Altering Mitochondrial Fusion and Fission Protein Levels Rescues Parkin and PINK1 Loss-of-Function Phenotypes

Abstract

Loss-of-function mutations in the PARK2 and PINK1 gene, encoding Parkin and PINK1 proteins, respectively, are the leading cause of autosomal recessive juvenile parkinsonism. While the mechanisms by which loss of function of these proteins causes selective death of nigral dopaminergic neurons continues to elude researchers, evidence overwhelmingly points to deficits in mitochondrial respiration, enhanced levels of reactive oxygen species (ROS), and apoptosis induction. Alterations in mitochondrial morphology reflect changes in cellular respiration, and changes in mitochondrial network connectivity are consistently observed in Parkin or PINK1 loss-of-function models; however, both increases and decreases in network connectivity have been reported. These seemingly conflicting observations may not be contradictory if the degree of deficit caused by Parkin or PINK1 loss depends on the cell’s energy demands and/or morphology, both of which vary dramatically and can change when cells move from in vivo to in vitro. Additionally, the mechanism by which immortalized cells produce ATP is shifted from the respiratory chain to glycolysis. Efforts to improve phenotypes and/or mitochondrial function and morphology in various PARK2 or PINK1 loss-of-function models by pushing the balance of fusion/fission events in both directions have been among the most encouraging. This chapter will review the processes of mitochondrial fusion and fission, the relationship between mitochondrial respiration and morphology, and some of the literature describing how Parkin and PINK1 loss of function cause mitochondrial deficits. A speculative proposal on how altering mitochondrial morphology may improve these deficits follows.