not only can induce type I IFN production but also can enhance IFN-JAK/STAT signaling, leading to a novel immunomodulatory mechanism against viral infection. In conclusion, our study reveals a previously unrecognized effect of 5-HMF in the antiviral innate immune response and suggests new potential of utilizing 5-HMF for controlling viral infection.

DOI: https://doi.org/10.1021/acsomega.1c03862
Sci Rep. 2021 Nov 02. 11(1): 21477

β2-adrenergic receptor regulates ER-mitochondria contacts.

Youngshin Lim, Il-Taeg Cho, Helmut G Rennke, Ginam Cho.

Interactions between the endoplasmic reticulum (ER) and mitochondria (Mito) are crucial for many cellular functions, and their interaction levels change dynamically depending on the cellular environment. Little is known about how the interactions between these organelles are regulated within the cell. Here we screened a compound library to identify chemical modulators for ER-Mito contacts in HEK293T cells. Multiple agonists of G-protein coupled receptors (GPCRs), beta-adrenergic receptors (β-ARs) in particular, scored in this screen. Analyses in multiple orthogonal assays validated that β2-AR activation promotes physical and functional interactions between the two organelles. Furthermore, we have elucidated potential downstream effectors mediating β2-AR-induced ER-Mito contacts. Together our study identifies β2-AR signaling as an important regulatory pathway for ER-Mito coupling and highlights the role of these contacts in responding to physiological demands or stresses.

DOI: https://doi.org/10.1038/s41598-021-00801-w
Cell Death Dis. 2021 Nov 01. 12(11): 1039

Paradoxical implication of BAX/BAK in the persistence of tetraploid cells.

Jiayin Deng, Lucía G Gutiérrez, Gautier Stoll, Omar Motiño, Isabelle Martins, Lucía Núñez, José Manuel Bravo-San Pedro, Juliette Humeau, Chloé Bordenave, Juncheng Pan, Hélène Fohrer-Ting, Sylvie Souquere, Gerard Pierron, Claudio Hetz, Carlos Villalobos, Guido Kroemer, Laura Senovilla.

Pro-apoptotic multi-domain proteins of the BCL2 family such as BAX and BAK are well known for their important role in the induction of mitochondrial outer membrane permeabilization (MOMP), which is the rate-limiting step of the intrinsic pathway of apoptosis. Human or mouse cells lacking both BAX and BAK (due to a double knockout, DKO) are notoriously resistant to MOMP and cell death induction. Here we report the surprising finding that BAX/BAK DKO cells proliferate less than control cells expressing both BAX and BAK (or either BAX or BAK) when they are driven into tetraploidy by transient exposure to the microtubule inhibitor nocodazole. Mechanistically, in contrast to their BAX/BAK-sufficient controls, tetraploid DKO cells activate a senescent program, as indicated by the overexpression of several cyclin-dependent kinase inhibitors and the activation of β-galactosidase. Moreover, DKO cells manifest alterations in ionomycin-mobilizable endoplasmic reticulum (ER) Ca2+ stores and store-operated Ca2+ entry that are affected by tetraploidization. DKO cells manifested reduced expression of endogenous sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (Serca2a) and transfection-enforced reintroduction of Serca2a, or reintroduction of an ER-targeted variant of BAK into DKO cells reestablished the same pattern of Ca2+ fluxes as observed in BAX/BAK-sufficient control cells. Serca2a reexpression and ER-targeted BAK also abolished the tetraploidy-induced senescence of DKO cells, placing ER Ca2+ fluxes downstream of the regulation of senescence by BAX/BAK. In conclusion, it appears that BAX/BAK prevent the induction of a tetraploidization-associated senescence program. Speculatively, this may contribute to the low incidence of cancers in BAX/BAK DKO mice and explain why human cancers rarely lose the expression of both BAX and BAK.

DOI: https://doi.org/10.1038/s41419-021-04321-3
Cell Death Dis. 2021 Nov 01. 12(11): 1038

PERK signaling through C/EBPδ contributes to ER stress-induced expression of immunomodulatory and tumor promoting chemokines by cancer cells.

Namratha Sheshadri, Dipak K Poria, Shikha Sharan, Ying Hu, Chunhua Yan, Vishal N Koparde, Kuppusamy Balamurugan, Esta Sterneck.

