An effective approach to modulate mitochondrial function in murine primary macrophages by a mitochondria-targeted...

Macrophages play crucial roles in various pathological conditions as well as maintenance of homeostasis. Many chronic inflammatory conditions, such as atherosclerosis, rheumatoid arthritis, and obesity, are known to involve the polarization of macrophages into a proinflammatory state. Therefore, controlling the function of macrophages is a potential strategy to intervene in such pathological conditions. Modulation of immune cell metabolism has recently received attention as a novel therapeutic strategy to counteract such conditions. Recently, a unique nanocapsule (MITO-Porter) that can deliver macromolecules specifically into mitochondria was generated, and its application to improve mitochondrial function was achieved by the direct action of the molecules at the site of the mitochondria in a wide range of cell types but not in immune cells. Therefore, we initiated this study by investigating the feasibility of mitochondria-targeted delivery of coenzyme Q10 (CoQ10), a known antioxidant and cofactor of mitochondrial oxidative phosphorylation, in primary murine bone marrow macrophages (BMDMs) and then evaluated the functional consequences of the treatment with MITO-Porter on mitochondrial function in BMDMs. At steady state, CoQ10-loaded MITO-Porter containing octaarginine (R8) was successfully delivered into the mitochondria, resulting in significant antioxidant effects and increased mitochondrial respiration. Furthermore, the effect of CoQ10 on mitochondrial function in BMDMs was more pronounced when CoQ10 was encapsulated in R8(+) MITO-Porter than when CoQ10 was added alone. This proof-of-concept study highlights the potential of the application of MITO-Porter in macrophages and other immune cells as a novel immunomodulatory therapy for chronic inflammatory conditions.