bims-mitinf 2019-02-24 papers

Issue of 2019‒02‒24
four papers selected by
Prafull Kumar Singh
University of Freiburg Medical Center

Cell Metab. 2019 Feb 12. pii: S1550-4131(19)30019-1. [Epub ahead of print]

Calcium Signaling Controls Pathogenic Th17 Cell-Mediated Inflammation by Regulating Mitochondrial Function.

Ulrike Kaufmann, Sascha Kahlfuss, Jun Yang, Elitza Ivanova, Sergei B Koralov, Stefan Feske.

Pathogenic Th17 cells play important roles in many autoimmune and inflammatory diseases. Their function depends on T cell receptor (TCR) signaling and cytokines that activate signal transducer and activator of transcription 3 (STAT3). TCR engagement activates stromal interaction molecule 1 (STIM1) and calcium (Ca2+) influx through Ca2+-release-activated Ca2+ (CRAC) channels. Here, we show that abolishing STIM1 and Ca2+ influx in T cells expressing a hyperactive form of STAT3 (STAT3C) attenuates pathogenic Th17 cell function and inflammation associated with STAT3C expression. Deletion of STIM1 in pathogenic Th17 cells reduces the expression of genes required for mitochondrial function and oxidative phosphorylation (OXPHOS) but enhances reactive oxygen species (ROS) production. STIM1 deletion or inhibition of OXPHOS is associated with a non-pathogenic Th17 gene expression signature and impaired pathogenic Th17 cell function. Our findings establish Ca2+ influx as a critical regulator of mitochondrial function and oxidative stress in pathogenic Th17 cell-mediated multiorgan inflammation.

Keywords: Ca2+; ETC; IL-17; OXPHOS; ROS; SOCE; STAT3; STIM1; Th17; airway inflammation; antioxidant; calcium; colitis; electron transport chain; metabolism; mitochondria; oxidative phosphorylation; pathogenic T helper 17 cells; reactive oxygen species; store-operated calcium entry

DOI: https://doi.org/10.1016/j.cmet.2019.01.019

Mol Cell. 2019 Feb 01. pii: S1097-2765(19)30013-9. [Epub ahead of print]

PINK1 Inhibits Local Protein Synthesis to Limit Transmission of Deleterious Mitochondrial DNA Mutations.

Yi Zhang, Zong-Heng Wang, Yi Liu, Yong Chen, Nuo Sun, Marjan Gucek, Fan Zhang, Hong Xu.

We have previously proposed that selective inheritance, the limited transmission of damaging mtDNA mutations from mother to offspring, is based on replication competition in Drosophila melanogaster. This model, which stems from our observation that wild-type mitochondria propagate much more vigorously in the fly ovary than mitochondria carrying fitness-impairing mutations, implies that germ cells recognize the fitness of individual mitochondria and selectively boost the propagation of healthy ones. Here, we demonstrate that the protein kinase PINK1 preferentially accumulates on mitochondria enriched for a deleterious mtDNA mutation. PINK1 phosphorylates Larp to inhibit protein synthesis on the mitochondrial outer membrane. Impaired local translation on defective mitochondria in turn limits the replication of their mtDNA and hence the transmission of deleterious mutations to the offspring. Our work confirms that selective inheritance occurs at the organelle level during Drosophila oogenesis and provides molecular entry points to test this model in other systems.

Keywords: AKAP1; DNA replication; Larp1; PINK1; local protein synthesis; mitochondria; mitochondrial quality control; mtDNA; oogenesis; selective inheritance

DOI: https://doi.org/10.1016/j.molcel.2019.01.013

Nat Cell Biol. 2019 Feb 18.

NAD+ metabolism governs the proinflammatory senescence-associated secretome.

Timothy Nacarelli, Lena Lau, Takeshi Fukumoto, Joseph Zundell, Nail Fatkhutdinov, Shuai Wu, Katherine M Aird, Osamu Iwasaki, Andrew V Kossenkov, David Schultz, Ken-Ichi Noma, Joseph A Baur, Zachary Schug, Hsin-Yao Tang, David W Speicher, Gregory David, Rugang Zhang.

Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+ metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.

DOI: https://doi.org/10.1038/s41556-019-0287-4

Front Immunol. 2019 ;10 103

Cell-Free Mitochondrial DNA in the CSF: A Potential Prognostic Biomarker of Anti-NMDAR Encephalitis.

Yu Peng, Dong Zheng, Xiaomei Zhang, Suyue Pan, Teng Ji, Jun Zhang, Hai-Ying Shen, Hong-Hao Wang.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune inflammatory brain disease that can develop a variety of neuropsychiatric presentations. However, the underlying nature of its inflammatory neuronal injury remains unclear. Mitochondrial DNA (mtDNA) is recently regarded as a damage-associated molecular pattern molecule (DAMP) that can initiate an inflammatory response. In the presenting study, we aimed to evaluate the levels of cell-free mtDNA in cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis and to determine a potential role of cell-free mtDNA in the prognosis of anti-NMDAR encephalitis. A total of 33 patients with NMDAR encephalitis and 17 patients with other non-inflammatory disorders as controls were included in this study. The CSF levels of cell-free mtDNA were measured by quantitative polymerase chain reaction (qPCR). Cytokines including interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNF-α) were measured by ELISA. The modified Rankin scale (mRS) score was evaluated for neurologic disabilities. Our data showed that the CSF levels of cell-free mtDNA and inflammation-associated cytokines were significantly higher in the patients with anti-NMDAR encephalitis compared with those in controls. Positive correlations were detected between the CSF levels of cell-free mtDNA and mRS scores of patients with anti-NMDAR encephalitis at both their admission and 6-month follow up. These findings suggest that the CSF level of cell-free mtDNA reflects the underlying neuroinflammatory process in patients with anti-NMDAR encephalitis and correlates with their clinical mRS scores. Therefore, cell-free mtDNA may be a potential prognostic biomarker for anti-NMDAR encephalitis.

Keywords: IL-10; IL-6; TNF-α; anti-NMDAR encephalitis; cell-free mitochondrial DNA; cerebrospinal fluid; cytokines; modified rankin scale

DOI: https://doi.org/10.3389/fimmu.2019.00103