The role of ER-mitochondria signalling in Parkin-associated Parkinson´s disease

The role of the E3 ubiquitin ligase Parkin in the pathogenesis of PD is not limited to the control of mitophagy. Instead, Parkin is also critically involved in the regulation of mitochondrial biogenesis, mtDNA maintenance and metabolic function, possibly by regulating the interplay of mitochondria and the ER. Parkin deficiency affects the mitochondrial energy metabolism as shown by an increased lactate: pyruvate ratio and reduced NAD+ production. A decrease in free NAD+ could explain the observed reduction of NAD+-dependent SIRT1 and of its downstream targets in the mitochondrial biogenesis pathway, thereby affecting mtDNA maintenance. Additionally, Parkin was shown to regulate the formation and function of MERCS, which are important hubs for mtDNA replication, mitochondrial biogenesis and energy production via regulation of the mitochondrial calcium level. Thus, we aim to further elucidate the hypothesis that dysfunction of MERCS is the critical upstream event causing mitochondrial impairments in Parkin-associated PD.