Optical boost of mitochondrial respiration and free calcium via their intrinsic photosensitivity

Targeting mitochondria, numerous pharmacological stimulants and activators designed to promote respiration have been developed. Mitochondria are also intrinsic photosensitizers, primarily due to their highly abundant flavoproteins (FPs) that can absorb blue light and play a crucial role in the electron transport chain (ETC). In this study, we report an optical method to promote the ETC and respiration by a specific two-photon excitation of mitochondrial intrinsic FPs. This excitation enhances the pumping of H+ out of the mitochondrial matrix, thus leading to its alkalization and facilitating the respiration promotion, which triggers a transient local free mitochondrial Ca2+ (mitoCa2+) flash. The mitoCa2+ flash activates mitochondrial K+ channels and the Na+/Ca2+ exchanger, thereby inducing the influx of K+, Na+, and H2O into the mitochondrial matrix and further inducing rapid and restorable fragmentations of the inner mitochondrial membrane. Our findings describe an optical method to promote respiration and provide insights into the regulatory mechanisms linking respiration and mitoCa2+.