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Mitochondria carry out essential functions for the cell, including energy production, various biosynthesis pathways, formation of co‐factors and cellular signalling in apoptosis and inflammation. The functionality of mitochondria requires the import of about 900–1300 proteins from the cytosol in baker's yeast Saccharomyces cerevisiae and human cells, respectively. The vast majority of these proteins pass the outer membrane in a largely unfolded state through the translocase of the outer mitochondrial membrane (TOM) complex. Subsequently, specific protein translocases sort the precursor proteins into the outer and inner membranes, the intermembrane space and matrix. Premature folding of mitochondrial precursor proteins, defects in the mitochondrial protein translocases or a reduction of the membrane potential across the inner mitochondrial membrane can cause stalling of precursors at the protein import apparatus. Consequently, the translocon is clogged and non‐imported precursor proteins accumulate in the cell, which in turn leads to proteotoxic stress and eventually cell death. To prevent such stress situations, quality control mechanisms remove non‐imported precursor proteins from the TOM channel. The highly conserved ubiquitin‐proteasome system of the cytosol plays a critical role in this process. Thus, the surveillance of protein import via the TOM complex involves the coordinated activity of mitochondria‐localized and cytosolic proteins to prevent proteotoxic stress in the cell. [ABSTRACT FROM AUTHOR]

Mogk and den Brave discuss exciting results from a comprehensive screen of heat shock response components in yeast, published in this issue by Pincus and colleagues (https://doi.org/10.1083/jcb.202401082). Their work reveals modulatory regulatory loops that fine-tune the timing of the shutdown of this highly conserved pathway. [ABSTRACT FROM AUTHOR]

Mitochondria import about 1000 proteins that are produced as precursors on cytosolic ribosomes. Defects in mitochondrial protein import result in the accumulation of nonimported precursor proteins and proteotoxic stress. The cell is equipped with different quality control mechanisms to monitor protein transport into mitochondria. First, molecular chaperones guide unfolded proteins to mitochondria and deliver non-imported proteins to proteasomal degradation. Second, quality control factors remove translocation stalled precursor proteins from protein translocases. Third, protein translocases monitor protein sorting to mitochondrial subcompartments. Fourth, AAA proteases of the mitochondrial subcompartments remove mislocalized or unassembled proteins. Finally, impaired efficiency of protein transport is an important sensor for mitochondrial dysfunction and causes the induction of cellular stress responses, which could eventually result in the removal of the defective mitochondria by mitophagy. In this review, we summarize our current understanding of quality control mechanisms that govern mitochondrial protein transport. [ABSTRACT FROM AUTHOR]

The majority of mitochondrial precursor proteins are imported through the Tom40 β-barrel channel of the translocase of the outer membrane (TOM). The sorting and assembly machinery (SAM) is essential for β-barrel membrane protein insertion into the outer membrane and thus required for the assembly of the TOM complex. Here, we demonstrate that the α-helical outer membrane protein Mco6 co-assembles with the mitochondrial distribution and morphology protein Mdm10 as part of the SAM machinery. MCO6 and MDM10 display a negative genetic interaction, and a mco6 - mdm10 yeast double mutant displays reduced levels of the TOM complex. Cells lacking Mco6 affect the levels of Mdm10 and show assembly defects of the TOM complex. Thus, this work uncovers a role of the SAMMco6 complex for the biogenesis of the mitochondrial outer membrane. [Display omitted] • Mco6 as a novel subunit of the mitochondrial sorting and assembly machinery (SAM) • Mco6 assembles with Mdm10 to form the SAMMco6 complex • Mdm10 and Mco6 cooperate in the biogenesis of the TOM complex Busto et al. report that the small protein Mco6 is a novel regulatory protein at the mitochondrial sorting and assembly machinery (SAM). Mco6 specifically associates with Mdm10 to form the SAMMco6 complex and is required for the efficient assembly of the translocase of the mitochondrial outer membrane. [ABSTRACT FROM AUTHOR]