Sato, M.; Tanabu, D.; Torigoe, D.; Kadomatsu, T.; Taniwaka, K.; Ogata, Y.; Shiiba, I.; Suzuki, Y.; Inatome, R.; Tokuyama, T.; Takeiwa, T.; Inoue, S.; Kanai, E.; Hamano, T.; Hirata, H.; Kanamitsu, K.; Kusuhara, H.; Yokosuka, A.; Mimaki, Y.; Abe, H.; Oike, Y.; Yanagi, S.

Mitochondria play a central role in cellular energy metabolism and homeostasis, and their dysfunction is closely linked to the progression of age-related diseases. The mitochondrial ubiquitin ligase MITOL (also known as MARCHF5) is a key regulator of mitochondrial dynamics and function, and reduced MITOL expression in the mouse heart has been implicated in mitochondrial dysfunction and cardiac aging. In this study, we identified berberrubine as a compound that promotes MITOL expression and activates mitochondria. We further assembled a group of berberrubine-based compounds, including its quinoid form and a newly developed water-soluble derivative, and collectively named them \'Mitorubin\' as mitochondria-activating compounds with therapeutic potential. While conventional berberrubine has poor water solubility, the addition of acetic acid significantly improved its solubility, enabling formulation as a solution. Mitorubin enhanced MITOL expression in cultured cells, increased mitochondrial DNA content and expression of mitochondrial proteins, and promoted mitochondrial respiration. In a model of age-related cardiac dysfunction, oral administration of Mitorubin restored mitochondrial function, improved cardiac performance, suppressed myocardial hypertrophy, and alleviated pulmonary congestion. Moreover, Mitorubin did not shorten lifespan in aged mice and significantly extended lifespan in high-fat diet-fed mice, suggesting both safety and efficacy under chronic administration. These findings suggest that Mitorubin is a promising mitochondrial activator and may represent a novel therapeutic strategy for age-related diseases.