Mitochondrial membrane potential (ΔΨ_m) is a universal selective indicator of mitochondrial function and is known to play a central role in many human pathologies, such as diabetes mellitus, cancer and Alzheimer’s and Parkinson’s diseases. Here, we report the design, synthesis and several applications of mitochondria-activatable luciferin (MAL), a bioluminescent probe sensitive to ΔΨ_m, and partially to plasma membrane potential (ΔΨ_p), for non-invasive, longitudinal monitoring of ΔΨ_m in vitro and in vivo. We applied this new technology to evaluate the aging-related change of ΔΨ_m in mice and showed that nicotinamide riboside (NR) reverts aging-related mitochondrial depolarization, revealing another important aspect of the mechanism of action of this potent biomolecule. In addition, we demonstrated application of the MAL probe for studies of brown adipose tissue (BAT) activation and non-invasive in vivo assessment of ΔΨ_m in animal cancer models, opening exciting opportunities for understanding the underlying mechanisms and for discovery of effective treatments for many human pathologies.

线粒体膜电位 (Δ Ψ _m ) 是线粒体功能的通用选择性指标，已知在许多人类病理学中发挥着核心作用，例如糖尿病、癌症、阿尔茨海默病和帕金森病。在这里，我们报告了线粒体可激活荧光素（MAL）的设计、合成和几种应用，这是一种对 Δ Ψ _m敏感的生物发光探针，部分对质膜电位（Δ Ψ _p）敏感，用于非侵入性纵向监测 Δ Ψ _m体外和体内。我们应用这项新技术来评估小鼠体内与衰老相关的 Δ Ψ _m变化，结果表明烟酰胺核苷 (NR) 可逆转与衰老相关的线粒体去极化，揭示了这种有效生物分子作用机制的另一个重要方面。此外，我们还展示了 MAL 探针在动物癌症模型中棕色脂肪组织 (BAT) 激活研究和 Δ Ψ _m无创体内评估中的应用，为了解潜在机制和发现有效治疗方法提供了令人兴奋的机会对于许多人类疾病。