Exploring the Role of Mitochondrial Hydrogen Sulfide in Maintaining Polarity and mtDNA Integrity with a Multichannel Fluorescent Probe

Abnormal mitochondrial state has been implicated in the pathogenesis of various diseases including neurodegenerative disorders, myopathies, cardiovascular diseases, and cancers. Assessing mitochondrial functionality can be achieved by monitoring alterations in mitochondrial polarity and mitochondrial DNA (mtDNA) integrity, which serve as valuable biomarkers. Hydrogen sulfide (H2S), a gaseous signaling molecule, plays a regulatory role in mitochondrial respiratory chain activity, ATP synthesis, and calcium ion balance, thereby influencing cellular metabolism and signal transduction. Investigating the interplay between mitochondrial H2S, polarity, and mtDNA can enhance our understanding of the underlying regulatory mechanisms involved in H2S-mediated mitochondrial functions. To address this, we designed a mitochondria-targeted multichannel fluorescent probe, HNA, capable of cascaded detection of H2S and polarity, as well as parallel detection of mtDNA. The probe exhibited a significant turn-on response to H2S, emitting at approximately 604 nm, while the product HNAP demonstrated high sensitivity to polarity within the wavelength range of 526–591 nm. Additionally, the probe was able to bind to DNA, resulting in an enhanced long-wave emission at 668 nm. Facilitated by HNA, our study provides novel insights into the role of mitochondrial H2S in maintaining mitochondrial polarity and validates its protective effect on mtDNA through antioxidative mechanisms. Overall, this work proposes a potential therapeutic strategy for modulating the inflammatory process in mitochondrial-related diseases.