Mitochondrial Oxidative Phosphorylation Regulates the Fate Decision between Pathogenic Th17 and Regulatory T Cells

Shin, Boyoung; Benavides, Gloria A.; Geng, Jianlin; Koralov, Sergei B.; Hu, Hui; Darley‐Usmar, Victor; Harrington, Laurie E.

doi:10.1016/j.celrep.2020.01.022

Cited by 123 publications

(104 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…OxPhos is most directly regulated by the activity and the amount of complexes I through V that carry it out (Hüttemann et al, 2007), but can also be affected by mitochondrial fusion (Rambold et al, 2015) and biogenesis (Le Bleu et al, 2014). Upregulation of OxPhos is known to be required for many important immune cell functions, such as B cell antibody production (Price et al, 2018), pathogenic T cell differentiation during autoimmunity (Shin et al, 2020), and CD8+ memory T cell development and expansion (van der Windt et al, 2012; van der Windt et al, 2013), T reg suppressive function (Angelin et al, 2017; Weinberg et al, 2019; Beir et al, 2015) and the maturation of anti-inflammatory macrophages (Vats et al, 2006). However, what genetic programs immune cells utilize to upregulate OxPhos remains unclear and how such shifts in metabolism could influence immune cell migration is unexplored.…”

Section: Introductionmentioning

confidence: 99%

A genetic program boosts mitochondrial function to power macrophage tissue invasion

Emtenani

Martin

Gyoergy

et al. 2021

Preprint

View full text Add to dashboard Cite

Metabolic adaptation to changing demands underlies homeostasis. During inflammation or metastasis, cells leading migration into challenging environments require an energy boost, however what controls this capacity is unknown. We identify a previously unstudied nuclear protein, Atossa, as changing metabolism in Drosophila melanogaster immune cells to promote tissue invasion. Atossa's vertebrate orthologs, FAM214A-B can fully substitute for Atossa, indicating functional conservation from flies to mammals. Atossa increases mRNA levels of Porthos, an unstudied RNA helicase and two metabolic enzymes, LKR/SDH and GR/HPR. Porthos increases translation of a gene subset, including those affecting mitochondrial functions, the electron transport chain, and metabolism. Respiration measurements and metabolomics indicate that Atossa and Porthos power up mitochondrial oxidative phosphorylation to produce sufficient energy for pioneer macrophages to forge a path into tissues. As increasing oxidative phosphorylation enables many crucial physiological responses, this unique genetic program may modulate a wide range of cellular behaviors beyond migration.

show abstract

Section: Introductionmentioning

confidence: 99%

A genetic program boosts mitochondrial function to power macrophage tissue invasion

Emtenani

Martin

Gyoergy

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Notably, another study showed that in vivo activated CD8 + T cells, in contrast to in vitro stimulation, operated at approximately 50% of maximal glycolysis and had decreased lactate production, particularly at the peak of their expansion phase, while displaying increased rates of oxidative metabolism [56]. Strikingly, increased OXPHOS favored differentiation to Th17 phenotype as TCRdependent induction of the Th17 transcription factor basic leucine zipper transcription factor TF-like (BATF) was partially regulated by mTORC1 activation, which required ATP-linked mitochondrial OXPHOS [57]. This effect might be partially dependent on mitochondria-driven ROS necessary to support TCR signaling for subsequent transition of quiescent naïve T cells into an activated state [58].…”

Section: Role Of Mitochondria In T Cell Effector Functionmentioning

confidence: 99%

T Cell Metabolism in Cancer Immunotherapy

et al. 2020

View full text Add to dashboard Cite

Immune checkpoint therapies aiming to enhance T cell responses have revolutionized cancer immunotherapy. However, although a small fraction of patients develops durable anti-tumor responses, the majority of patients display only transient responses, underlying the need for finding auxiliary approaches. Tumor microenvironment poses a major metabolic barrier to efficient anti-tumor T cell activity. As it is now well accepted that metabolism regulates T cell fate and function, harnessing metabolism may be a new strategy to potentiate T cell-based immunotherapies.

show abstract

“…5D; Supplementary Fig. S10F), both known to be involved in mitochondrial and oxidative metabolism 65,66 . Moreover, p53 and E2F4 were identified as the two common active regulons (Fig.…”

Section: Oxphos-dependent Resistance Of Aml Cells To Cytarabinementioning

confidence: 99%

Mitochondrial determinants of response and resistance to venetoclaxpluscytarabine duplet therapy in acute myeloid leukemia

Bosc

Gadaud

Bousard

et al. 2020

Preprint

View full text Add to dashboard Cite

The development of resistance to conventional and targeted therapy represents a major clinical barrier in treatment of acute myeloid leukemia (AML). We show that the resistance to cytarabine (AraC) and its associated mitochondrial phenotype were reversed by genetic silencing or pharmacological inhibition of BCL2 in a caspase-dependent manner. BCL2-inhibitor venetoclax (VEN) enhancement of AraC efficacy was independent of differentiation phenotype, a characteristic of response to another combination of VEN with hypomethylating agents (HMA). Furthermore, transcriptional profiles of patients with low response to VEN+AraC mirrored those of low responders to VEN+HMA in clinical trials. OxPHOS was found to be a patient stratification marker predictive of effective response to VEN+AraC but not to VEN+AZA. Importantly, whereas three cell subpopulations specifically emerged in VEN+AraC residual disease and were characterized by distinct developmental and transcriptional programs largely driven by MITF, E2F4 and p53 regulons, they each encoded proteins involved in assembly of NADH dehydrogenase complex. Notably, treatment of VEN+AraC-persisting AML cells with an ETCI inhibitor significantly increased the time-to-relapse in vivo. These findings provide the scientific rationale for new clinical trials of VEN+AraC combinations, especially in patients relapsing or non-responsive to chemotherapy, or after failure of frontline VEN+HMA regimen

show abstract

Mitochondrial Oxidative Phosphorylation Regulates the Fate Decision between Pathogenic Th17 and Regulatory T Cells

Cited by 123 publications

References 56 publications

A genetic program boosts mitochondrial function to power macrophage tissue invasion

A genetic program boosts mitochondrial function to power macrophage tissue invasion

T Cell Metabolism in Cancer Immunotherapy

Mitochondrial determinants of response and resistance to venetoclaxpluscytarabine duplet therapy in acute myeloid leukemia

Contact Info

Product

Resources

About