Figure 3: Mitochondrial Electron Transport Directionality Dictates Distinct ROS-Mediated Immune Responses.
(A) During forward electron transport, electrons flow from NADH to complex I, then to coenzyme Q (Q), complex III, cytochrome c, and finally to complex IV where oxygen is reduced to water. Complex III generates superoxide (O2−•) that is released into the intermembrane space (IMS) and the matrix. Complex III-derived ROS is essential for both transcriptional regulation of IL-10 through activating transcription factors and post-translational control of IL-10 secretion. (B) Reverse electron transport (RET) occurs under conditions of high protonmotive force and a highly reduced coenzyme Q pool. When succinate accumulates and is oxidized by complex II (succinate dehydrogenase), electrons flow to coenzyme Q. Due to the highly reduced state of the Q pool and elevated membrane potential, electrons can flow backwards into complex I, leading to superoxide production into the matrix. RET-derived ROS promotes gasdermin D (GSDMD) activation, enhancing its pore-forming activity and facilitating the release of pro-inflammatory cytokines such as IL-1β.