Mitochondrial Dysfunction Combined with High Calcium Load Leads to Impaired Antioxidant Defense Underlying the Selective Loss of Nigral Dopaminergic Neurons

Abstract

Mitochondrial dysfunction is critically involved in Parkinson's disease, characterized by loss of dopaminergic neurons (DaNs) in the substantia nigra (SNc), whereas DaNs in the neighboring ventral tegmental area (VTA) are much less affected. In contrast to VTA, SNc DaNs engage calcium channels to generate action potentials, which lead to oxidant stress by yet unknown pathways. To determine the molecular mechanisms linking calcium load with selective cell death in the presence of mitochondrial deficiency, we analyzed the mitochondrial redox state and the mitochondrial membrane potential in mice of both sexes with genetically induced, severe mitochondrial dysfunction in DaNs (MitoPark mice), at the same time expressing a redox-sensitive GFP targeted to the mitochondrial matrix. Despite mitochondrial insufficiency in all DaNs, exclusively SNc neurons showed an oxidized redox-system, i.e., a low reduced/oxidized glutathione (GSH-GSSG) ratio. This was mimicked by cyanide, but not by rotenone or antimycin A, making the involvement of reactive oxygen species rather unlikely. Surprisingly, a high mitochondrial inner membrane potential was maintained in MitoPark SNc DaNs. Antagonizing calcium influx into the cell and into mitochondria, respectively, rescued the disturbed redox ratio and induced further hyperpolarization of the inner mitochondrial membrane. Our data therefore show that the constant calcium load in SNc DaNs is counterbalanced by a high mitochondrial inner membrane potential, even under conditions of severe mitochondrial dysfunction, but triggers a detrimental imbalance in the mitochondrial redox system, which will lead to neuron death. Our findings thus reveal a new mechanism, redox imbalance, which underlies the differential vulnerability of DaNs to mitochondrial defects.

Mitochondria exert age-divergent effects on recovery from spinal cord injury

“…Specifically, a biproduct of mitochondrial respiration is the generation of reactive oxygen species (ROS), which under normal physiological conditions function in vital cell signaling. In excess however, increases in ROS drive pathophysiological processes such as protein and lipid oxidation that can induce senescence and accelerate disease pathology ( Birla et al, 2020 ; Cherubini et al, 2020 ; Hall et al, 2015 ; Ricke et al, 2020 ; Saxena et al, 2019 ; Zhang et al, 2019 ).…”

“…An increase in ROS production from mitochondria is a known consequence of aging ( Yonutas et al, 2015 ) and is further exacerbated by several neurodegenerative or neurotraumatic conditions ( Birla et al, 2020 ; Cherubini et al, 2020 ; Pandya et al, 2007 ; Ricke et al, 2020 ). One way ROS is generated by mitochondria is when resistance to electron transfer increases, which induces slippage of electrons onto soluble oxygen forming the free radical superoxide ( Suski et al, 2012 ; Zhao et al, 2019 ).…”

The Impact of Mitochondrial Dysfunction on Dopaminergic Neurons in the Olfactory Bulb and Odor Detection

“…2e), i.e. 28 weeks after TFAM inactivation at around P14, whereas midbrain DaNs uniformly present COX-deficiency already after 12 weeks of age [39], i.e. 13 weeks after TFAM inactivation at around E15.5.…”

“…Conversely, SNc pacemaker activity is associated with Ca 2+ influx through plasma membrane Ca v 1.3 channels, postulated to cause oxidant stress in the mitochondrial compartment [ 59 , 60 ]. Combined with a low intrinsic calcium buffering capacity, mitochondrial dysfunction leads to an oxidized RedOx-system and hyperpolarized membrane potential in mitochondria of SNc DaNs, which thereby causes neuron death [ 39 ].…”

“…Loss of TFAM is accompanied by loss of mtDNA-encoded transcripts [32]. Consequently, respiratory chain defects become apparent in midbrain DaNs of 12-week-old MitoPark mice even before the onset of neurodegeneration [39]. In order to verify mitochondrial impairment in OB DaNs, a histochemical staining procedure for COX/SDH activity was performed ( Fig.…”