Nacarelli 2018 Geroscience

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Nacarelli T, Azar A, Altinok O, Orynbayeva Z, Sell C (2018) Rapamycin increases oxidative metabolism and enhances metabolic flexibility in human cardiac fibroblasts. Geroscience [Epub ahead of print].

» PMID: 29931650

Nacarelli T, Azar A, Altinok O, Orynbayeva Z, Sell C (2018) Geroscience

Abstract: Inhibition of mTOR signaling using rapamycin has been shown to increase lifespan and healthspan in multiple model organisms; however, the precise mechanisms for the beneficial effects of rapamycin remain uncertain. We have previously reported that rapamycin delays senescence in human cells and that enhanced mitochondrial biogenesis and protection from mitochondrial stress is one component of the benefit provided by rapamycin treatment. Here, using two models of senescence, replicative senescence and senescence induced by the presence of the Hutchinson-Gilford progeria lamin A mutation, we report that senescence is accompanied by elevated glycolysis and increased oxidative phosphorylation, which are both reduced by rapamycin. Measurements of mitochondrial function indicate that direct mitochondria targets of rapamycin are succinate dehydrogenase and matrix alanine aminotransferase. Elevated activity of these enzymes could be part of complex mechanisms that enable mitochondria to resume their optimal oxidative phosphorylation and resist senescence. This interpretation is supported by the fact that rapamycin-treated cultures do not undergo a premature senescence in response to the replacement of glucose with galactose in the culture medium, which forces a greater reliance on oxidative phosphorylation. Additionally, long-term treatment with rapamycin increases expression of the mitochondrial carrier protein UCP2, which facilitates the movement of metabolic intermediates across the mitochondrial membrane. The results suggest that rapamycin impacts mitochondrial function both through direct interaction with the mitochondria and through altered gene expression of mitochondrial carrier proteins.

Keywords: Senescence, Cardiac fibroblasts, Oxidative phosphorylation, Alanine aminotransferase, Rapamycin, Aging Bioblast editor: Kandolf G O2k-Network Lab: US PA Philadelphia Orynbayeva Z


Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Pharmacology;toxicology  Pathology: Aging;senescence 

Organism: Human  Tissue;cell: Heart, Fibroblast  Preparation: Isolated mitochondria 


Coupling state: OXPHOS  Pathway: F, N, S, NS  HRR: Oxygraph-2k 

Labels, 2018-08