Mitochondrial Respiration Controls Lysosomal Function during Inflammatory T Cell Responses

Published on Sep 1, 2015in Cell Metabolism22.41
· DOI :10.1016/j.cmet.2015.07.020
Francesc Baixauli10
Estimated H-index: 10
(ISCIII: Instituto de Salud Carlos III),
Rebeca Acín-Pérez30
Estimated H-index: 30
(ISCIII: Instituto de Salud Carlos III)
+ 10 AuthorsMaría Mittelbrunn15
Estimated H-index: 15
(ISCIII: Instituto de Salud Carlos III)
Summary The endolysosomal system is critical for the maintenance of cellular homeostasis. However, how endolysosomal compartment is regulated by mitochondrial function is largely unknown. We have generated a mouse model with defective mitochondrial function in CD4 + T lymphocytes by genetic deletion of the mitochondrial transcription factor A (Tfam). Mitochondrial respiration deficiency impairs lysosome function, promotes p62 and sphingomyelin accumulation, and disrupts endolysosomal trafficking pathways and autophagy, thus linking a primary mitochondrial dysfunction to a lysosomal storage disorder. The impaired lysosome function in Tfam-deficient cells subverts T cell differentiation toward proinflammatory subsets and exacerbates the in vivo inflammatory response. Restoration of NAD + levels improves lysosome function and corrects the inflammatory defects in Tfam-deficient T cells. Our results uncover a mechanism by which mitochondria regulate lysosome function to preserve T cell differentiation and effector functions, and identify strategies for intervention in mitochondrial-related diseases.
  • References (42)
  • Citations (60)
Published on Mar 1, 2015in Immunity21.52
Samuel E. Weinberg11
Estimated H-index: 11
(NU: Northwestern University),
Laura A. Sena6
Estimated H-index: 6
(NU: Northwestern University),
Navdeep S. Chandel81
Estimated H-index: 81
(NU: Northwestern University)
Mitochondria are well appreciated for their role as biosynthetic and bioenergetic organelles. In the past two decades, mitochondria have emerged as signaling organelles that contribute critical decisions about cell proliferation, death, and differentiation. Mitochondria not only sustain immune cell phenotypes but also are necessary for establishing immune cell phenotype and their function. Mitochondria can rapidly switch from primarily being catabolic organelles generating ATP to anabolic organe...
Published on Mar 1, 2015in Nature Cell Biology17.73
Diego L. Medina21
Estimated H-index: 21
Simone Di Paola3
Estimated H-index: 3
+ 15 AuthorsAlison Forrester3
Estimated H-index: 3
Medina, Ballabio and colleagues report that calcium release from the lysosome stimulates calcineurin, which dephosphorylates and activates TFEB. These findings reveal a central role for calcium signalling in autophagy and lysosome homeostasis.
Published on Jan 2, 2015in Journal of Clinical Investigation12.28
Valerie A. Gerriets15
Estimated H-index: 15
(Duke University),
Rigel J. Kishton14
Estimated H-index: 14
(Duke University)
+ 19 AuthorsMarta E. Slawinska1
Estimated H-index: 1
Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and re...
Published on Jan 1, 2015in Neuroscience3.24
Feng Wu1
Estimated H-index: 1
(Soochow University (Taiwan)),
H-D Xu1
Estimated H-index: 1
(Soochow University (Taiwan))
+ 4 AuthorsZheng-Hong Qin2
Estimated H-index: 2
(Soochow University (Taiwan))
Abstract Background Rotenone is an environmental neurotoxin that induces accumulation of α-synuclein and degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc), but the molecular mechanisms are not fully understood. We investigated whether rotenone induced impairment of autophagic flux and lysosomal functions. Methods Autophagy flux, accumulation of α-synuclein, lysosomal membrane integrity and neurodegeneration were assessed in the rotenone-treated rat model and PC12 cell...
Published on Dec 1, 2014in Cell36.22
W. Lu60
Estimated H-index: 60
(NIH: National Institutes of Health),
Yu Zhang18
Estimated H-index: 18
(NIH: National Institutes of Health)
+ 23 AuthorsJeremy H. Lakey47
Estimated H-index: 47
(Newcastle University)
Proteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cell...
Published on Dec 1, 2014in Nature Medicine30.64
Ana Paula Arruda19
Estimated H-index: 19
Benedicte Mengel Pers3
Estimated H-index: 3
+ 3 AuthorsGökhan S. Hotamisligil99
Estimated H-index: 99
(Harvard University)
Obesity-induced mitochondria stress and dysfunction results from disorganized mitochondria-associated ER membranes and excess calcium flux.
