Loss of dCHCHD2 and introduction of PD-associated human CHCHD2 mutations destabilize cytochrome c, which transports an electron from complex III to complex IV during oxidative phosphorylation (OXPHOS), leading to a reduction in ATP production and the generation of reactive oxygen species (ROS) owing to the electron leak 2. Drosophila CHCHD2 ( dCHCHD2) knockout flies exhibit PD-like phenotypes in an age-dependent manner, which include dysfunction in motor ability, DA neuron loss, increased oxidative stress and mitochondrial cristae degeneration 2. CHCHD2 (mutations of which cause an autosomal dominant form of PD) encodes a mitochondrial intermembrane protein 1. Parkinson’s disease (PD) is a neurodegenerative disorder characterized by selective loss of midbrain DA neurons. This study suggests the enhancement of Δp by mito-dR as a therapeutic mechanism that ameliorates neurodegeneration by protecting mitochondrial functions. Moreover, mito-dR reversed the pathology caused by the CHCHD2 deficiency to suppress α-synuclein aggregation, DA neuronal loss, and elevated lipid peroxidation in brain tissue, improving motor behaviors. These cellular defects were improved by the light-dependent activation of mitochondrion-targeted dR (mito-dR). The loss of the PD-associated mitochondrial gene CHCHD2 resulted in reduced ATP production, enhanced mitochondrial peroxide production and lower Ca 2+-buffering activity in dopaminergic (DA) terminals in flies. In this study, we introduced a light-driven proton transporter, Delta-rhodopsin (dR), to Drosophila mitochondria, where the mitochondrial proton-motive force (Δp) and mitochondrial membrane potential are maintained in a light-dependent manner. Improved mitochondrial functions are expected to be a promising therapeutic strategy for PD. Mitochondrial degeneration is considered one of the major causes of Parkinson’s disease (PD).
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