Mitochondrial Transfer by Photothermal Nanoblade Restores Respiration in Mammalian Cells with Dysfunctional Mitochondria

Abstract

Despite a wealth of publications about the role of alpha-synuclein in Parkinson's disease, very little has been reported about this protein's physiological function in health. This current study established an important function for native a-synuclein in the regulation of ATP synthase activity. Life cell imaging and mitochondrial respiration analysis revealed that deficiency in synuclein (a,b,g-synuclein knockout mouse) leads to mitochondrial uncoupling characterized by increased mitochondrial respiration (V2; 12658.1% of control) and reduced mitochondrial membrane potential (8553% of control). Furthermore, a reduced efficiency of the ATP synthase (7454.2% of control) and lower ATP levels (8751.3%) were detected in synuclein deficient cells. Application of exogenous, native a-synuclein rescued the mitochondrial membrane potential (by 50%) and improved ATP synthase efficiency (by 113%). To provide direct evidence that a-synuclein acts on the ATP synthase, ATP synthase from brain mitochondria were immunocaptured and exposure to unfolded a-synuclein was able to directly increase its activity. These data suggest that asynuclein is a physiological modulator of mitochondrial bioenergetics through its ability to alter ATP synthase efficiency.