Cancer cells experience endoplasmic reticulum (ER) stress due to activated oncogenes and conditions of nutrient deprivation and hypoxia. The ensuing unfolded protein response (UPR) is executed by ATF6, IRE1 and PERK pathways. Adaptation to mild ER stress promotes tumor cell survival and aggressiveness. Unmitigated ER stress, however, will result in cell death and is a potential avenue for cancer therapies. Because of this yin-yang nature of ER stress, it is imperative that we fully understand the mechanisms and dynamics of the UPR and its contribution to the complexity of tumor biology. The PERK pathway inhibits global protein synthesis while allowing translation of specific mRNAs, such as the ATF4 transcription factor. Using thapsigargin and tunicamycin to induce acute ER stress, we identified the transcription factor C/EBPδ (CEBPD) as a mediator of PERK signaling to secretion of tumor promoting chemokines. In melanoma and breast cancer cell lines, PERK mediated early induction of C/EBPδ through ATF4-independent pathways that involved at least in part Janus kinases and the STAT3 transcription factor. Transcriptional profiling revealed that C/EBPδ contributed to 20% of thapsigargin response genes including chaperones, components of ER-associated degradation, and apoptosis inhibitors. In addition, C/EBPδ supported the expression of the chemokines CXCL8 (IL-8) and CCL20, which are known for their tumor promoting and immunosuppressive properties. With a paradigm of short-term exposure to thapsigargin, which was sufficient to trigger prolonged activation of the UPR in cancer cells, we found that conditioned media from such cells induced cytokine expression in myeloid cells. In addition, activation of the CXCL8 receptor CXCR1 during thapsigargin exposure supported subsequent sphere formation by cancer cells. Taken together, these investigations elucidated a novel mechanism of ER stress-induced transmissible signals in tumor cells that may be particularly relevant in the context of pharmacological interventions.

DOI: https://doi.org/10.1038/s41419-021-04318-y
EMBO J. 2021 Nov 02. 40(21): e109149

BAX inhibitor-1 regulates autophagy by controlling the IRE1α branch of the unfolded protein response.

Karen Castillo, Diego Rojas-Rivera, Fernanda Lisbona, Benjamín Caballero, Melissa Nassif, Felipe A Court, Sebastian Schuck, Consuelo Ibar, Peter Walter, Jimena Sierralta, Alvaro Glavic, Claudio Hetz.

DOI: https://doi.org/10.15252/embj.2021109149
Science. 2021 Jun 25. 372(6549): eabf6548

Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner.

Youngdae Gwon, Brian A Maxwell, Regina-Maria Kolaitis, Peipei Zhang, Hong Joo Kim, J Paul Taylor.

Tailoring stress responsesWhen faced with environmental stress, cells respond by shutting down cellular processes such as translation and nucleocytoplasmic transport. At the same time, cells preserve cytoplasmic messenger RNAs in structures known as stress granules, and many cellular proteins are modified by the covalent addition of ubiquitin, which has long been presumed to reflect degradation of stress-damaged proteins (see the Perspective by Dormann). Maxwell et al. show that cells generate distinct patterns of ubiquitination in response to different stressors. Rather than reflecting the degradation of stress-damaged proteins, this ubiquitination primes cells to dismantle stress granules and reinitiate normal cellular activities once the stress is removed. Gwon et al. show that persistent stress granules are degraded by autophagy, whereas short-lived granules undergo a process of disassembly that is autophagy independent. The mechanism of this disassembly depends on the initiating stress.Science, abc3593 and abf6548, this issue p. eabc3593 and p. eabf6548; see also abj2400, p. 1393.

DOI: https://doi.org/10.1126/science.abf6548
Nat Commun. 2021 Nov 04. 12(1): 6409

Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation.

Chih-Yao Chung, Kritarth Singh, Vassilios N Kotiadis, Gabriel E Valdebenito, Jee Hwan Ahn, Emilie Topley, Joycelyn Tan, William D Andrews, Benoit Bilanges, Robert D S Pitceathly, Gyorgy Szabadkai, Mariia Yuneva, Michael R Duchen.

Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy - tissues express both wild-type and mutant mtDNA. While the level of heteroplasmy broadly correlates with disease severity, the relationships between specific mtDNA mutations, heteroplasmy, disease phenotype and severity are poorly understood. We have carried out extensive bioenergetic, metabolomic and RNAseq studies on heteroplasmic patient-derived cells carrying the most prevalent disease related mtDNA mutation, the m.3243 A > G. These studies reveal that the mutation promotes changes in metabolites which are associated with the upregulation of the PI3K-Akt-mTORC1 axis in patient-derived cells and tissues. Remarkably, pharmacological inhibition of PI3K, Akt, or mTORC1 reduced mtDNA mutant load and partially rescued cellular bioenergetic function. The PI3K-Akt-mTORC1 axis thus represents a potential therapeutic target that may benefit people suffering from the consequences of the m.3243 A > G mutation.

