Fig 1: Mitochondria-related signaling responses to extreme HBO2. HBO2 increases brain tissue PO2 leading to amplified production of oxidants, i.e., superoxide (·O2-), hydrogen peroxide (H2O2), and hydroxyl (·OH) that target nuclear and mitochondrial DNA resulting in inflammation. The brain immediately activates antioxidant and anti-inflammation defenses that are linked to mitophagy and mitochondrial biogenesis programs. TGB prevents cerebral hyperemia and a further increase in brain tissue PO2 that delays neuroexcitation. The result is less oxidant damage and inflammation that may reduce mitophagy flux and mitochondrial biogenesis signaling. HO-1, heme oxygenase 1 (antioxidant/anti-inflammation); SOD2, manganese-dependent superoxide dismutase (mitochondrial antioxidant); PINK1, PTEN-induced kinase 1 (mitophagy initiation); FIP200, focal adhesion kinase family interacting protein of 200 kD (phagophore formation); ATG9A, autophagy-related protein 9A (phagophore growth); LC3-II, conjugated microtubule-associated protein 1A/1B-light chain 3 (autophagosome-lysosome fusion); p-CREB, phosphorylated cyclic-AMP responsive element binding protein (mitochondrial biogenesis); PGC-1a, peroxisome proliferator-activated receptor ? coactivator 1-a (mitochondrial biogenesis); NRF-1, nuclear respiratory 1 (transcriptional activation of TFAM); and TFAM, mitochondrial transcription factor A (mitochondrial DNA transcription, replication, and packaging).