1. Mitochondrial biogenesis by the endogenous gases.
Mitochondrial biogenesis by the endogenous gases. Nitric oxide (NO) and carbon monoxide (CO) are generated enzymatically by the NOS (1-3) and HO (1-2) isoforms, respectively. H2S is generated enzymatically from l-cysteine. The mitochondrion is a common organelle target of all three gases. Pharmaceutical development has leveraged these systems to design exogenous molecules to simulate the endogenous gases. Illustrated are ROS pathways for CO (and H2S), activation of cGMP by NO (or CO), and phosphorylation of peroxisome proliferator-activated receptor gamma coactivator (PGC-1α) via PKA. ROS, mainly H2O2, can activate Akt, leading to NRF-1 phosphorylation and its nuclear translocation (CO, H2S and their releasing molecules). NRF-1, NRF-2, and other nuclear transcription factors (NTFs) are coactivated by PGC-1α, leading to transcription of nuclear-encoded mitochondrial proteins (NEMPs), such as mitochondrial transcription factor A (Tfam), needed to activate mtDNA transcription and replication. NEMPs are imported into mitochondria through multiple outer (Tom)- and inner (Tim)-membrane transport machinery, and the proteins are folded and assembled. For the outer membrane, fission through the dynamin-related protein 1 (DRP1) and for the inner membrane OPA1 allow mitochondrial division, whereas mitofusins (Mfn) regulate fusion. Dynamic control of fusion/fission allows for mitochondrial network organization. Damaged mitochondria are tagged by Park and Pink for ubiquitination (Ub) and elimination by mitophagy; CORM, CO-releasing molecule; HO-1, heme oxygenase-1; NOS, NO synthase; OXPHOS: oxidative phosphorylation; PKA protein kinase A; ROS, reactive oxygen species.
Hagir B. Suliman, and Claude A. Piantadosi Pharmacol Rev 2016;68:20-48
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