Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex
Abstract
:1. Introduction
2. The Yeast TIM23 and Human TIMM23 Complexes
- In humans, due to the presence of isoforms of Tim17 and DnaJC (the homolog of yeast Tim14/Pam18), three TIMM23MOTOR complex formations are presently known, namely, (i) translocase A consisting of Tim17a and DnaJC15, (ii) translocase B1 consisting of Tim17b1 and DnaJC19, and (iii) translocase B2 consisting of Tim17b2 and DnaJC19 [49,50]. Similar to the yeast complex, translocases B1 and B2 are expected to play major roles in protein import via the presequence pathway [50]. Interestingly, high expression of Tim17A mRNA has been reported in patients suffering from breast cancer [68,69]. Such elevated expression is closely linked to the aggressive growth of cancerous cells and adverse pathological and clinical outcomes [68,69]. Therefore, Tim17A is thought to be a prognostic biomarker for human breast cancer and a potential target for therapeutic developments.
- Interestingly, no homolog of Pam17 has yet been identified in humans. As discussed above, Pam17 plays a supportive role within the PAM complex. Although not essential, Pam17 is crucial for optimizing the activity of the import motor. Therefore, it would be worthwhile to identify those human subunits that fulfill the same function.
- In yeast, Tim50 contains an extra, so-called presequence-binding domain (PBD) at its C-terminus (residues 395 to 476) thought to contribute to four major functions: (i) interaction with Tom22IMS [22]; (ii) interaction with the presequence [71]; (iii) interaction with the conserved core domain of Tim50 (residues 164 to 361) [72]; and (iv) interaction with Tim21IMS [73]. This suggests that Tim50 plays a highly dynamic and intricate role, especially the PBD, in IM and matrix protein import. However, in humans, Timm50 lacks the PBD. It is thus not surprising that human Timm50 was unable to complement its yeast homolog [74].
3. Genetic Variants in the TIM23 Complex
3.1. Genetic Diseases Associated with Tim50
3.2. Genetic Diseases Associated with mHsp70
3.3. Genetic Diseases Associated with Tim14 and Tim16
4. Future Perspectives
5. