In tissues affected by mitochondrial disease, the ISR activates the mitochondrial 1-carbon pathway (Kühl et al., 2017; Tyynismaa et al., 2010; Bao et al., 2016; Nikkanen et al., 2016) and is thought to underlie secretion of the circulating cytokines fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15) that are under consideration as disease biomarkers (Lehtonen et al., 2016; Fujita et al., 2015; Yatsuga et al., 2015; Chung et al., 2017; Miyake et al., 2016; Restelli et al., 2018). The gene discussed is GDF15; the disease is mitochondrial disease.