What Lies at the Heart of Photobiomodulation: Light, Cytochrome C Oxidase, and Nitric Oxide—Review of the Evidence

Objective: The underlying mechanisms of photobiomodulation (PBM) remain elusive. The most attractive hypotheses revolve around the role of cytochrome c oxidase (CCO) and cellular energetics. Background: No reliable demonstration of any PBM-related light-induced mechanistic effect on CCO has been reported. Studies on PBM have proven to be either nonreproducible, of questionable relevance, or involve wavelengths unlikely to be operative in vivo. The literature reveals very few demonstrable mechanistic light effects of any sort on CCO. Nitric oxide (NO) is involved in a number of the reported light effects on CCO. NO inhibits CCO at high reductive pressures by binding to the heme a(3) moiety. This complex is white light labile. Methods: The reported photolability of the heme–NO complex seems to be a prime target for PBM studies, as removal of inhibiting NO from the active site of CCO could restore normal activity to inhibited CCO. Another aspect of CCO–NO chemistry has been revealed that shows intriguing possibilities. Results: A novel nitrite reductase activity of solubilized mitochondria has been demonstrated attributable to CCO. NO production was optimal under hypoxic conditions. It was also found that 590 nm irradiation increased NO production by enhancing NO release. The presence of cellular NO has usually been considered metabolically detrimental, but current thinking has expanded the importance and the physiological roles of NO. Evidence shows that NO production is likely to play a role in cardioprotection and defenses against hypoxic damage. Conclusions: Studies combining PBM and hypoxia also point to a connection between light irradiation, hypoxia protection, and NO production. This leads the authors to the possibility that the intrinsic nature of PBM involves the production of NO. The combination of CCO and hemoglobin/myoglobin NO production with photorelease of NO may constitute the heart of PBM.