bims-nenemi 2023-10-01 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2023–10–01
eight papers selected by
Marco Tigano, Thomas Jefferson University

Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.
Novel insights into double-stranded RNA-mediated immunopathology.
Cellular Stress: Modulator of Regulated Cell Death.
Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease.
Caspase-3 cleaved tau impairs mitochondrial function through the opening of the mitochondrial permeability transition pore.
Genotype-specific precision tumor therapy using mitochondrial DNA mutation-induced drug release system.
Multi-Omics Analyses Reveal Mitochondrial Dysfunction Contributing to Temozolomide Resistance in Glioblastoma Cells.
Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.

Nat Cell Biol. 2023 Sep 28.

Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.

Nicholas J Kramer, Gyan Prakash, R Stefan Isaac, Karine Choquet, Iliana Soto, Boryana Petrova, Hope E Merens, Naama Kanarek, L Stirling Churchman.

Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed fluorescence-activated cell-sorting-based genome-wide screens analysing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, whereas NME6, an uncharacterized nucleoside diphosphate kinase, controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. Firstly, NME6 forms a complex with RCC1L, which together perform nucleoside diphosphate kinase activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Secondly, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.

DOI: https://doi.org/10.1038/s41556-023-01244-3
Nat Rev Immunol. 2023 Sep 26.

Novel insights into double-stranded RNA-mediated immunopathology.

Richard de Reuver, Jonathan Maelfait.

Recent progress in human and mouse genetics has transformed our understanding of the molecular mechanisms by which recognition of self double-stranded RNA (self-dsRNA) causes immunopathology. Novel mouse models recapitulate loss-of-function mutations in the RNA editing enzyme ADAR1 that are found in patients with Aicardi-Goutières syndrome (AGS) - a monogenic inflammatory disease associated with increased levels of type I interferon. Extensive analyses of the genotype-phenotype relationships in these mice have now firmly established a causal relationship between increased intracellular concentrations of endogenous immunostimulatory dsRNA and type I interferon-driven immunopathology. Activation of the dsRNA-specific immune sensor MDA5 perpetuates the overproduction of type I interferons, and chronic engagement of the interferon-inducible innate immune receptors PKR and ZBP1 by dsRNA drives immunopathology by activating an integrated stress response or by inducing excessive cell death. Biochemical and genetic data support a role for the p150 isoform of ADAR1 in the cytosol in suppressing the spontaneous, pathological response to self-dsRNA.

DOI: https://doi.org/10.1038/s41577-023-00940-3
Biology (Basel). 2023 Aug 25. pii: 1172. [Epub ahead of print]12(9):

Cellular Stress: Modulator of Regulated Cell Death.

Prem Prasad Lamichhane, Parimal Samir.

  Cellular stress response activates a complex program of an adaptive response called integrated stress response (ISR) that can allow a cell to survive in the presence of stressors. ISR reprograms gene expression to increase the transcription and translation of stress response genes while repressing the translation of most proteins to reduce the metabolic burden. In some cases, ISR activation can lead to the assembly of a cytoplasmic membraneless compartment called stress granules (SGs). ISR and SGs can inhibit apoptosis, pyroptosis, and necroptosis, suggesting that they guard against uncontrolled regulated cell death (RCD) to promote organismal homeostasis. However, ISR and SGs also allow cancer cells to survive in stressful environments, including hypoxia and during chemotherapy. Therefore, there is a great need to understand the molecular mechanism of the crosstalk between ISR and RCD. This is an active area of research and is expected to be relevant to a range of human diseases. In this review, we provided an overview of the interplay between different cellular stress responses and RCD pathways and their modulation in health and disease.

Keywords:  GCN2; HRI; PERK; PKR; apoptosis; integrated stress response; necroptosis; programmed cell death; pyroptosis; stress granules

DOI:  https://doi.org/10.3390/biology12091172
Life (Basel). 2023 Sep 03. pii: 1863. [Epub ahead of print]13(9):

Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease.

Paola Loguercio Polosa, Francesco Capriglia, Francesco Bruni.

