Respirometry‐Based Screening of Marine Natural Products Identifies Leptochelin A as a Novel Modulator of Mitochondrial Function

While mitochondria are recognized as promising therapeutic targets for common pathologies of aging, existing drug discovery platforms fail to capture the adequate physiological and biological contexts necessary to identify translatable, clinically-relevant leads. The goal of this study was to identify marine natural products that modulate mitochondrial function using a screening pipeline leveraging primary human cells in a cell-based phenotypic primary screen. Using this approach, we identified leptochelin A, a recently described metallophore, as a candidate hit with strong potency and efficacy towards the inhibition of mitochondrial function. Using high-resolution respirometry and fluorescence imaging, we validated the mitochondrial-modulatory ("mito-modulatory") effects of leptochelin A and found that it inhibits multiple pathways in the electron transfer system (ETS) while having little effect on mitochondrial mass or superoxide production. It also increases mitochondrial ATP levels, though this may be attributable to a parallel increase in glycolysis. Our findings demonstrate the utility of phenotypic screening using human primary cells to identify novel mitochondrial modulators with translational potential. Leptochelin A's ability to inhibit mitochondrial function without imposing significant toxicity, coupled with its metal-chelating properties, make it a unique compound with therapeutic potential for aging and age-related disorders. Screening strategies focused on mitochondrial respiration can serve as a platform for the advancement of drug discovery within the pharmacology space of human aging.