Itaconate

Question 1

How and where is itaconate synthesised?

Answer 1

Itaconate is synthesised by IRG1 out of aconitate and citrate in the mitochondrial matrix.

Question 2

For itaconate to be functional it must do one important thing, what?

Answer 2

For itaconate to be functional, it must cross the mitochondrial inner membrane to act on Nrf2 in the cytosol.

Question 3

Give the functional pathway of itaconate.

Answer 3

In response to LPS, in part through type 1 IFNs, itaconate is synthesised by IRG1. Subsequently, itaconate moves across the mitochondrial inner membrane to activate Nrf2 in the cytosol by alkylation of KEAP1 cysteine residues. KEAP1 normally associates with and promotes the degradation of Nrf2, but alkylation of KEAP1 cysteine residues allows newly synthesised Nrf2 to accumulate, migrate to the nucleus and activate a transcriptional anti-oxidant and anti-inflammatory program. This limits further inflammatory gene expression, and its own production by downregulating the IFN response.