Parkin is an E3 ubiquitin ligase that facilitates clearance of damaged mitochondria by ubiquitinating proteins on the outer mitochondrial membrane. Although Parkin is mainly studied for its role at the mitochondria, it is unclear the extent to which Parkin functions in other subcellular compartments. In this dissertation, I demonstrate that a portion of Parkin localizes to the nucleus in vitro and in vivo. Furthermore, Parkin’s nuclear localization is dynamic; Parkin rapidly exits the nucleus during nutrient deprivation and translocates to the nucleus in response to hypoxia.
To focus on roles of Parkin at distinct subcellular locations, I generated mitochondrial- and nuclear-targeted Parkin constructs. Nuclear-localized Parkin can contribute to mitochondrial-stress-induced mitophagy. Further, I demonstrate widespread transcriptional changes in response to Parkin in the nucleus, especially across a variety of metabolic pathways and pathways regulated by nuclear receptors and nuclear receptor cofactors.
Through a non-biased proteomics screen, I identified the transcription factor estrogen related receptor α (ERRα) as a potential Parkin target. I demonstrate that nuclear-targeted Parkin interacts with ERRα but does not affect its stability or degradation. Instead, expressing nuclear-Parkin promotes transcription of ERRα targets.
Overexpression of Parkin in tissues has been shown to reduce age-associated cardiac dysfunction and preserve mitochondrial function in mice. Although several studies have identified a role for Parkin in acute cardiac stress, whether Parkin plays a role in adaptation to chronic cardiovascular stressors is still unclear. Therefore, I investigate the role of Parkin in a chronic cardiovascular disease model. In hearts from Parkin transgenic mice, mitochondrial Complex II activity was increased in response to chronic pressure-overload. However, Parkin overexpression did not rescue pressure overload-induced cardiac dysfunction or hypertrophy.
My findings reveal an expanded role for Parkin in response to a variety of acute cellular stressors. I identify a novel role for Parkin in mediating transcription of metabolic genes from the nucleus that could contribute to understanding how mutations in Parkin lead to Parkinson’s Disease. Additionally, I verify that although Parkin functions to protect the heart against acute damage, increasing Parkin levels does not protect the heart from chronic pressure-overload.