DOI: https://doi.org/10.1038/s41467-021-26746-2
Front Oncol. 2021 ;11 740720

High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy.

Marco Fiorillo, Béla Ózsvári, Federica Sotgia, Michael P Lisanti.

  Recently, we presented evidence that high mitochondrial ATP production is a new therapeutic target for cancer treatment. Using ATP as a biomarker, we isolated the "metabolically fittest" cancer cells from the total cell population. Importantly, ATP-high cancer cells were phenotypically the most aggressive, with enhanced stem-like properties, showing multi-drug resistance and an increased capacity for cell migration, invasion and spontaneous metastasis. In support of these observations, ATP-high cells demonstrated the up-regulation of both mitochondrial proteins and other protein biomarkers, specifically associated with stemness and metastasis. Therefore, we propose that the "energetically fittest" cancer cells would be better able to resist the selection pressure provided by i) a hostile micro-environment and/or ii) conventional chemotherapy, allowing them to be naturally-selected for survival, based on their high ATP content, ultimately driving tumor recurrence and distant metastasis. In accordance with this energetic hypothesis, ATP-high MDA-MB-231 breast cancer cells showed a dramatic increase in their ability to metastasize in a pre-clinical model in vivo. Conversely, metastasis was largely prevented by treatment with an FDA-approved drug (Bedaquiline), which binds to and inhibits the mitochondrial ATP-synthase, leading to ATP depletion. Clinically, these new therapeutic approaches could have important implications for preventing treatment failure and avoiding cancer cell dormancy, by employing ATP-depletion therapy, to target even the fittest cancer cells.

Keywords:  ATP; anti-oxidant capacity; bedaquiline; cancer stem cells (CSCs); dormancy; metastasis; mitochondria; multi-drug resistance

DOI:  https://doi.org/10.3389/fonc.2021.740720
Mol Oncol. 2021 Nov 05.

PELI1 promotes radiotherapy sensitivity by inhibiting noncanonical NF-κB in esophageal squamous cancer.

Dongfang Dai, Hongping Zhou, Li Yin, Fei Ye, Xiao Yuan, Tao You, Xiaohui Zhao, Weiguo Long, Deqiang Wang, Xia He, Jifeng Feng, Deyu Chen.

  The low sensitivity of radiotherapy is the main cause of tumor tolerance against ionizing radiation (IR). However, the molecular mechanisms by which radiosensitivity is controlled remain elusive. Here, we observed that high expression of pellino E3 ubiquitin protein ligase 1 (PELI1) was correlated with improved prognosis in human esophageal squamous cell carcinoma (ESCC) stage III patients that received adjuvant radiotherapy. Moreover, we found PELI1-mediated IR-induced tumor cell apoptosis in vivo and in vitro. Mechanistically, PELI1 mediated the lysine 48 (Lys48)-linked polyubiquitination and degradation of NF-κB-inducing kinase (NIK; also known as MAP3K14), the master kinase of the noncanonical NF-κB pathway, thereby inhibiting IR-induced activation of the noncanonical NF-κB signaling pathway during radiotherapy. As a consequence, PELI1 inhibited the noncanonical NF-κB-induced expression of the anti-apoptotic gene BCL2 like 1 (Bclxl; also known as BCL2L1), leading to an enhancement of the IR-induced apoptosis signaling pathway and ultimately promoting IR-induced apoptosis in tumor cells. Therefore, Bclxl or NIK knockdown abolished the apoptosis-resistant effect in PELI1-knockdown tumor cells after radiotherapy. These findings establish PELI1 as a critical tumor intrinsic regulator in controlling the sensitivity of tumor cells to radiotherapy through modulating IR-induced noncanonical NF-κB expression.

Keywords:  NIK; PELI1; Radiotherapy; noncanonical NF-κB; polyubiquitination

DOI:  https://doi.org/10.1002/1878-0261.13134
Commun Biol. 2021 Nov 04. 4(1): 1262

Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease.

Aine Fairbrother-Browne, Aminah T Ali, Regina H Reynolds, Sonia Garcia-Ruiz, David Zhang, Zhongbo Chen, Mina Ryten, Alan Hodgkinson.

Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases. The mitochondrial genome encodes core respiratory chain proteins, but the vast majority of mitochondrial proteins are nuclear-encoded, making interactions between the two genomes vital for cell function. Here, we examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. We find strong regional patterns that are modulated by cell-type and reflect functional specialisation. Nuclear genes causally implicated in sporadic Parkinson's and Alzheimer's disease (AD) show much stronger relationships with the mitochondrial genome than expected by chance, and mitochondrial-nuclear relationships are highly perturbed in AD cases, particularly through synaptic and lysosomal pathways, potentially implicating the regulation of energy balance and removal of dysfunction mitochondria in the etiology or progression of the disease. Finally, we present MitoNuclearCOEXPlorer, a tool to interrogate key mitochondria-nuclear relationships in multi-dimensional brain data.

