Exposure of cells to prions induces prion strain dependent changes in mitochondrial redox state and respiration.
TL;DR
During initial prion infection, PrPSc drives mitochondrial dysfunction in a manner that is both strain dependent and independent of PrPC expression, while persistent prion infection increases mitochondrial sensitivity to cellular stress.
Abstract
Prion diseases are transmissible, neurodegenerative diseases caused by misfolded, protease-resistant, and infectious aggregates of the mammalian prion protein (PrPSc) that replicate by converting properly folded prion protein (PrPC) into PrPSc. Spongiform change and cellular loss in the brain are hallmarks of prion disease, but our understanding of how prions alter cellular fitness remains incomplete. Here we characterized changes in mitochondrial redox state and respiration in neural cells following uptake of two different PrPSc strains, 22L and 87V. Only 22L PrPSc induced changes in cellular respiration and mitochondrial redox state, even in cells that did not produce PrPC. These effects were disrupted by detergent and dependent upon endo-lysosomal acidification, suggesting that both PrPSc membrane association and lysosomal degradation are involved. Interestingly, cells chronically infected with 22L appeared to adapt to infection, showing no signs of mitochondrial dysfunction, but were more susceptible to oxidative stress even though mitochondrial respiration was normal. Thus, during initial prion infection, PrPSc drives mitochondrial dysfunction in a manner that is both strain dependent and independent of PrPC expression, while persistent prion infection increases mitochondrial sensitivity to cellular stress.
