FIG. 6.

Inflammation can drive mitochondria toward fission, with severe consequences to mitochondrial function and cell survival: a simplified model. The protein phosphatase upregulated via NR4A1 has not yet been identified; pAMPK dephosphorylation is known for PP1, PP2A, and PP2C. The model is restricted to the best understood details regarding fission and may have to be expanded by additional routes and factors. Additional mitochondrial effects of inflammation regarding ^•NO and its derivatives, ROS, the GSSG/GSH balance, and DAMP factors have been omitted. In this model, the counteraction by melatonin has been restricted to the mitigation of the cytokine storm, which is sufficiently documented. Upregulation of SIRT1 and, perhaps, SIRT3 by melatonin is indicated, but it remains uncertain whether this effect can prevail over the NAD⁺-dependent regulation. DAMP, damage-associated molecular pattern; GSH, reduced glutathione; GSSG, oxidized glutathione; mtPTP, mitochondrial permeability transition pore; NR4A1, nuclear receptor subfamily 4, group A, member 1; ROS, reactive oxygen species.