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Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase

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International Journal of Molecular Sciences Review Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase Minu Chaudhuri *, Anuj Tripathi and Fidel Soto Gonzalez Department of Microbiology, Immunology, and Physiology, Meharry Medical College, Nashville, TN 37208, USA; [email protected] (A.T.); [email protected] (F.S.G.) * Correspondence: [email protected]; Tel.: +1-615-327-5726 Abstract: Mitochondria are essential in eukaryotes. Besides producing 80% of total cellular ATP, mito- chondria are involved in various cellular functions such as apoptosis, inflammation, innate immunity, stress tolerance, and Ca2+ homeostasis. Mitochondria are also the site for many critical metabolic pathways and are integrated into the signaling network to maintain cellular homeostasis under stress. Mitochondria require hundreds of proteins to perform all these functions. Since the mitochondrial genome only encodes a handful of proteins, most mitochondrial proteins are imported from the cytosol via receptor/translocase complexes on the mitochondrial outer and inner membranes known as TOMs and TIMs. Many of the subunits of these protein complexes are essential for cell survival in model yeast and other unicellular eukaryotes. Defects in the mitochondrial import machineries are also associated with various metabolic, developmental, and neurodegenerative disorders in multicellular organisms. In addition to their canonical functions, these protein translocases also help maintain mitochondrial structure and dynamics, lipid metabolism, and stress response. This review focuses on the role of Tim50, the receptor component of one of the TIM complexes, in different cellular Citation: Chaudhuri, M.; Tripathi, functions, with an emphasis on the Tim50 homologue in parasitic protozoan Trypanosoma brucei. A.; Gonzalez, F.S. Diverse Functions of Tim50, a Component of the Keywords: Tim50; TOM; TIM; Trypanosoma; TIMM50; HAD-phosphatase family Mitochondrial Inner Membrane Protein Translocase. Int. J. Mol. Sci. 2021, 22, 7779. https://doi.org/ 10.3390/ijms22157779 1. Introduction Mitochondria are evolved from the endosymbiont proteobacteria [1]. Thus, like its Academic Editor: Andrey ancestor, mitochondria are surrounded by double membranes. The mitochondrial outer V. Kuznetsov membrane (MOM) is semipermeable due to the presence of multiple pores created by the most abundant mitochondrial protein, voltage-dependent anion channel (VDAC) that Received: 1 June 2021 allows fluxes of small molecules and metabolites [2]. Whereas mitochondrial inner mem- Accepted: 16 July 2021 Published: 21 July 2021 brane (MIM) is impermeable even to ions and is folded inwards to form cristae [3]. MIM separates two aqueous compartments in the mitochondria, the innermost matrix and inter Publisher’s Note: MDPI stays neutral membrane space (IMS). At the invagination site, MIM forms a tubular structure, known as with regard to jurisdictional claims in cristae junction site, that is held together near the periphery by a large protein complex published maps and institutional affil- known as the mitochondrial contact site and cristae organizing system (MICOS) [4]. Mito- iations. chondrial respiratory complexes and ATP synthase are localized in the cristae membrane and are functionally coupled via chemiosmotic proton pump that is required for energy production [5] (Figure1). The size of mitochondrial proteomes varies among eukaryotes; ~1800 in mammals, ~2000 in plants, and ~1000 in yeast [6–8]. The residual genome of the bacterial endosym- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. biont only encodes 1% of these proteins and the rest of the proteins (99%) are nuclear This article is an open access article DNA encoded [8–10]. These proteins are synthesized by the cytosolic ribosomes and stay distributed under the terms and unfolded by binding through cytosolic chaperones till they are recognized by the receptor conditions of the Creative Commons translocases of the TOM [8–10]. Most of the mitochondrial proteins are in the MIM and the Attribution (CC BY) license (https:// matrix thus require crossing both membranes [8]. The MOM and IMS also possess several creativecommons.org/licenses/by/ important proteins [11,12]. Proteins are translocated through TOM and TIMs either as fully 4.0/). or partially unfolded conditions [8–10]. Once reached their destination, newly translocated Int. J. Mol. Sci. 2021, 22, 7779. https://doi.org/10.3390/ijms22157779 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 26 Int. J. Mol. Sci. 2021, 22, 7779 the matrix thus require crossing both membranes [8]. The MOM and IMS also possess2 of 26 several important proteins [11,12]. Proteins are