Editing Protein targeting (section)

==== Mitochondrial matrix ====
Proteins destined for the mitochondrial matrix have specific signal sequences at their beginning (N-terminus) that consist of a string of 20 to 50 amino acids. These sequences are designed to interact with receptors that guide the proteins to their correct location inside the mitochondria. The sequences have a unique structure with clusters of water-loving (hydrophilic) and water-avoiding (hydrophobic) amino acids, giving them a dual nature known as amphipathic. These amphipathic sequences typically form a spiral shape (alpha-helix) with the charged amino acids on one side and the hydrophobic ones on the opposite side. This structural feature is essential for the sequence to function correctly in directing proteins to the matrix. If mutations occur that mess with this dual nature, the protein often fails to reach its intended destination, although not all changes to the sequence have this effect. This indicates the importance of the amphipathic property for the protein to be correctly targeted to the mitochondrial matrix.<ref name="Lodish-2016" />[[File:Inner membrane and matrix protein targeting.png|thumb|The pre-sequence pathway into the mitochondrial inner membrane (IM) and mitochondrial matrix.]]Proteins targeted to the mitochondrial matrix first involves interactions between the matrix targeting sequence located at the N-terminus and the outer membrane import receptor complex TOM20/22.<ref name="Lodish, Berk, Kaiser, Krieger, Bretscher, Ploegh, Martin, Yaffe, Amon-2021" /><ref name="Araiso Y, Endo T-2022" /><ref name="Pfanner N, Geissler A-2001">{{Cite journal |last=Pfanner N, Geissler A |date=2001 |title=Versatility of the mitochondrial protein import machinery |url=https://www.nature.com/articles/35073006 |journal=Nature Reviews Molecular Cell Biology |volume=2 |issue=5 |pages=339–349 |doi=10.1038/35073006 |pmid=11331908 |s2cid=21011113 |via=Nature}}</ref> In addition to the docking of internal sequences and [[cytosolic]] [[Chaperone (protein)|chaperones]] to TOM70.<ref name="Lodish, Berk, Kaiser, Krieger, Bretscher, Ploegh, Martin, Yaffe, Amon-2021" /><ref name="Araiso Y, Endo T-2022" /><ref name="Pfanner N, Geissler A-2001" /> Where TOM is an abbreviation for translocase of the outer membrane. Binding of the matrix targeting sequence to the import receptor triggers a handoff of the polypeptide to the general import core (GIP) known as TOM40.<ref name="Lodish, Berk, Kaiser, Krieger, Bretscher, Ploegh, Martin, Yaffe, Amon-2021" /><ref name="Araiso Y, Endo T-2022" /><ref name="Pfanner N, Geissler A-2001" /> The general import core (TOM40) then feeds the polypeptide chain through the intermembrane space and into another translocase complex TIM17/23/44 located on the inner mitochondrial membrane.<ref name="Lodish, Berk, Kaiser, Krieger, Bretscher, Ploegh, Martin, Yaffe, Amon-2021" /><ref name="Eaglesfield R, Tokatlidis K-2021" /><ref name="Wiedemann N, Pfanner N-2017" /><ref name="Bauer M, Hofmann S, Neupert W, Brunner M-2000">{{Cite journal |last=Bauer M, Hofmann S, Neupert W, Brunner M |date=2000 |title=Protein translocation into mitochondria: the role of TIM complexes |journal=Trends in Cell Biology |volume=10 |issue=1 |pages=25–31 |doi=10.1016/S0962-8924(99)01684-0 |pmid=10603473 |via=Elsevier Science Direct}}</ref> This is accompanied by the necessary release of the [[cytosolic]] [[Chaperone (protein)|chaperones]] that maintain an unfolded state prior to entering the mitochondria. As the polypeptide enters the matrix, the signal sequence is cleaved by a processing [[Protease|peptidase]] and the remaining sequences are bound by mitochondrial chaperones to await proper folding and activity.<ref name="Wiedemann N, Pfanner N-2017" /><ref name="Truscott K, Pfanner N, Voos W-2001" /> The push and pull of the polypeptide from the cytosol to the intermembrane space and then the matrix is achieved by an [[electrochemical gradient]] that is established by the mitochondrion during [[oxidative phosphorylation]].<ref name="Nelson-2017" /><ref name="Eaglesfield R, Tokatlidis K-2021" /><ref name="Wiedemann N, Pfanner N-2017" /><ref name="Truscott K, Pfanner N, Voos W-2001" /> In which a mitochondrion active in [[metabolism]] has generated a [[Membrane potential|negative potential]] inside the matrix and a [[Membrane potential|positive potential]] in the intermembrane space.<ref name="Wiedemann N, Pfanner N-2017" /><ref>{{Cite book |last=Nelson D, Cox M |title=Principles of Biochemistry |publisher=W.H. Freeman and Company |year=2017 |isbn=978-1-4641-2611-6 |edition=7th |location=New York, NY}}</ref> It is this negative potential inside the matrix that directs the positively charged regions of the targeting sequence into its desired location.