Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line

Moris Sangineto; Martina Ciarnelli; Archana Moola; Vidyasagar Naik Bukke; Tommaso Cassano; Rosanna Villani; Antonino D Romano; Giuseppe Di Gioia; Carlo Avolio; Gaetano Serviddio

doi:10.1016/j.mito.2024.101966

Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line

Mitochondrion. 2024 Sep 12:79:101966. doi: 10.1016/j.mito.2024.101966. Online ahead of print.

Affiliations

¹ Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. Electronic address: moris.sangineto@unifg.it.
² Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
³ Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
⁴ Neurology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

PMID: 39276907
DOI: 10.1016/j.mito.2024.101966

Abstract

Metabolic reprogramming drives inflammatory activity in macrophages, including microglia, with Krebs cycle (KC) intermediates playing a crucial role as signaling molecules. Here, we show that the bioenergetic profile of LPS-activated human microglialclone 3 cell line (HMC3) is characterized by high levels of glycolysis and mitochondrial (mt) respiration, and the treatment with KC derivatives, namely dimethyl-fumarate (DMF) and itaconate (ITA), almost restores normal metabolism. However, despite comparable bioenergetic and anti-inflammatory effects, the mt hyper-activity was differentially modulated by DMF and ITA. DMF normalized complex I activity, while ITA dampened both complex I and II hyper-activity counteracting oxidative stress more efficiently.

Keywords: Dimethyl fumarate; Immunometabolism; Itaconate; Krebs cycle; Microglia; Mitochondria.