Mitochondrial Redox-changes causing selective neurodegeneration in a mouse model of mitochondrial Parkinson`s disease

Identification: Wiesner, Rudolf


Mitochondrial Redox-changes causing selective neurodegeneration in a mouse model of mitochondrial Parkinson`s disease
K. Ricke1,2, T. Pass1,2, T.M. Eriksson Faelker2, O. Baris1,2, M. Bergami2, M. Aradjanski2, A.Trifunovic2, C. Jüngst2, A. Schauss2 and R.J. Wiesner1,2
1Center for Physiology and Pathophysiology and 2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Köln, Germany
High turnover of dopamine induces mtDNA deletions, therefore dopaminergic neurons preferentially accumulate such deletions during aging. Parkinson's disease is characterized by the loss of dopaminergic neurons (DaNs) in the S. nigra (SNc), while the neighboring dopaminergic VTA region is far less affected. However, mtDNA deletions accumulate in both neuron types. It is unclear which factors, in addition to mitochondrial dysfunction, lead to the accelerated death of SNc-DaNs. These neurons are pacemakers, display extremely large arborizations of their axons and intrinsically generate action potentials using Ca++-channels, while VTA neurons are much smaller and use Na+-channels. The resulting Ca++-oscillations were shown to lead to increased mitochondrial "oxidant stress", which was postulated to cause selective vulnerability. To determine whether and how this "stress" is linked to the specific degeneration of SNc-DaNs, we analysed the state of the mitochondrial redox system in MitoPark mice with a DaN specific k.o. of Tfam, which also express a redox sensitive GFP targeted to the matrix (mito-roGFP2; yielding a RedOx-ratio). Two-photon microscopy of acute midbrain slices of these mice at the onset of neurodegeneration revealed that low COX activity in both SNc and VTA DaNs (revealed by COX/SDH staining) leads to an increased mitochondrial RedOx-ratio in vulnerable SNc, indicating low levels of NAD(P)H and thus low levels of reduced glutathione in the matrix, but not in VTA DaNs. This was mimicked in wt mito-roGFP2 mice by KCN, but not by rotenone or antimycin A, clearly showing that an increased RedOx ratio is not due to high levels of ROS. Antagonizing calcium influx through the plasma membrane as well as into the matrix using the Ca++-channel blocker isradipine or Ru369, respectively, normalized the high RedOx-ratio in MitoPark SNc DaNs.
In conclusion, severe respiratory chain dysfunction leads to mitochondrial Ca++-overload in these neurons as well as to an impaired antioxidant defense system in the matrix as likely causes of neuron death.


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