Published on Nov 1, 2014in Nature Immunology23.53
Rut Valdor1
Estimated H-index: 1
(Yeshiva University),
Enric Mocholi1
Estimated H-index: 1
(Yeshiva University)
+ 6 AuthorsFernando Macian26
Estimated H-index: 26
Chaperone-mediated autophagy selectively targets single cytoplasmic proteins for degradation. Macian and colleagues show that such autophagy is induced by engagement of the TCR to target negative regulators of T cell activation.
Published on Jul 1, 2014in Developmental Cell9.19
Carina Hönscher4
Estimated H-index: 4
(University of Osnabrück),
Muriel Mari27
Estimated H-index: 27
+ 7 AuthorsChristian Ungermann45
Estimated H-index: 45
(University of Osnabrück)
Summary Emerging evidence suggests that contact sites between different organelles form central hubs in the coordination of cellular physiology. Although recent work has emphasized the crucial role of the endoplasmic reticulum in interorganellar crosstalk, the cooperative behavior of other organelles is largely unexplored. Here, we identify a contact site named vCLAMP ( v a c uo l e a nd m itochondria p atch) that integrates mitochondria with the lysosome-like vacuole and thus the endocytic path...
Published on Jul 1, 2014in Developmental Cell9.19
Yael Elbaz-Alon5
Estimated H-index: 5
(Weizmann Institute of Science),
Eden Rosenfeld-Gur3
Estimated H-index: 3
(Weizmann Institute of Science)
+ 3 AuthorsMaya Schuldiner32
Estimated H-index: 32
(Weizmann Institute of Science)
Summary Cellular life depends on continuous transport of lipids and small molecules between mitochondria and the endomembrane system. Recently, endoplasmic reticulum-mitochondrial encounter structure (ERMES) was identified as an important yet nonessential contact for such transport. Using a high-content screen in yeast, we found a contact site, marked by Vam6/Vps39, between vacuoles (the yeast lysosomal compartment) and mitochondria, named vCLAMP ( v a c uo l e a nd m itochondria p atch). vCLAMP...
Published on Jun 1, 2014in Cell Metabolism22.41
Raffaele Cerutti6
Estimated H-index: 6
(MRC Mitochondrial Biology Unit),
Eija Pirinen20
Estimated H-index: 20
(EPFL: École Polytechnique Fédérale de Lausanne)
+ 9 AuthorsJohan Auwerx134
Estimated H-index: 134
(EPFL: École Polytechnique Fédérale de Lausanne)
Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD+-dependent protein deacetylase. As NAD+ boosts the activity of Sirtuin1 and ot...
Cited By60
Published on 2019in Biomaterials10.27
Yi Hu (JNU: Jinan University), Ting Liu (JNU: Jinan University)+ 7 AuthorsJunyi He1
Estimated H-index: 1
(Translational Research Institute)
Abstract Immune cell therapy presents a paradigm for the treatment of malignant tumors. Human Vγ9Vδ2 T cells, a subset of peripheral γδ T cells, have been shown to have promising anti-tumor activity. However, new methodology on how to achieve a stronger anti-tumor activity of Vγ9Vδ2 T cells is under continuous investigation. In this work, we used selenium nanoparticles (SeNPs) to strengthen the anti-tumor cytotoxicity of Vγ9Vδ2 T cells. We found SeNPs pretreated γδ T cells had significantly stro...
Published on Sep 23, 2019in bioRxiv
David A. Harris3
Estimated H-index: 3
(Brigham and Women's Hospital),
Amir Mina (BIDMC: Beth Israel Deaconess Medical Center)+ 5 AuthorsEric G. Sheu12
Estimated H-index: 12
(Brigham and Women's Hospital)
Objective: Sleeve gastrectomy (SG) induces weight-loss independent improvements in glucose homeostasis by unknown mechanisms. We sought to identify the metabolic adaptations responsible for these improvements. Methods: Non-obese C57Bl6/J mice on standard chow underwent SG or sham surgery. Functional testing and indirect calorimetry were used to capture metabolic phenotypes. Tissue-specific glucose uptake was assessed by 18-FDG PET/CT and RNA sequencing was used for gene expression analysis. Resu...
Published on 2019in bioRxiv
Justyna Okarmus1
Estimated H-index: 1
(University of Southern Denmark),
Helle Bogetofte1
Estimated H-index: 1
(University of Southern Denmark)
+ 5 AuthorsMorten Meyer21
Estimated H-index: 21
(University of Southern Denmark)
Mutations in the PARK2 gene encoding parkin, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinson9s disease (PD). While parkin has been implicated in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration in both sporadic and familial PD upon parkin loss-of-function mutations remains unknown. Cultures of isogenic induced pluripotent stem cell (iPSC) lines with and without PARK2 knockout (KO) enable mechanistic ...
