Mitochondrial protein import stress augments α-synuclein aggregation and neural damage independent of bioenergetics

Genetic and environmental factors are known to converge on mitochondria to cause Parkinson's disease (PD). However, the mechanisms by which mitochondrial dysfunction contributes to neurodegeneration remain incompletely understood. Non-bioenergetic pathways of the mitochondria are increasingly appreciated, but confounding bioenergetic defects are a major barrier to experimental validation. Here, we show that mild mitochondrial protein import stress augments neural damage independent of bioenergetics. We induce protein import stress in a mouse model of PD expressing α-synuclein(A53T). The double mutant mice demonstrate increased size of α-synuclein aggregates, increased aggregation of mitochondrial preproteins, heightened neuroinflammation and worsened motor defect relative to α-synuclein(A53T) single mutants. Importantly, we found no evidence of bioenergetic defects in any of the mutant mice. These data suggest that mitochondrial protein import stress, which can be induced by many types of mitochondrial injuries, can contribute to neural damage through cytosolic proteostatic stress and possible co-aggregation of mitochondrial and neuropathogenic proteins independent of bioenergetics.