Cellular senescence is a biological process by which cells lose their capacity to proliferate yet remain metabolically active. Although originally considered a protective mechanism to limit the formation of cancer, it is now appreciated that cellular senescence also contributes to the development of disease, including common respiratory ailments such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. While many factors have been linked to the development of cellular senescence, mitochondrial dysfunction has emerged as an important causative factor. In this study, we uncovered that the mitochondrial biogenesis pathway driven by the mammalian target of rapamycin/peroxisome proliferator-activated receptor-γ complex 1α/β (mTOR/PGC-1α/β) axis is markedly upregulated in senescent lung epithelial cells. Using two different models, we show that activation of this pathway is associated with other features characteristic of enhanced mitochondrial biogenesis, including elevated number of mitochondrion per cell, increased oxidative phosphorylation, and augmented mitochondrial reactive oxygen species (ROS) production. Furthermore, we found that pharmacological inhibition of the mTORC1 complex with rapamycin not only restored mitochondrial homeostasis but also reduced cellular senescence to bleomycin in lung epithelial cells. Likewise, mitochondrial-specific antioxidant therapy also effectively inhibited mTORC1 activation in these cells while concomitantly reducing mitochondrial biogenesis and cellular senescence. In summary, this study provides a mechanistic link between mitochondrial biogenesis and cellular senescence in lung epithelium and suggests that strategies aimed at blocking the mTORC1/PGC-1α/β axis or reducing ROS-induced molecular damage could be effective in the treatment of senescence-associated lung diseases.
Background Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and platelet dysfunction and can sometimes lead to a highly aggressive form of pulmonary fibrosis that mimics the fatal lung condition called idiopathic pulmonary fibrosis (IPF). Although the activities of various matrix metalloproteinases (MMPs) are known to be dysregulated in IPF, it remains to be determined whether similar changes in these enzymes can be detected in HPS. Results Here, we show that transcript and protein levels as well as enzymatic activities of MMP-2 and -9 are markedly increased in the lungs of mice carrying the HPS Ap3b1 gene mutation. Moreover, immunohistochemical staining localized this increase in MMP expression to the distal pulmonary epithelium, and shRNA knockdown of the Ap3b1 gene in cultured lung epithelial cells resulted in a similar upregulation in MMP-2 and -9 expression. Mechanistically, we found that upregulation in MMP expression associated with increased activity of the serine/threonine kinase Akt, and pharmacological inhibition of this enzyme resulted in a dramatic suppression of MMP expression in Ap3b1 deficient lung epithelial cells. Similarly, levels and activity of different MMPs were also found to be increased in the lungs of mice carrying the Bloc3 HPS gene mutation and in the bronchoalveolar lavage fluid of subjects with HPS. However, an association between MMP activity and disease severity was not detected in these individuals. Conclusions In summary, our findings indicate that MMP activity is dysregulated in the HPS lung, suggesting a role for these proteases as biological markers or pathogenic players in HPS lung disease. Electronic supplementary material The online version of this article (10.1186/s13023-019-1143-0) contains supplementary material, which is available to authorized users.
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