Mitochondrial unfolded protein response (UPRmt)

The mtUPR appears to be initiated by the accumulation of reactive oxygen species (ROS) and mitochondrial precursor proteins in the cytosol. The ROS oxidize cysteine residues on DNAJA1, causing DNAJA1 to displace HSF1 from the chaperone HSPA1A,B (HSP70). HSF1 then transits to the nucleus, trimerizes, and activates expression of genes encoding chaperones.

The transcription factor ATF5, which is normally imported into mitochondria, instead accumulates in the cytosol and transits to the nucleus, where it acts with HSF1 to increase expression of chaperone genes. ATF5 may act downstream of HSF1, as ATF5 is not required to initiate the mtUPR.

ROS also activate the protein kinase AKT1 (PKB), which phosphorylates the estrogen receptor ESR1. Phosphorylated ESR1 transits to the nucleus and, independently of estrogen, activates the expression of HTRA2 (OMI), NRF1, and other genes involved in mitochondrial homeostasis as part of the mitochondrial unfolded response.

Through an uncharacterized mechanism, ROS cause increased expression of the deacetylase SIRT3, which directly or indirectly causes the deacetylation of the transcription factor FOXO3. Deacetylated FOXO3 in the nucleus increases expression of the antioxidant enzymes mitochondrial superoxide dismutase (SOD2, MnSOD) and peroxisomal catalase (CAT) in the mitochondrial unfolded response.

Though ATF4 and CHOP are also key regulators of the mtUPR, the mechanisms that activate them in response to unfolded protein are not well characterized and may involve the phosphorylation of the EIF2S1 subunit of the translation factor eIF2alpha; however, none of the four known EIF2S1 kinases (GCN2, HRI, PERK, and PKR) are required for activation of CHOP.