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


Maximus Peto’s Commentary

Perhaps I missed this association in my PubMed screening, but I don’t think I’ve heard of this association between cellular senescence and increased mitochondrial biogenesis. I assumed increased mitochondrial biogenesis was almost unconditionally a good thing, but this group reports that it occurs in senescent lung epithelial cells. I wonder: could this increased biogenesis be caused by a reduction in ATP availability experienced by the senescent cell? I presume that would be a normal signal for increased mitochondrial biogenesis (a decline in ATP or an increase in AMP), but I’m not well-read on this subject.


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.
Summer R, Shaghaghi H, Schriner D, Roque W, Sales D, Cuevas-Mora K, Desai V, Bhushan A, Ramirez MI, Romero F
DOI: 10.1152/ajplung.00244.2018
PubMed publication date (edat): 3/21/2019

Abstract

…..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.

PMID: 30892080
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Maximus Peto

Max Peto is a longevity researcher and founder of Long Life Labs. A biochemist by training, he studies the biochemistry of aging and longevity and has worked with research organizations such as SENS Research Foundation, Methuselah Foundation, BioAge Labs, Life Extension Foundation, and Ichor Therapeutics. His work at Long Life Labs is focused on empowering people to understand and manage the most critical factors for better health and longer life.

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