  In mammalian mitochondria, the processing of primary RNA transcripts involves a coordinated series of cleavage and modification events, leading to the formation of processing intermediates and mature mt-RNAs. RNA19 is an unusually stable unprocessed precursor, physiologically polyadenylated, which includes the 16S mt-rRNA, the mt-tRNALeuUUR and the mt-ND1 mRNA. These peculiarities, together with the alteration of its steady-state levels in cellular models with defects in mitochondrial function, make RNA19 a potentially important molecule for the physiological regulation of mitochondrial molecular processes as well as for the pathogenesis of mitochondrial diseases. In this work, we quantitatively and qualitatively examined RNA19 in MELAS trans-mitochondrial cybrids carrying the mtDNA 3243A>G transition and displaying a profound mitochondrial translation defect. Through a combination of isokinetic sucrose gradient and RT-qPCR experiments, we found that RNA19 accumulated and co-sedimented with the mitoribosomal large subunit (mt-LSU) in mutant cells. Intriguingly, exogenous expression of the isolated LARS2 C-terminal domain (Cterm), which was shown to rescue defective translation in MELAS cybrids, decreased the levels of mt-LSU-associated RNA19 by relegating it to the pool of free unbound RNAs. Overall, the data reported here support a regulatory role for RNA19 in mitochondrial physiopathological processes, designating this RNA precursor as a possible molecular target in view of therapeutic strategy development.

Keywords:  Cterm; LARS2; MELAS; RNA19; mitochondrial disease; mitochondrial translation; mitoribosome; mt-RNA processing; trans-mitochondrial cybrids

DOI:  https://doi.org/10.3390/life13091863
Biochim Biophys Acta Mol Basis Dis. 2023 Sep 27. pii: S0925-4439(23)00264-8. [Epub ahead of print] 166898

Caspase-3 cleaved tau impairs mitochondrial function through the opening of the mitochondrial permeability transition pore.

María José Pérez, Rodrigo Ibarra-García-Padilla, Maoping Tang, George A Porter, Gail V W Johnson, Rodrigo A Quintanilla.

  Mitochondrial dysfunction is a significant factor in the development of Alzheimer's disease (AD). Previous studies have demonstrated that the expression of tau cleaved at Asp421 by caspase-3 leads to mitochondrial abnormalities and bioenergetic impairment. However, the underlying mechanism behind these alterations and their impact on neuronal function remains unknown. To investigate the mechanism behind mitochondrial dysfunction caused by this tau form, we used transient transfection and pharmacological approaches in immortalized cortical neurons and mouse primary hippocampal neurons. We assessed mitochondrial morphology and bioenergetics function after expression of full-length tau and caspase-3-cleaved tau. We also evaluated the mitochondrial permeability transition pore (mPTP) opening and its conformation as a possible mechanism to explain mitochondrial impairment induced by caspase-3 cleaved tau. Our studies showed that pharmacological inhibition of mPTP by cyclosporine A (CsA) prevented all mitochondrial length and bioenergetics abnormalities in neuronal cells expressing caspase-3 cleaved tau. Neuronal cells expressing caspase-3-cleaved tau showed sustained mPTP opening which is mostly dependent on cyclophilin D (CypD) protein expression. Moreover, the impairment of mitochondrial length and bioenergetics induced by caspase-3-cleaved tau were prevented in hippocampal neurons obtained from CypD knock-out mice. Interestingly, previous studies using these mice showed a prevention of mPTP opening and a reduction of mitochondrial failure and neurodegeneration induced by AD. Therefore, our findings showed that caspase-3-cleaved tau negatively impacts mitochondrial bioenergetics through mPTP activation, highlighting the importance of this channel and its regulatory protein, CypD, in the neuronal damage induced by tau pathology in AD.

Keywords:  Alzheimer's disease; Cyclophilin D; Mitochondria; Mitochondrial permeability pore; Tau

DOI:  https://doi.org/10.1016/j.bbadis.2023.166898
Sci Adv. 2023 Sep 29. 9(39): eadi1965

Genotype-specific precision tumor therapy using mitochondrial DNA mutation-induced drug release system.

Yanan Li, Ru Xu, Yonghua Wu, Jialing Guo, Fenglei Quan, Yiran Pei, Di Huang, Xiu Zhao, Hua Gao, Junjie Liu, Zhenzhong Zhang, Jinjin Shi, Kaixiang Zhang.

