Characterising the Role of Mitochondrial Dysfunction in Ageing Liver Regeneration and Inflammation

Abstract

Ageing is a major risk factor for chronic liver disease in which reduced regeneration and age-associated chronic inflammation or “inflammageing” is observed. In ageing, mitochondrial respiratory chain dysfunction is shown to be a key arbitrator of the process, accruing somatic mitochondrial DNA (mtDNA) mutations with increasing time. Mechanisms linking these themes remain elusive; however, respiratory dysfunction is thought to be important in excess ROS production and apoptosis. Knock-in mitochondrial replicase γ (PolgA) mice are known to recapitulate some progeroid and phenotypic features of human ageing as a result of clonally expanded somatic mtDNA mutations. Basally whilst PolgA+/mut and PolgAmut/mut ageing mice livers was shown to be histologically normal, immunohistological analysis of tissues revealed reduced hepatocellular turnover in the presence of increasing mitochondrial respiratory deficiency. This proliferative defect was attributed to mitochondrial dysfunction within the liver parenchyma and specifically hepatocytes, observing reduced complex I expression. Subsequent subjection to mechanical stress by means of two-thirds partial hepatectomy in PolgA+/mut and PolgA+/mut mice also showed a blunted proliferative response. Additionally, accelerating ageing, mitochondrial dysfunction and downstream ROS production is linked to oxidative stress and altered proinflammatory signalling. Indeed, this study of PolgA+/mut and PolgAmut/mut mice reveals skewing towards a proinflammatory environment. Analysis revealed increased honing of neutrophils within the liver that when stimulated, releases increased amounts of ROS. Such a proinflammatory phenotype appears secondary to the proliferative defect, in which the PolgAmut/mut liver following exposure to acute oxidative CCl4 stress revealed delayed regeneration and cell cycle p16 induction, as well as a failure to clear proinflammatory immune cells. Observations coincided with increasing induction of mitochondrial dysfunction and additional compensatory mechanisms of mitochondrial and antioxidant gene expression. The findings of this thesis suggests that complex I mitochondrial respiratory dysfunction plays a role in ageing hepatocellular regeneration, with ETC deficiency having further roles in regulating proinflammatory cell signalling. Dissecting the role of respiratory dysfunction in liver homeostasis and regeneration would enable understanding for therapeutic intervention in the context of ageing liver disease.