GDF15 modifies NAD+ salvage pathway and dampens immune response in mitochondrial disease

Mitochondrial integrated stress response (ISRmt) is a main mammalian metabolic stress pathway, with local ISRmt and a systemic response via circulating metabokines GDF15 and FGF21 as early signs of the response in mitochondrial diseases. FGF21 has been reported to regulate ISRmt progression and nutrient homeostasis, but the roles of GDF15 have remained unclear. Here, we explored the effects of inactivation of FGF21 or GDF15 or them together in Deletor mice. These mice endogenously activate the full ISRmt and metabokines as part of their mitochondrial muscle disease. GDF15 inactivity upregulated the skeletal muscle enzyme NMRK2, which converts nicotinamide riboside (NR) to nicotinamide mononucleotide (NMN) and NAD+. FGF21 was required for glutathione homeostasis. GDF15 inactivation also induced immune cell invasion in the muscle, aggravated by FGF21 loss, suggesting synergistic anti-inflammatory effects. Our findings indicate that in addition to their systemic effects, FGF21 and GDF15 are autocrine controllers of redox homeostasis in mitochondrial disease muscle.