Mitochondrial fusion mediated by mitofusin 1 regulates macrophage mycobactericidal activity by enhancing autophagy

Abstract

Mitochondria as a highly dynamic organelle continuously changes morphology and position during its life cycle. Mitochondrial dynamics including fission and fusion play a critical role in maintaining functional mitochondria for ATP production, which is directly linked to host defense against Mtb infection. However, how macrophages regulate mitochondrial dynamics during Mycobacterium tuberculosis (Mtb) infection remains elusive. In this study, we found that Mtb infection induced mitochondrial fusion through enhancing the expression of mitofusin 1 (MFN1), which resulted in increased ATP production. Silencing MFN1 inhibited mitochondrial fusion and subsequently reduced ATP production, which, in turn, severely impaired macrophage mycobactericidal activity by inhibiting autophagy. Impairment of mycobactericidal activity and autophagy was replicated using oligomycin, an inhibitor of ATP synthase. In summary, our study revealed MFN1-mediated mitochondrial fusion is essential for macrophage mycobactericidal activity through the regulation of ATP dependent autophagy. MFN1-mediated metabolism pathway might be targets for development of host direct therapy (HDT) strategy against TB. ImportanceHow mitochondrial dynamic is regulated in attempt to fight against Mtb remains elusive. Our study revealed that the fission/fusion dynamics of mitochondria during Mtb infection is regulated by MFN1, through which mitochondrial respiration and autophagy activity are affected. Our findings suggested that intervention of energy metabolism by targeting MFN1 might be a strategy against Mtb infection.