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

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.

Suppressing toxic aggregates: let MIA do it!

Mitochondrial activity is becoming an inherent aspect of cellular protein homeostasis (proteostasis). In this issue, Schlagowski et al (2021) report on the attractive notion that modulating mitochondrial protein import activity stimulates protein aggregate clearance in the cytosol, thereby affecting cytosolic proteostasis and its collapse observed in neurodegenerative diseases.

Mitochondrial control of cellular protein homeostasis.

Mitochondria are involved in several vital functions of the eukaryotic cell. The majority of mitochondrial proteins are coded by nuclear DNA. Constant import of proteins from the cytosol is a prerequisite for the efficient functioning of the organelle.

Structural Basis for the Inhibitory Effects of Ubistatins in the Ubiquitin-Proteasome Pathway.

The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel of new ubistatin derivatives using functional and binding assays.