Figure 7.

(a) IDH3 catalyzes the oxidative decarboxylation of isocitrate, producing α-ketoglutarate and CO₂ while converting NAD⁺ to NADH (I). Because IDH3 activity is negatively regulated by its product CO₂ we conclude that under hypocapnic conditions IDH3 activity (II) and thus NADH production (III) rises. (b) Proposed sequence of events underlying Ca²⁺-dependent CO₂-sensing mechanism. Alveolar perfusion failure in ventilated lung regions, equivalent to a V_D/V_T increase, leads to alveolar hypocapnia (I). Alveolar hypocapnia elevates IDH3 activity via a feedback mechanism (II). In turn, NADH (III) production and ΔΨ (IV) increases leading to a calcium shift from cytosol into the mitochondrium (V). Further, the hypocapnia-induced mitochondrial Ca²⁺ uptake leads to mitochondrial ROS production (VI). Finally, the mitochondrial Ca²⁺ uptake and/or ROS production results in apoptosis