Fig. 7. Proposed role for complexes I and III in ROS generation as ischemia progresses.

Early ischemia impairs electron flow through ETC and causes a sudden increase in NADH [7–9], and a mild gradual increase in Ca²⁺ [7–9] and impairs complex I activity [13]. The increase in Ca²⁺ may increase NADH via the Krebs cycle and stimulate respiration (Table 1). More NADH leads to more electron flow through the impaired complex I and thus a mild increase in ROS [7–10]. Late ischemia causes a large increase in Ca²⁺ [7–9], accumulation of succinate [18, 19], and impaired complex III activity [13]. Excess Ca²⁺ causes mitochondrial membrane permeability [52, 67], Δψ depolarization which prevents reversed electron flow to complex I [38, 45] and the subsequent generation of NADH (Fig. 6B), and direct inhibition of the antioxidant systems [63]. Furthermore, the antioxidant enzymes may be lost due to increased membrane permeability [62]. This enhances ROS emission due to complex III impairment during late ischemia.