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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]

Mitochondrial proteins are organized in an unexpectedly large number of protein complexes, supercomplexes, and dynamic protein networks. Protein networks have been observed for different categories of mitochondrial function, such as preprotein transport, energetics, membrane organization, and quality control. The mitochondrial import network (MitimNet) forms an overarching cross-cutting network that couples mitochondrial protein translocases to machineries of energy conversion, metabolite transport, cellular proteostasis, and membrane contact sites. MitimNet is highly dynamic to ensure the plasticity of mitochondrial biogenesis, function, and quality control in response to cellular and mitochondrial demands. Mitochondria perform crucial functions in cellular metabolism, protein and lipid biogenesis, quality control, and signaling. The systematic analysis of protein complexes and interaction networks provided exciting insights into the structural and functional organization of mitochondria. Most mitochondrial proteins do not act as independent units, but are interconnected by stable or dynamic protein–protein interactions. Protein translocases are responsible for importing precursor proteins into mitochondria and form central elements of several protein interaction networks. These networks include molecular chaperones and quality control factors, metabolite channels and respiratory chain complexes, and membrane and organellar contact sites. Protein translocases link the distinct networks into an overarching network, the mitochondrial import network (MitimNet), to coordinate biogenesis, membrane organization and function of mitochondria. [ABSTRACT FROM AUTHOR]

Mitochondria import 1000–1300 different precursor proteins from the cytosol. The main mitochondrial entry gate is formed by the translocase of the outer membrane (TOM complex). Molecular coupling and modification of TOM subunits control and modulate protein import in response to cellular signaling. The TOM complex functions as regulatory hub to integrate mitochondrial protein biogenesis and quality control into the cellular proteostasis network. • Multifunctional properties of translocase of outer mitochondrial membrane (TOM) • TOM complex interacts with preproteins, cytosolic chaperones and translocases. • TOM participates in quality control pathways and stress response reactions. • TOM as regulatory hub in protein biogenesis, cellular proteostasis and signaling [ABSTRACT FROM AUTHOR]