Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins

Abstract

Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases.

Role of Mitochondrial Protein Import in Age-Related Neurodegenerative and Cardiovascular Diseases

“…These findings obtained for human cells are supported by similar data for S. cerevisiae and C. elegans . In the latter case, cytosolic aggregation of mitochondrial preproteins was observed, which are known to be downregulated in AD, and the aggregation of ASYN and Aβ was enhanced because of mitochondrial protein import dysfunction [ 113 ].…”

Cytosolic Quality Control of Mitochondrial Protein Precursors—The Early Stages of the Organelle Biogenesis

“…In certain conditions, protective mechanisms that adjust the influx of mitochondrial precursor proteins and modulate degradation systems are insufficient. If these mechanisms fail, unimported mitochondrial precursors may form aggregate-like deposits [ 136 , 177 ] ( Figure 4 ). Collecting excess precursors within insoluble deposits might reduce their toxicity and allow for safer storage [ 136 , 178 ].…”

“…The potential to form cytosolic deposits of mitochondrial precursors is significant in cells susceptible to protein aggregation, such as neurons. Significantly, mitochondrial precursor aggregates were shown to increase misfolding of α-synuclein or amyloid β proteins [ 177 ], oligomerization and aggregation of which are responsible for Parkinson’s and Alzheimer’s diseases.…”

“…In response to precursor aggregation, cells upregulate specific molecular chaperones at the transcriptomic and protein levels [ 177 ]. In parallel, the overexpression of Mia40 protein and the resulting increase in protein import capacity were shown to suppress aggregation of an aggregation-prone protein [ 179 ].…”

Tom70-based transcriptional regulation of mitochondrial biogenesis and aging

“…Our results indicate that Tom70 not only controls the import of mitochondrial proteins, but also regulates their biogenesis. The nascent mitochondrial proteins synthesized in the cytosol are aggregation-prone and can cause cytosolic proteostasis stress and protein aggregation if not imported in a timely manner (Nowicka et al, 2021;Wang and Chen, 2015;Wrobel et al, 2015). It has been shown that impaired mitochondrial import triggers cellular responses to reduce the biogenesis of mitochondrial proteins in order to achieve a new balance between biogenesis and import of nascent mitochondrial proteins, alleviating their cytosolic accumulation and aggregation (Samluk et al, 2018;Topf et al, 2019;Wrobel et al, 2015).…”