translocated through TOM and TIMs ei- ther as fully or partially unfolded conditions [8–10]. Once reached their destination, newly translocatedproteins are foldedproteins properly are folded by chaperones properly by for chaperones being functional. for being Translocation functional. ofTransloca- proteins tionthrough of proteins TIM requires through mitochondrial TIM requires membrane mitochondrial potential. membrane In addition, potential. ATP hydrolysisIn addition, is ATPneeded hydrolysis for proteins is needed to enter for mitochondrial proteins to enter matrix. mitochondrial The contact matrix. site between The contact the MOM site andbe- tweenMIM facilitates the MOM protein and MIM import facilitates by bringing protein TOM impo nearrt by one bringing of the TIM TOM complexes near one of [13 the]. To TIM be complexesdiscriminated [13]. from To be the discrimi other cytosolicnated from proteins, the other mitochondrial cytosolic proteins, proteins mito harborchondrial at least pro- one teinsmitochondrial harbor attargeting least one signal mitochondrial (MTS). In targeting most of the signal cases (MTS). MTS is In located most atof thethe N-terminal;cases MTS ishowever, located certainat the N-terminal; proteins have however, multiple certain internal proteins targeting have signals. multiple The MTSsinternal do targeting not have signals.any consensus The MTSs sequence, do not have although any consensus N-terminal sequence, MTSs possess although certain N-terminal characteristics. MTSs pos- It sessconsists certain of ancharacteristics. amphipathic Itα -helixconsists with of an several amphipathic positively α-helix charged with residues several positioned positively chargedon one side residues of the positioned helix and the on hydrophobicone side of the residues helix and face the the hydrophobic other side of theresidues helix [face14]. theThe other internal side MTSs of the are helix less [14]. characterized. The internal Tim50, MTSs aare component less characterized. of the one Tim50, of the a two compo- TIM nentcomplexes of the foundone of inthe fungi, two TIM plants, complexes and animals foun recognizesd in fungi, theplants, N-terminal and animals MTS-containing recognizes theproteins N-terminal for translocating MTS-containing them throughproteins the for MIMtranslocating [8–10]. them through the MIM [8–10]. Figure 1. Schematics of protein complexes of the mitochondrial ou outerter and inner membranes as id identifiedentified in yeast. Mito- chondrial cristae junction and the contactcontact site for the outer and inner membranes are enlarged. The Sorting and Assembly of the β-barrel-barrel proteins proteins (SAM), (SAM), MIM, MIM, and and the the translocase translocase of of the the outer outer membrane membrane (TOM), (TOM), are are involved involved in inthe the import import of ofβ- βbarrel,-barrel, α-helical,α-helical, and and all all other other nuclear-encoded nuclear-encoded mitochondrial mitochondrial prot proteinseins in in and and through through the the mitochondrial mitochondrial outer outer membrane, membrane, respectively. The The voltage-dependent voltage-dependent anion anion channel channel (VDAC) (VDAC) mediates mediates small small molecules molecules and and metabolite metabolite fluxes fluxes through through the mitochondrial outer membrane. TIM23 and TIM22 are the major protein translocases of the mitochondrial inner mem- the mitochondrial outer membrane. TIM23 and TIM22 are the major protein translocases of the mitochondrial inner brane. Presequence translocase (TIM23)-associated motor complex (PAM) imports protein into the matrix. Small Tim com- membrane. Presequence translocase (TIM23)-associated motor complex (PAM) imports protein into the matrix. Small Tim plexes acts as chaperones for hydrophobic inner membrane proteins to cross the intermembrane space. MIA40 and OXA1 complexesimports proteins acts as to chaperones the intermembrane for hydrophobic space and inner the inner membrane membrane, proteins respectively. to cross the Mitochondrial intermembrane contact space. site MIA40 and cristae and OXA1organization imports system proteins (MICOS) to the intermembraneform the cristae space junction. and Respir the inneratory membrane, complexes respectively. and ATP synthase Mitochondrial (CI, CII, contact CIII, CIV, site and cristaeCV) are organization localized in systemthe cristae (MICOS) membrane. form the The cristae picture junction. was created Respiratory with the complexes BioRender.com. and ATP synthase (CI, CII, CIII, CIV, and CV) are localized in the cristae membrane. The picture was created with the BioRender.com. 2. Mitochondrial Protein Translocases Mitochondrial protein import is mostly studied for the eukaryotic supergroup opisthokonta, that includes fungi and mammals
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