Pirnes-Karhu, S. | Search bioRxiv

bioRxiv2023

Alternative oxidase expression in mtDNA mutator mice improves blood phenotype but enhances inflammatory and stress responses in skeletal muscle

Energetic insufficiency, excess production of reactive oxygen species (ROS) and aberrant signalling partially account for the diverse pathology of mitochondrial diseases. Whether interventions affecting ROS, a regulator of stem-cell pools, could modify somatic stem-cell homeostasis remains unknown. Previous data from mitochondrial DNA (mtDNA) mutator mice showed that increased ROS leads to oxidative damage in erythroid progenitors, causing lifespan-limiting anemia. Also unclear is how ROS-targeted interventions affect terminally differentiated tissues. Here, we set out to test in mtDNA mutator mice how ubiquitous expression of the Ciona intestinalis alternative oxidase (AOX), which attenuates ROS production, affects murine stem-cell pools. We found that AOX does not affect neural stem cells but delays the progression of mutator-driven anemia. Furthermore, when combined with the mutator, AOX potentiates mitochondrial stress and inflammatory responses in skeletal muscle. These differential cell-type-specific findings demonstrate that AOX expression is not a global panacea for the cure of mitochondrial dysfunction. ROS attenuation needs to be carefully studied regarding specific underlying defects before AOX can be safely used in therapy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/530968v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@17bfd6org.highwire.dtl.DTLVardef@1338f2aorg.highwire.dtl.DTLVardef@1fc269borg.highwire.dtl.DTLVardef@14abc5e_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

Nicotinamide riboside alleviates Parkinson's disease symptoms but downregulates dopamine metabolism upon lactacystin-induced proteostasis failure

Activation of mitochondrial metabolism and proteostasis with the NAD+ precursor nicotinamide riboside (NR) has emerged as a potential therapeutic approach for neurodegenerative disorders including Parkinsons disease (PD). However, despite recently started clinical trials, studies on NR in animal models of PD are scarce. In this study, we investigated the effect of NR in multiple models of PD. In transgenic C. elegans overexpressing -synuclein, a protein of which aggregation is believed to promote PD, NR rescued PD-like phenotypes including mitochondrial dysfunction and motility defects, decreased oxidative stress, and age-related dopamine (DA) neuron loss. We found that NR eased symptoms of disease by activating the mitochondrial unfolded protein response (UPRmt) via the transcription factor atfs-1. Similarly, in a proteasome inhibitor, lactacystin, -induced mouse model of PD, NR rescued mitochondrial dysfunction and behavioural deficits caused by lactacystin lesion. However, long-term NR supplementation, in conjunction with proteasome inhibition, resulted in decreased DA levels in both the lesioned and unlesioned sides of the substantia nigra with concomitant downregulation of key genes in DA metabolism. Our results suggest specific endpoints that should be monitored in ongoing NR clinical trials.

neuroscience↗