Published on 2019in Nature Reviews Immunology44.02
Nicole M. Chapman9
Estimated H-index: 9
(St. Jude Children's Research Hospital),
Mark R. Boothby (VUMC: Vanderbilt University Medical Center), Hongbo Chi39
Estimated H-index: 39
(St. Jude Children's Research Hospital)
Naive T cells are actively maintained in a quiescent state that promotes their survival and persistence. On antigen stimulation, T cells exit quiescence to initiate clonal expansion and effector differentiation. Initial studies focused on the immune receptors and transcriptional regulators involved in T cell quiescence and activation, but recent findings highlight cell metabolism as a crucial regulator of these processes. Here we summarize these intrinsic metabolic programmes and also describe h...
Published on Jul 15, 2019in Molecular and Cellular Biochemistry2.88
Paresh Prajapati8
Estimated H-index: 8
(MSU: Maharaja Sayajirao University of Baroda),
Pooja Dalwadi1
Estimated H-index: 1
(MSU: Maharaja Sayajirao University of Baroda)
+ 9 AuthorsJoe E. Springer34
Estimated H-index: 34
(UK: University of Kentucky)
Antibiotics are the front-line treatment against many bacterial infectious diseases in human. The excessive and long-term use of antibiotics in human cause several side effects. It is important to understand the underlying molecular mechanisms of action of antibiotics in the host cell to avoid the side effects due to the prevalent uses. In the current study, we investigated the crosstalk between mitochondria and lysosomes in the presence of widely used antibiotics: erythromycin (ERM) and clindam...
Published on Jul 1, 2019in Cell Reports7.82
Zheng Fu (UF: University of Florida), Jian Ye2
Estimated H-index: 2
(UF: University of Florida)
+ 8 AuthorsNavdeep S. Chandel81
Estimated H-index: 81
(NU: Northwestern University)
Summary Regulatory T cells (Tregs) are pivotal for immune suppression. Cellular metabolism is important for Treg homeostasis and function. However, the exact role of mitochondrial respiration in Tregs remains elusive. Mitochondrial transcription factor A (Tfam) is essential for mitochondrial respiration and controls mitochondrial DNA replication, transcription, and packaging. Here, we show that genetic ablation of Tfam in Tregs impairs Treg maintenance in non-lymphoid tissues in the steady state...
Published on Jun 27, 2019in International Journal of Molecular Sciences4.18
Qin Chu , Yi Ding3
Estimated H-index: 3
+ 3 AuthorsJiuzhou Song16
Estimated H-index: 16
Mitochondria are crucial cellular organelles in eukaryotes and participate in many cell processes including immune response, growth development, and tumorigenesis. Marek’s disease (MD), caused by an avian alpha-herpesvirus Marek’s disease virus (MDV), is characterized with lymphomas and immunosuppression. In this research, we hypothesize that mitochondria may play roles in response to MDV infection. To test it, mitochondrial DNA (mtDNA) abundance and gene expression in immune organs were examine...
Published on Jun 1, 2019in Trends in Cell Biology16.59
Yvette C. Wong7
Estimated H-index: 7
(NU: Northwestern University),
Soojin Kim13
Estimated H-index: 13
(NU: Northwestern University)
+ 1 AuthorsDimitri Krainc47
Estimated H-index: 47
(NU: Northwestern University)
Mitochondrial and lysosomal function are intricately related and critical for maintaining cellular homeostasis, as highlighted by multiple diseases linked to dysfunction of both organelles. Recent work using high-resolution microscopy demonstrates the dynamic formation of inter-organelle membrane contact sites between mitochondria and lysosomes, allowing for their direct interaction in a pathway distinct from mitophagy or lysosomal degradation of mitochondrial-derived vesicles. Mitochondria–lyso...
Published on Jun 1, 2019in Biochimica et Biophysica Acta3.79
Kritarth Singh7
Estimated H-index: 7
(MSU: Maharaja Sayajirao University of Baroda),
Milton Roy4
Estimated H-index: 4
(MSU: Maharaja Sayajirao University of Baroda)
+ 8 AuthorsP. M. Chumakov26
Estimated H-index: 26
(EIMB: Engelhardt Institute of Molecular Biology)
Abstract An increased level of proinflammatory cytokines, including TNF-α in tumor microenvironment regulates the bioenergetic capacity, immune evasion and survival of cancer cells. Emerging evidences suggest that mitochondrial immune signaling proteins modulates mitochondrial bioenergetic capacity, in addition to the regulation of innate immune response. The optimal oxidative phosphorylation (OxPhos) capacity is required for the maintenance of functional lysosomes and autophagy flux. NLRX1, a m...
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