Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation

Chen, Xuyong; Sunkel, Benjamin D.; Wang, Meng; Kang, Siwen; Wang, Tingting; Gnanaprakasam, JN Rashida; Liu, Lingling; Cassel, Teresa; Scott, David A.; Muñoz-Cabello, Ana M.; López‐Barneo, José; Yang, Jun; Lane, Andrew N.; Xu, Gang; Fan, Teresa W.‐M.; Wang, Ruoning

doi:10.1126/sciimmunol.abm8161

Cited by 28 publications

(13 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, SDH acts as a key regulator in neurodegenerative disorders 140 , neuroendocrine tumors 141 , Chronic obstructive pulmonary disease 142 . In addition, SDH is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation, SDH deficiency induced a proinflammatory gene signature in T cells and promoted T helper 1 and T helper 17 lineage differentiation 143 .…”

Section: Mitochondrial Function In Cancer Cell Metabolismmentioning

confidence: 99%

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

Liu¹,

Sun²,

Guo³

et al. 2023

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Mitochondria are intracellular organelles involved in energy production, cell metabolism and cell signaling. They are essential not only in the process of ATP synthesis, lipid metabolism and nucleic acid metabolism, but also in tumor development and metastasis. Mutations in mtDNA are commonly found in cancer cells to promote the rewiring of bioenergetics and biosynthesis, various metabolites especially oncometabolites in mitochondria regulate tumor metabolism and progression. And mutation of enzymes in the TCA cycle leads to the unusual accumulation of certain metabolites and oncometabolites. Mitochondria have been demonstrated as the target for cancer treatment. Cancer cells rely on two main energy resources: oxidative phosphorylation (OXPHOS) and glycolysis. By manipulating OXPHOS genes or adjusting the metabolites production in mitochondria, tumor growth can be restrained. For example, enhanced complex I activity increases NAD + /NADH to prevent metastasis and progression of cancers. In this review, we discussed mitochondrial function in cancer cell metabolism and specially explored the unique role of mitochondria in cancer stem cells and the tumor microenvironment. Targeting the OXPHOS pathway and mitochondria-related metabolism emerging as a potential therapeutic strategy for various cancers.

show abstract

Section: Mitochondrial Function In Cancer Cell Metabolismmentioning

confidence: 99%

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

Liu¹,

Sun²,

Guo³

et al. 2023

Int. J. Biol. Sci.

View full text Add to dashboard Cite

show abstract

“…Therefore, it is conceivable that the carbon input from Glu or GAB may change the intracellular α-KG to succinate ratio reciprocally. Hence, the GABA shunt in T cells may impact the hypoxia signalling response and/or DNA/histone methylation patterns by modulating the enzymatic activities of the α-KG-dependent dioxygenase family [37][38][39][40] , and Glu and Put are highly abundant intracellular metabolites that can be secreted to the extracellular environment by T H 17 cells (Fig. 1a) 10,41 .…”

Section: Articlementioning

confidence: 99%

GAB functions as a bioenergetic and signalling gatekeeper to control T cell inflammation

et al. 2022

Self Cite

View full text Add to dashboard Cite

Abstractγ-Aminobutyrate (GAB), the biochemical form of (GABA) γ-aminobutyric acid, participates in shaping physiological processes, including the immune response. How GAB metabolism is controlled to mediate such functions remains elusive. Here we show that GAB is one of the most abundant metabolites in CD4+ T helper 17 (TH17) and induced T regulatory (iTreg) cells. GAB functions as a bioenergetic and signalling gatekeeper by reciprocally controlling pro-inflammatory TH17 cell and anti-inflammatory iTreg cell differentiation through distinct mechanisms. 4-Aminobutyrate aminotransferase (ABAT) funnels GAB into the tricarboxylic acid (TCA) cycle to maximize carbon allocation in promoting TH17 cell differentiation. By contrast, the absence of ABAT activity in iTreg cells enables GAB to be exported to the extracellular environment where it acts as an autocrine signalling metabolite that promotes iTreg cell differentiation. Accordingly, ablation of ABAT activity in T cells protects against experimental autoimmune encephalomyelitis (EAE) progression. Conversely, ablation of GABAA receptor in T cells worsens EAE. Our results suggest that the cell-autonomous control of GAB on CD4+ T cells is bimodal and consists of the sequential action of two processes, ABAT-dependent mitochondrial anaplerosis and the receptor-dependent signalling response, both of which are required for T cell-mediated inflammation.

show abstract

“…Previous studies have demonstrated the proinflammatory effects of succinate in macrophages and T cells ( 28 – 30 ). Our work also shows that accumulation of succinate within tumor cells is proinflammatory by increasing antigen presentation that activates T cell–mediated killing.…”

Section: Increasing Relative Electron Flow Through Mitochondrial CI E...mentioning

confidence: 99%

Manipulating mitochondrial electron flow enhances tumor immunogenicity

Mangalhara,

Varanasi,

Johnson

et al. 2023

Science

View full text Add to dashboard Cite

Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell–mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex–antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.

show abstract

Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation

Cited by 28 publications

References 86 publications

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

GAB functions as a bioenergetic and signalling gatekeeper to control T cell inflammation

Manipulating mitochondrial electron flow enhances tumor immunogenicity

Contact Info

Product

Resources

About