Exposure of cells to prions induces prion strain-dependent changes in mitochondrial redox state and respiration.

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, encoded by PRNP in humans) 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 mouse 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 treatment with detergent and dependent upon endolysosomal 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, whereas persistent prion infection increases mitochondrial sensitivity to cellular stress.