Pten-induced kinase 1 (PINK1) and its role in mitochondrial function and dynamics
Thomas, Kelly Jean.
Thesis (Ph.D.)--Georgetown University, 2008.; Includes bibliographical references. Parkinson disease (PD) is a neurodegenerative disorder with progressive loss of dopaminergic neurons in the substantia nigra. The majority of PD cases involve the sporadic form with unknown etiology, but mitochondrial dysfunction and oxidative stress are considered to play a role in disease pathogenesis. The discoveries of the genes parkin, PINK1 and DJ-1 that are linked to familial forms of parkinsonism have provided insight into the molecular mechanisms that cause disease. Recent findings implicate mitochondrial dysfunction associated with oxidative damage as a key molecular mechanism that compromises dopaminergic neurons in familial parkinsonism. Studies within this thesis characterize the mitochondrial function of PINK1 in human neuroblastoma cells. PINK1 prevents cell death mediated by mitochondrial toxins that inhibit complex one of the respiratory chain, which in turn contributes to oxidative stress. PINK1 protects against oxidative stress and secondary mitochondrial dysfunction; therefore, the role of PINK1 in mitochondrial function and morphology was further investigated.; Mitochondria are dynamic organelles that undergo the antagonizing events of fusion and fission. While fusion of mitochondrial membranes promotes cell survival, mitochondrial fission is associated with apoptosis. Defects in mitochondrial membrane potential influence mitochondrial morphology in PINK1 deficient cells shifting phenotypes towards Dynamin-related protein 1 (Drp1)-mediated fission. PINK1 silencing results in mitochondrial fission by enhancing calcineurin activity, which promotes mitochondrial fragmentation via Drp1 dephosphorylation and increased Drp1 GTPase activity.; Exogenous expression of parkin in PINK1 deficient cells rescues mitochondrial fission, which confirms that PINK1 and parkin genetically interact to regulate mitochondrial morphology. Cells deficient in parkin or DJ-1 phenocopy PINK1 silencing and exhibit mitochondrial fission. Dephosphorylation of Drp1 is enhanced in DJ-1 deficient cells, suggesting that modulation of fission machinery may be dependent upon the generation of oxidative stress. PINK1, parkin and DJ-1 all act individually to limit the effects of agents that induce oxidative stress and trigger mitochondrial fission. Expression of PINK1 or parkin in DJ-1 deficient cells rescues mitochondrial phenotypes associated with DJ-1 silencing, which suggests DJ-1 lies upstream of the PINK1/parkin pathway to inhibit mitochondrial fission. These studies suggest that oxidative stress can influence mitochondrial shape, structure and function, which might contribute to parkinsonian phenotypes.
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