DOI: https://doi.org/10.1038/s42003-021-02792-w
Ann Indian Acad Neurol. 2021 Jul-Aug;24(4):24(4): 506-512

Alteration of Mitochondrial Function in Oxidative Stress in Parkinsonian Neurodegeneration: A Cross-Sectional Study.

Rizwana Qadri, Vinay Goyal, Madhuri Behari, Arulselvi Subramanian, Sudip Kumar Datta, Asok Kumar Mukhopadhyay.

  Context: Appropriate mitochondrial function and oxidative balance are critical to neuronal survival. Accumulation of reactive oxygen species leads to oxidative stress that can cause free radical damage to biomolecules of the cell components and the molecules in the cellular milieu that eventually lead to a variety of chronic diseases including neurodegenerative disorders. Mitochondrial dysfunction initiates neuronal apoptosis thereby leading to neurodegenerative diseases including Parkinson's disease (PD).Aim: To evaluate oxidative stress vis-a-vis mitochondrial function (Cytochrome C oxidase activity) in PD patients, Parkinson plus syndrome (PPS) patients in comparison with healthy controls (HCs).
Settings and Design: Cross-sectional Study.
Methods: We assessed oxidative stress by chemiluminescence using luminol, and cytochrome c oxidase activity (CCO) by CCO kit using spectrophotometry in PD patients (n = 80), PPS patients (n = 40), and HCs (n = 40).
Statistical Analysis: Data were presented as number (%) or mean ± SD/median as approximate. Quantitative baseline variables were compared among the groups using one-way ANOVA and qualitative variables were compared using Chi-square test. The difference in median was compared using Kruskal-Wallis test followed by Post-hoc Bonferronni correction.
Results: Compared to HCs (Median 7.53 ± 15.58 RLU/sec/cell), ROS level in PD (14.13 ± 29.5), and PPS (17.43 ± 15.91) patients was significantly higher (P = 0.0029: HC vs, PD & P = 0.0500: HC vs. PPS). Also, ROS in PD patients (14.13 ± 29.5) was higher that PPS patients (17. 43 ± 15.91) but the difference was not statistically significant (P = 0.84). The CCO activity was found to be diminished in PD (Median: 0.025 ± 0.013 units/ml) and PPS patients (0.027 ± 0.008) in comparison to HCs (0.117 ± 0.049).
Conclusion: Mitochondrial dysfunction and oxidative stress is associated with PD and PPS and may play an important role in etiopathogenesis. Though the cause-effect conundrum has not been comprehensively probed but addressing oxidative stress and mitochondrial damage may serve as an adjunctive therapy for PD and PPS. Iron metabolism as reflected in the red cell indices may aid in differentiating PD from PPS.

Keywords:  Cytochrome C oxidase; mitochondrial dysfunction; neurodegeneration; oxidative stress; parkinsonism; reactive oxygen species

DOI:  https://doi.org/10.4103/aian.AIAN_392_20
Eur J Neurosci. 2021 Nov 02.

The loss of enzymatic activity of the PHARC associated lipase ABHD12 results in increased phagocytosis that causes neuroinflammation.

Shubham Singh, Siddhesh S Kamat.

  Phagocytosis is an important evolutionary conserved process, essential for clearing pathogens and cellular debris in higher organisms, including humans. This well-orchestrated innate immunological response is intricately regulated by numerous cellular factors, important amongst which, are the immunomodulatory lysophosphatidylserines (lyso-PSs) and the pro-apoptotic oxidized phosphatidylserines (PSs) signaling lipids. Interestingly, in mammals, both these signaling lipids are physiologically regulated by the lipase ABHD12, mutations of which, cause the human neurological disorder PHARC. Despite the biomedical significance of this lipase, detailed mechanistic studies and the specific contribution of ABHD12 to innate processes like phagocytosis remain poorly understood. Here, by immunohistochemical and immunofluorescence approaches, using the murine model of PHARC, we show, that upon an inflammatory stimulus, activated microglial cells in the cerebellum of mice deficient in ABHD12 have an amoeboid morphology, increased soma size, and display heightened phagocytosis activity. We also report that upon an inflammatory stimulus, cerebellar levels of ABHD12 increase to possibly metabolize the heightened oxidized PS levels, temper phagocytosis and in turn control neuroinflammation during oxidative stress. Next, to complement these findings, using biochemical approaches in cultured microglial cells, we show that the pharmacological inhibition and/or genetic deletion of ABHD12 results in increased phagocytic uptake in a fluorescent bead uptake assay. Together, our studies provide compelling evidence that ABHD12 plays an important role in regulating phagocytosis in cerebellar microglial cells, and provides a possible explanation, as to why human PHARC subjects display neuroinflammation and atrophy in the cerebellum.

