Many mitochondrial proteins are synthesized as preproteins carrying amino-terminal presequences in the cytosol. The preproteins are imported by the translocase of the outer mitochondrial membrane (TOM) and the presequence translocase of the inner membrane (TIM). Tim50 and Tim23 transfer preproteins through the intermembrane space to the inner membrane. We report the crystal structure of the intermembrane space domain of yeast Tim50 to 1.83 Å resolution. A protruding β-hairpin of Tim50 is crucial for interaction with Tim23, providing a molecular basis for the cooperation of Tim50 and Tim23 in preprotein translocation to the protein-conducting channel of the mitochondrial inner membrane.
The mitochondrial inner membrane harbors the complexes of the respiratory chain and protein translocases required for the import of mitochondrial precursor proteins. These complexes are functionally interdependent, as the import of respiratory chain precursor proteins across and into the inner membrane requires the membrane potential. Vice versa the membrane potential is generated by the proton pumping complexes of the respiratory chain. Besides this basic codependency four different systems for protein import, processing and assembly show further connections to the respiratory chain. The mitochondrial intermembrane space import and assembly machinery oxidizes cysteine residues within the imported precursor proteins and is able to donate the liberated electrons to the respiratory chain. The presequence translocase of the inner membrane physically interacts with the respiratory chain. The mitochondrial processing peptidase is homologous to respiratory chain subunits and the carrier translocase of the inner membrane even shares a subunit with the respiratory chain. In this review we will summarize the import of mitochondrial precursor proteins and highlight these special links between the mitochondrial protein import machinery and the respiratory chain. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.
SummaryThe mitochondrial inner membrane harbors three protein translocases. Presequence translocase and carrier translocase are essential for importing nuclear-encoded proteins. The oxidase assembly (OXA) translocase is required for exporting mitochondrial-encoded proteins; however, different views exist about its relevance for nuclear-encoded proteins. We report that OXA plays a dual role in the biogenesis of nuclear-encoded mitochondrial proteins. First, a systematic analysis of OXA-deficient mitochondria led to an unexpected expansion of the spectrum of OXA substrates imported via the presequence pathway. Second, biogenesis of numerous metabolite carriers depends on OXA, although they are not imported by the presequence pathway. We show that OXA is crucial for the biogenesis of the Tim18-Sdh3 module of the carrier translocase. The export translocase OXA is thus required for the import of metabolite carriers by promoting assembly of the carrier translocase. We conclude that OXA is of central importance for the biogenesis of the mitochondrial inner membrane.
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