Systems modelling predicts chronic inflammation and genomic instability prevent effective mitochondrial regulation during biological ageing

Abstract

The regulation of mitochondrial turnover under conditions of stress occurs partly through the AMPK-NAD⁺-PGC1α-SIRT1 signalling pathway. This pathway can be affected by both genomic instability and chronic inflammation since these will result in an increased rate of NAD⁺ degradation through PARP1 and CD38 respectively. In this work we develop a computational model of this signalling pathway, calibrating and validating it against experimental data. The computational model is used to study mitochondrial turnover under conditions of stress and how it is affected by genomic instability, chronic inflammation and biological ageing in general. We report that the AMPK-NAD⁺-PGC1α-SIRT1 signalling pathway becomes less responsive with age and that this can prime for the accumulation of dysfunctional mitochondria.

Keywords: Cell Signalling; DNA damage; Mito-nuclear communication; Mitochondria; NAD; Systems modelling.