Keywords:  ABHD12; PHARC; cerebellum; lyso-PS; microglia; neuroinflammation; neurons; oxidized PS; phagocytosis

DOI:  https://doi.org/10.1111/ejn.15516
Cell Rep. 2021 Nov 02. pii: S2211-1247(21)01384-X. [Epub ahead of print]37(5): 109911

Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.

Maria I Matias, Carmen S Yong, Amir Foroushani, Chloe Goldsmith, Cédric Mongellaz, Erdinc Sezgin, Kandice R Levental, Ali Talebi, Julie Perrault, Anais Rivière, Jonas Dehairs, Océane Delos, Justine Bertand-Michel, Jean-Charles Portais, Madeline Wong, Julien C Marie, Ameeta Kelekar, Sandrina Kinet, Valérie S Zimmermann, Ilya Levental, Laurent Yvan-Charvet, Johannes V Swinnen, Stefan A Muljo, Hector Hernandez-Vargas, Saverio Tardito, Naomi Taylor, Valérie Dardalhon.

  Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.

Keywords:  CAR T cells; DNA methylation; T cell differentiation; TCA cycle; Th1; Treg; lipidome; mitochondrial metabolism; triacylglyceride synthesis; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.celrep.2021.109911
J Agric Food Chem. 2021 Nov 02.

Cynaropicrin Induces Cell Cycle Arrest and Apoptosis by Inhibiting PKM2 to Cause DNA Damage and Mitochondrial Fission in A549 Cells.

Zhenjiang Ding, Junmin Xi, Miao Zhong, Fan Chen, Huanhuan Zhao, Baoxin Zhang, Jianguo Fang.

  Metabolic reprogramming is critical for tumorigenesis. Pyruvate kinase M2 (PKM2) is overexpressed in lung carcinoma cells and plays a critical role in the Warburg effect, making the enzyme a research hotspot for anticancer drug development. Cynaropicrin (CYN), a natural sesquiterpene lactone compound from artichoke, has received increasing consideration due to its consumable esteem and pharmacological properties. Our data reveal that CYN not only inhibited the purified PKM2 activity but also decreased the cellular PKM2 expression in A549 cells. The inhibition of PKM2 leads to the upregulation of p53 and the downregulation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP), and subsequently causes the cell cycle arrest. Additionally, CYN inhibits the interaction of PKM2 and Nrf2, resulting in the impairment of cellular antioxidant capacity, induction of oxidative stress, and mitochondrial damages. Overexpression of PKM2 attenuates the CYN-induced DNA damage, mitochondrial fission, and cell viability. Thus, targeting PKM2 provides an original mechanism for understanding the pharmacological impact of CYN and assists in the further development of CYN as an anticancer agent.

Keywords:  apoptosis; cell cycle arrest; cynaropicrin; mitochondrial damage; pyruvate kinase M2

DOI:  https://doi.org/10.1021/acs.jafc.1c05394
Cell Death Dis. 2021 Nov 02. 12(11): 1044

A gene toolbox for monitoring autophagy transcription.

Matteo Bordi, Rossella De Cegli, Beatrice Testa, Ralph A Nixon, Andrea Ballabio, Francesco Cecconi.

Autophagy is a highly dynamic and multi-step process, regulated by many functional protein units. Here, we have built up a comprehensive and up-to-date annotated gene list for the autophagy pathway, by combining previously published gene lists and the most recent publications in the field. We identified 604 genes and created main categories: MTOR and upstream pathways, autophagy core, autophagy transcription factors, mitophagy, docking and fusion, lysosome and lysosome-related genes. We then classified such genes in sub-groups, based on their functions or on their sub-cellular localization. Moreover, we have curated two shorter sub-lists to predict the extent of autophagy activation and/or lysosomal biogenesis; we next validated the "induction list" by Real-time PCR in cell lines during fasting or MTOR inhibition, identifying ATG14, ATG7, NBR1, ULK1, ULK2, and WDR45, as minimal transcriptional targets. We also demonstrated that our list of autophagy genes can be particularly useful during an effective RNA-sequencing analysis. Thus, we propose our lists as a useful toolbox for performing an informative and functionally-prognostic gene scan of autophagy steps.

DOI: https://doi.org/10.1038/s41419-021-04121-9