Inflammatory stimulation of monocyte-macrophages inhibits mitophagy

BACKGROUND: Mitochondria play an important role in chronic inflammation. Originating from bacteria, mitochondria contain molecules known as alarmins. The release of these molecules into the cytoplasm can trigger an inflammatory response. To prevent this, a quality control mechanism called mitophagy ensures the lysosomal degradation of dysfunctional mitochondria. A relationship between mitophagy and the inflammatory activity of cells remains unclear. We assessed whether the pro-inflammatory stimulant lipopolysaccharide (LPS) is able to regulate the efficiency of mitophagy in monocyte-macrophages. We then assessed the ability of the mitophagy activator (FCCP) to modulate the cellular inflammatory response.METHODS: Primary monocytes were isolated from whole blood of healthy donors. Mitophagy was evaluated by staining the cells with MitoTracker Green and LysoTracker DR. The colocalization of these dyes was used for the quantitative evaluation mitophagy. Additionally, to activate mitophagy, FCCP was used. Concentrations of cytokines TNF-alpha, CCL2, IL-113, IL-6, IL-8 and IL-10 were assessed by ELISA.RESULTS: LPS stimulation of monocyte-macrophages inhibited both basal and FCCP-induced mitophagy. Short-term incubation of cells with FCCP, accompanied by mitochondrial depolarization, led to an increase in the secretion of CCL2 and IL-8 and a decrease in the secretion of the IL-113. Longer cell incubation with FCCP, accompanied by mitophagy activation, led to a decrease in the secretion of all studied cytokines.CONCLUSIONS: Probably, activation of TLR4-signaling pathway leads to the inhibition of mitophagy. It can be assumed that long-term up regulation of the TLR4 signaling, which is observed in chronic diseases, can lead to defective mitophagy contributing chronic inflammation.(Cite this article as: Nikiforov NG, Chegodaev YS, Zhuravlev AD, Vysokikh M, Marey M, Grechko AV, et al. Inflammatory stimulation of monocytemacrophages inhibits mitophagy. Minerva Biotechnol Biomol Res 2023;35:145-50.DOI: 10.23736/S2724-542X.23.02954-1)