Elucidating the molecular mechanisms that control the switch between mitochondrial repair and destruction after mitochondrial damage

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons from the substantia nigra pars compacta, resulting in tremors at rest, bradykinesia, stiffness of muscles, retropulsion, and poor balance. A leading hypothesis on the cause of PD is dysfunction of the mitophagy pathway. Mitophagy is a mitochondrial quality control pathway that destroys dysfunctional mitochondria. Currently, it is unclear how this pathway responds to minor or transient impairment of function. Here we show that intermediate doses of the mitochondrial poison, CCCP, cause partial depolarization of mitochondria and transient association of PINK1 proteins with the outer mitochondrial membrane (OMM) lasting ~60-90 minutes. Our data suggests that this mechanism enables the cell to ‘abort’ the mitophagy process if mitochondrial function is restored, preventing inappropriate destruction of healthy mitochondria. These new insights into PINK1 function may inform future studies that seek to enhance or maintain mitochondrial health in PD patients.