Fumarate hydratase as a metabolic regulator of immunity

Christian G Peace; Shane M O'Carroll; Luke A J O'Neill

doi:10.1016/j.tcb.2023.10.005

Fumarate hydratase as a metabolic regulator of immunity

Trends Cell Biol. 2023 Nov 6:S0962-8924(23)00209-X. doi: 10.1016/j.tcb.2023.10.005. Online ahead of print.

Authors

Christian G Peace¹, Shane M O'Carroll², Luke A J O'Neill²

Affiliations

¹ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. Electronic address: peacec@tcd.ie.
² School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.

PMID: 37940417
DOI: 10.1016/j.tcb.2023.10.005

Abstract

Tricarboxylic acid (TCA) cycle metabolites have been implicated in modulating signalling pathways in immune cells. Notable examples include succinate and itaconate, which have pro- and anti-inflammatory roles, respectively. Recently, fumarate has emerged as having specific roles in macrophage activation, regulating the production of such cytokines as interleukin (IL)-10 and type I interferons (IFNs). Fumarate hydratase (FH) has been identified as a control point. Notably, FH loss in different models and cell types has been found to lead to DNA and RNA release from mitochondria which are sensed by cytosolic nucleic acid sensors including retinoic acid-inducible gene (RIG)-I, melanoma differentiation-associated protein (MDA)5, and cyclic GMP-AMP synthase (cGAS) to upregulate IFN-β production. These findings may have relevance in the pathogenesis and treatment of diseases associated with decreased FH levels such as systemic lupus erythematosus (SLE) or FH-deficient kidney cancer.

Keywords: immunometabolism; innate immunity; interferon; mitochondria.

Publication types

Review