Precise killing of tumor cells without affecting surrounding normal cells is a challenge. Mitochondrial DNA (mtDNA) mutations, a common genetic variant in cancer, can directly affect metabolic homeostasis, serving as an ideal regulatory switch for precise tumor therapy. Here, we designed a mutation-induced drug release system (MIDRS), using the single-nucleotide variation (SNV) recognition ability and trans-cleavage activity of Cas12a to convert tumor-specific mtDNA mutations into a regulatory switch for intracellular drug release, realizing precise tumor cell killing. Using Ce6 as a model drug, MIDRS enabled organelle-level photodynamic therapy, triggering innate and adaptive immunity simultaneously. In vivo evaluation showed that MIDRSMT could identify tumor tissue carrying SNVs in mtDNA in unilateral, bilateral, and heterogeneous tumor models, producing an excellent antitumor effect (~82.6%) without affecting normal cells and thus resulting in a stronger systemic antitumor immune response. Additionally, MIDRS was suitable for genotype-specific precision drug release of chemotherapeutic drugs. This strategy holds promise for mutation-specific personalized tumor treatment approaches.

DOI: https://doi.org/10.1126/sciadv.adi1965
Biomolecules. 2023 09 19. pii: 1408. [Epub ahead of print]13(9):

Multi-Omics Analyses Reveal Mitochondrial Dysfunction Contributing to Temozolomide Resistance in Glioblastoma Cells.

Huaijin Zhang, Yuling Chen, Xiaohui Liu, Haiteng Deng.

  Glioblastoma (GBM) is the most common and aggressive malignant brain tumor with poor prognosis. Temozolomide (TMZ) is the standard chemotherapy for glioblastoma treatment, but TMZ resistance significantly compromises its efficacy. In the present study, we generated a TMZ-resistant cell line and identified that mitochondrial dysfunction was a novel factor contributing to TMZ resistance though multi-omics analyses and energy metabolism analysis. Furthermore, we found that rotenone treatment induced TMZ resistance to a certain level in glioblastoma cells. Notably, we further demonstrated that elevated Ca2+ levels and JNK-STAT3 pathway activation contributed to TMZ resistance and that inhibiting JNK or STAT3 increases susceptibility to TMZ. Taken together, our results indicate that co-administering TMZ with a JNK or STAT3 inhibitor holds promise as a potentially effective treatment for glioblastoma.

Keywords:  chemoresistance; glioblastoma; mitochondrial dysfunction; mitochondrial retrograde signaling; temozolomide

DOI:  https://doi.org/10.3390/biom13091408
Front Immunol. 2023 ;14 1243548

Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.

Bo-Ram Bang, Haruka Miki, Young Jun Kang.

  Macrophages play a critical role in the regulation of inflammation and tissue homeostasis. In addition to their vital functions for cell survival and physiology, mitochondria play a crucial role in innate immunity as a platform for the induction of inflammatory responses by regulating cell signaling and dynamics. Dynamin-related protein 1 (Drp1) plays a role in the induction of inflammatory responses and the subsequent development of various diseases. PGAM5 (phosphoglycerate mutase member 5) is a mitochondrial outer membrane phosphatase that dephosphorylates its substrate, Drp1. Previous studies showed that PGAM5 regulates the phosphorylation of Drp1 for the activation of NKT cells and T cells. However, it is not clear how PGAM5 regulates Drp1 activity for the induction of inflammation in macrophages. Here, we demonstrate that PGAM5 activity regulates the dephosphorylation of Drp1 in macrophages, leading to the induction of proinflammatory responses in macrophages. In TLR signaling, PGAM5 regulates the expression and production of inflammatory cytokines by regulating the activation of downstream signaling pathways, including the NF-κB and MAPK pathways. Upon LPS stimulation, PGAM5 interacts with Drp1 to form a complex, leading to the production of mtROS. Furthermore, PGAM5-Drp1 signaling promotes the polarization of macrophages toward a proinflammatory phenotype. Our study further demonstrates that PGAM5-Drp1 signaling promotes metabolic reprogramming by upregulating glycolysis and mitochondrial metabolism in macrophages. Altogether, PGAM5 signaling is a linker between alterations in Drp1-mediated mitochondrial dynamics and inflammatory responses in macrophages and may be a target for the treatment of inflammatory diseases.

Keywords:  inflammatory response; innate immunity; macrophages; metabolism; mitochondria; signaling/signaling pathways

DOI:  https://doi.org/10.3389/fimmu.2023.1243548