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.
Hauke Holthusen· Universitätsbibliothek der L...· 0 citations
Proteostasis failure is a hallmark of stress and disease, yet how it compromises mitochondrial integrity remains unclear. Here, we identify mitochondrial protein import as a critical pathway linking proteostasis failure to mitochondrial injury. We show that Raptinal, previously characterized as a rapid inducer of apoptosis, impairs the folding of newly synthesized proteins rather than directly disrupting mitochondrial membranes. The resulting proteotoxic stress drives mitochondrial outer membrane permeabilization and intrinsic apoptosis independently of BCL-2 family pore-forming proteins. VBIT4, a compound commonly used to maintain mitochondrial integrity, inhibited this pathway, and chemical proteomics with a photoaffinity analogue implicated the TIM23 import machinery. Genetic or pharmacological inhibition of the TIM23–PAM axis suppressed mitochondrial permeabilization without affecting canonical BAX–BAK-dependent apoptosis. These findings establish that mitochondrial protein import couples translation-associated proteotoxic stress to mitochondrial injury and identify regulation of import flux as a determinant of mitochondrial integrity during proteostasis failure.
Zhiqi Sun, Hauke Holthusen, Sara Berndl et al.· bioRxiv· 0 citations
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