Consequences of mitochondrial protein aggregation

Abstract

Toxic protein aggregates can accumulate in the cytosol and within organelles of cells when protein quality control machinery fails. Here, we systematically analyzed the consequences of protein aggregation in mitochondria by targeting aggregation-prone proteins to the mitochondrial matrix in Saccharomyces cerevisiae and human cells. Mitochondrial aggregates sequestered mitoribosomal subunits and other RNA binding proteins (mito-RBPs). As a result, mitochondrial translation was disrupted, respiratory complexes were reduced, and growth under respiratory conditions was impaired. Ultimately, cells lost their mitochondrial DNA, culminating in high toxicity. We further showed that HSP60 folds proteins prone to sequestration by aggregates and that LONP1 is the major protease that degrades such proteins, thereby preventing aggregate formation. These findings reveal that protein aggregates sequester the same groups of proteins that are affected by a collapse of the proteostatic machinery. In conclusion, our results reveal a conserved mechanism underlying the toxic gain-of-function of mitochondrial aggregates in higher eukaryotes. These findings advance our understanding of how mitochondrial proteostatic stress in disease and aging may affect cell function.