Abstract:Most mitochondrial proteins are imported by the translocase of the outer mitochondrial membrane (TOM). Tom22 functions as central receptor and transfers preproteins to the import pore. Casein kinase 2 (CK2) constitutively phosphorylates the cytosolic precursor of Tom22 at Ser44 and Ser46 and, thus, promotes its import. It is unknown whether Tom22 is regulated under different metabolic conditions. We report that CK1, which is involved in glucose-induced signal transduction, is bound to mitochondria. CK1 phospho… Show more
“…The predicted transmembrane sequence at the Cterminus in combination with protease sensitivity indicated that the bulk of the KOC1 protein faces the cytosol. The only other known organelle-associated kinase facing the cytosol apart from KOC1 is mitochondrial CK1 (casein kinase 1) which phosphorylates TOM20 and stimulates assembly of the TOM complex (44).…”
“…The predicted transmembrane sequence at the Cterminus in combination with protease sensitivity indicated that the bulk of the KOC1 protein faces the cytosol. The only other known organelle-associated kinase facing the cytosol apart from KOC1 is mitochondrial CK1 (casein kinase 1) which phosphorylates TOM20 and stimulates assembly of the TOM complex (44).…”
More than 70% of mitochondrial proteins utilize N-terminal presequences as targeting signals. Presequence interactions with redundant cytosolic receptor domains of the translocase of the outer mitochondrial membrane (TOM) are well established. However, after the presequence enters the protein-conducting Tom40 channel, the recognition events that occur at the trans side leading up to the engagement of the presequence with inner membrane-bound receptors are less well defined. Using a photoaffinity-labeling approach with modified presequence peptides, we identified Tom40 as a presequence interactor of the TOM complex. Utilizing mass spectrometry, we mapped Tom40's presequence-interacting regions to both sides of the -barrel. Analysis of a phosphorylation site within one of the presequence-interacting regions revealed altered translocation kinetics along the presequence pathway. Our analyses assess the relation between the identified presequence-binding region of Tom40 and the intermembrane space domain of Tom22. The identified presequence-interacting region of Tom40 is capable of functioning independently of the established trans-acting TOM presequence-binding domain during matrix import.
Mitochondria receive the majority of their resident proteins from the cytoplasm. Therefore, mitochondria must mediate the influx of proteins, which have been translated on cytosolic ribosomes, in a spatially constrained manner, i.e., all substrates are required to be unfolded during membrane passage. This constraint is in part due to the static dimensions of the pore within the translocase of the outer mitochondrial membrane (TOM). The TOM complex is involved in the majority of mitochondrial import traffic and therefore serves as the main gateway into the mitochondrion (for reviews, see references 1 to 4).About two-thirds of mitochondrial proteins are targeted into mitochondria by N-terminal targeting signals (presequences) (5). These signals consist of amphipathic ␣-helices with a net positive charge and direct the precursors across the outer and inner mitochondrial membranes. Presequence recognition at the TOM complex is thought to commence with the interaction of the hydrophobic surface of the amphipathic presequence-helix with the Tom20 binding groove (6-8). Subsequently, the hydrophilic side is recognized by the cytosolic domain of the central receptor Tom22 that interacts with the presequence in a salt-sensitive manner (6). The exact series of initial presequence-binding events is still debated; however, there is growing support for a tertiary complex in which both Tom20 and Tom22 interact with the presequence simultaneously (9, 10). Following the positioning of the presequence via Tom22, the substrate is passed to the pore-forming subunit of the TOM complex, Tom40. This process involves Tom5, which serves as a TOM assembly and presequence-interacting subunit (11). As the presequence emerges from the Tom40 pore on the trans side, the intermembrane space (IMS) domain of Tom22 engages with the precursor (10,(12)(13)(14). From...
“…Three core components of the TOM complex, TOM70, TOM22 and TOM40, are phosphorylated by PKA in response to the glucose-induced cAMP increase triggered by a metabolic switch from respiratory to fermentable conditions [51–53]. Phosphorylation by PKA impairs the interaction between TOM70 and metabolite carrier/chaperone complexes (e.g., AAC/Hsp70) [51], inhibits the translocation of TOM22 to mitochondria [52] and prevents the integration of TOM40 into the OMM [53]. Thus, elevated cAMP-PKA signaling slows down the import of mitochondrial proteins, and fosters the metabolic switch from OXPHOS to glycolysis in conditions of increased glucose or reduced oxygen availability.Fig.…”
Section: Camp Signaling In the Outer-mitochondrial Compartment (Fig 2)mentioning
Cyclic adenosine 3, 5′-monophosphate (cAMP) is a ubiquitous second messenger regulating many biological processes, such as cell migration, differentiation, proliferation and apoptosis. cAMP signaling functions not only on the plasma membrane, but also in the nucleus and in organelles such as mitochondria. Mitochondrial cAMP signaling is an indispensable part of the cytoplasm-mitochondrion crosstalk that maintains mitochondrial homeostasis, regulates mitochondrial dynamics, and modulates cellular stress responses and other signaling pathways. Recently, the compartmentalization of mitochondrial cAMP signaling has attracted great attentions. This new input should be carefully taken into account when we interpret the findings of mitochondrial cAMP signaling. In this review, we summarize previous and recent progress in our understanding of mitochondrial cAMP signaling, including the components of the signaling cascade, and the function and regulation of this signaling pathway in different mitochondrial compartments.
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