New Alkaloids from the Hydrothermal Vent-Derived Fungus Aspergillus clavatus C2WU and Their Mitochondrial Protective and Anti-Photoaging Effects

Four new compounds (1–4), including two new quinazoline-containing indole alkaloids, tryptoquivaline Z1 (1) and clavutoine V (2); a new cytochalasan alkaloid, cytochalasin Z29 (3); and methyl (S)-2-(2,5-dihydroxyphenyl)-2-methoxyacetate (4), along with one known compound (5), were isolated from culture extracts of the hydrothermal vent crab-derived fungus Aspergillus clavatus C2WU. The structures of the new compounds, including their absolute configurations, were determined by NMR and MS spectroscopic data analyses and comparison between the calculated and experimental ECD spectra. In vitro, compound 2 (clavutoine V) preserves mitochondrial function by reducing the level of mitochondrial membrane potential (MMP) and increasing mitochondrial ATP production. Furthermore, compound 2 might regulate lipid metabolism by reducing ROS. Complementary molecular dynamics simulations support a cardiolipin-associated membrane-modulation mechanism, suggesting that compound 2 may melt rigid lipid domains to restore membrane electrostatic homeostasis. Compounds 1 (tryptoquivaline Z1), 2 (clavutoine V), and 5 (arthriniumnin A) effectively attenuated UVB-induced mitochondrial dysfunction and ROS overproduction in skin cells, demonstrating their anti-photoaging potential. Additionally, compound 4 (methyl (S)-2-(2,5-dihydroxyphenyl)-2-methoxyacetate) displayed strong ability to scavenge free radicals with an IC50 value of 34.3 μM. It not only reduced UVB-induced ROS production in HaCaT cells but also attenuated glucose-induced AGE formation in HDF cells, further confirming its antioxidant capacity. These findings highlight the potential of hydrothermal vent-derived fungi as a source of bioactive leads for dermatological applications, anti-aging interventions, and mitochondrial medicine.