Activation of the mTORC1/PGC-1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium

Abstract

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.

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

“…With this in mind, we next assessed whether mitochondrial respiration, a primary driver of ROS production, was increased in H 2 O 2 -treated lung fibroblasts. Here, mitochondrial OCR was measured using the Seahorse Bioanalyzer as previously described [21]. As shown in figure S1, we found that basal and ATP-linked respiration were both significantly increased in senescent cells (Fig.…”

“…Although induction of cellular senescence has been attributed to a variety of factors, such as telomere attrition or mitochondrial dysfunction [20, 21], decline in the proteostasis network (PN) has recently emerged as an important causal factor [22-24]. The PN is a nexus of pathways that act in concert to maintain the integrity of the proteome.…”

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

“…In this sense, several studies attributed to mTORC1 a fundamental role in mitochondria turnover and activity by regulating ERR-α and PGC1-α target genes and through 4E-BP-dependent translational regulation, resulting in increased oxidative phosphorylation and mitochondrial ROS production [95][96][97].…”

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

“…The presence of this secretory phenotype has already been confirmed in AE2 cells and lung fibroblasts of IPF patients (2,54). We previously demonstrated that chronic activation of the mTOR/PGC-1β pathway induces lung epithelial cells into a senescence phenotype, possibly due to augmented ROS-induced molecular damage (51). The expression of SASP has been recognized as another driver of the lung fibroblast to myofibroblast differentiation and a direct contributor to the excessive collagen deposition (21,30).…”

“…Emerging evidence indicates that mitochondrial dysfunction and metabolic reprogramming occur in a wide range of respiratory disorders, including a variety of fibrotic lung conditions (15,29,39). For example, we recently demonstrated that diverse types of profibrotic insults (bleomycin, radiation, silica) induce similar metabolic changes in the alveolar epithelium of the lung (51). These changes include decreased ATP production and a shift toward the use of glycolysis as a means for driving cellular metabolism.…”