Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress

Abstract

Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration—defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbiased forward genetic screen designed to isolate mutations that cause photoreceptor degeneration, we identified mutations in a nuclear-encoded mitochondrial gene, ppr, a homolog of human LRPPRC. We found that ppr is required for protection against light-induced degeneration. Its function is essential to maintain membrane depolarization of the photoreceptors upon repetitive light exposure, and an impaired phototransduction cascade in ppr mutants results in excessive Rhodopsin1 endocytosis. Moreover, loss of ppr results in a reduction in mitochondrial RNAs, reduced electron transport chain activity, and reduced ATP levels. Oxidative stress, however, is not induced. We propose that the reduced ATP level in ppr mutants underlies the phototransduction defect, leading to increased Rhodopsin1 endocytosis during light exposure, causing photoreceptor degeneration independent of oxidative stress. This hypothesis is bolstered by characterization of two other genes isolated in the screen, pyruvate dehydrogenase and citrate synthase. Their loss also causes a light-induced degeneration, excessive Rhodopsin1 endocytosis and reduced ATP without concurrent oxidative stress, unlike many other mutations in mitochondrial genes that are associated with elevated oxidative stress and light-independent photoreceptor demise.

The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D

“…To further dissect the metabolites involved in lipid synthesis, we used heterozygous mutants of Pdha A (Jaiswal et al, 2015) or CS ( Kdn A ) (Yamamoto et al, 2014) in flies that express Rh-ND42 IR , Rh-Marf-IR or Rh-Aats-met IR and accumulate numerous LD in glia. We observe a systematic decrease in glial LD accumulation when the metabolic enzymes are decreased via RNAi or incorporation of a mutant allele (Figure 4B and S3C).…”

WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin/Reptin Complexes

“…We generated mosaic eyes that contain homozygous mutant cells using the FLP-FRT system (Xu and Rubin, 1993) and recorded electroretinograms (ERGs) from mutant clones (Jaiswal et al, 2015; Sandoval et al, 2014; Tian et al, 2015; Wang et al, 2014; Xiong et al, 2012; Zhang et al, 2013). The ERG response consists of a depolarization, which is a measure of the strength of phototransduction, and the on and off transients, which gauge synaptic transmission.…”

Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration

“…In flies, the phenotypes associated with the loss of either protein are very similar as they lead to a very slow, progressive neurodegeneration that is not observed in most mitochondrial mutants (Jaiswal et al, 2015; Liu et al, 2015). In mice, loss of mNrd1 also causes a slow progression of neurological phenotypes, including impairment of motor coordination and balance, impaired memory, a thin cerebral cortex, and myelination defects in the corpus callosum (Ohno et al, 2009).…”