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

Am J Physiol Lung Cell Mol Physiol. 2019 Jun 1;316(6):L1049-L1060. doi: 10.1152/ajplung.00244.2018. Epub 2019 Mar 20.

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.

Keywords: cellular senescence; chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; lung epithelium; mammalian target of rapamycin; mitochondria.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antioxidants / pharmacology
  • Bleomycin / pharmacology
  • Cell Line
  • Cellular Senescence / physiology*
  • Idiopathic Pulmonary Fibrosis / pathology
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Mitochondria / metabolism*
  • Oxidative Stress / physiology
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Pulmonary Disease, Chronic Obstructive / pathology
  • Rats
  • Reactive Oxygen Species / metabolism
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / metabolism*
  • Sirolimus / pharmacology

Substances

  • Antineoplastic Agents
  • Antioxidants
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Reactive Oxygen Species
  • Bleomycin
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus