The mitochondrion is an essential cellular compartment in eukaryotes. Although it contains its own genome organized in a circular DNA molecule and an independent transcriptional/translational machinery, 98% of the approximately 1500 proteins that constitute the mitochondrial proteome are encoded by nuclear DNA and are imported from the cytosol after their synthesis. A small number of highly hydrophobic proteins is encoded by mtDNA and transcribed and synthesized inside the organelle.

Like nuclei, mitochondria have two membranes: the outer mem brane (MOM) contacts the cytosol, whereas the inner membrane (mitochondrial import machinery [MIM]) forms numerous invaginations named cristae, where the enzymes reside that synthesize ATP through reactions of the electron transport chain and oxidative phosphorylation. The MOM is permeable to small molecules (less than 5 kDa) and ions, whereas the inner membrane is highly impermeable, a property essential to create an electrochemical gradient necessary to drive the synthesis of ATP. Protein transport into mitochondria appears to be unidirectional because no proteins are known to be exported from mitochondria. Posttranslational translocation and sorting of proteins into the various mitochondrial subcompartments are achieved by the concerted action of translocases. Precursor proteins usually have one of two targeting signals: (1) an amino-terminal presequence that is generally between 10 and 80 amino acids long and forms an amphipathic α-helix, which is rich in positively charged, hydrophobic, and hydroxylated amino acids (see Table 1); or (2) a less well-defined, hydrophobic targeting sequence distributed throughout the protein. The translocase of the outer membrane (TOM) complex functions as a single entry point of incoming pre cursors into the mitochondria and is crucial for the biogenesis of the organelle and for the viability of eukaryotic cells. After crossing the outer membrane, proteins segregate according to their signals and recognize two distinct translocases of the inner membrane (TIM23 and TIM22). The intermembrane space import and assembly machinery (MIA) drives the import of proteins with cysteine-rich motifs, the sorting/assembly machinery (SAM) inserts precursors of proteins with a transmembrane β-barrel domains in the MOM, and the MIM imports outer membrane proteins with α-helical transmembrane segments after their recognition by the TOM complex.[1] Interestingly, cryoelectron microscopy images in cells show that translation-arrested cytosolic ribosomes are in close proximity of the surface of mitochondria. These ribosomes are organized in the clusters with the TOM complex, suggesting localized translation of mitochondrial proteins.[2]

Table1. Examples of Sorting Signals

In the context of cell biology, mitochondria play relevant roles in apoptosis, in the communication with the ER, and in oxidative stress. Among the proteins associated with the cytosolic side of MOM, those of the Bcl-2 family have both proapoptotic or antiapoptotic functions. BCL-2 family proteins function through direct protein-protein interactions. When BH3-only proteins are released by antiapoptotic BCL-2-like family members, they promote homo-oligomerization of the effector proteins BAX and BAK and induce mitochondrial outer membrane permeabilization, release of cytochrome c, and activation of the caspase cascade. BCL-2–mediated antiapoptotic effects are critical to the survival of CLL cells and inhibition of BCL-2 in CLL has led to complete responses even in relapsed, refractory CLL [3]; expansion of inhibition of BCL-2 and other antiapoptotic proteins in CLL and other hematologic malignancies is focus of intense studies.

References

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[1] Wiedemann N, Pfanner N. Mitochondrial machineries for protein import and assembly. Annu Rev Biochem. 2017;86:685–714.

[2] Gold VA, Chroscicki P, Bragoszewski P, Chacinska A. Visualization of cytosolic ribosomes on the surface of mitochondria by electron cryotomography. EMBO Rep. 2017;18(10):1786–1800.

[3] Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4): 311–322.

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مواضيع ذات صلة

Intra-Golgi Transport and Protein Processing

Cotranslational Protein Translocation Into the Endoplasmic Reticulum

The Isolation and Structure of Operator

The Migration Retardation Assay and DNA Looping

Repressor Binds to DNA: The Operator is DNA

Detection and Purification of lac Repressor

The Difficulty of Detecting Wild-Type lac Repressor

An Assay for lac Repressor

Proving lac Repressor is a Protein

The Role of Inducer Analogs in the Study of the lac Operon

Background of the lac Operon

Mutagenesis with Chemically Synthesized DNA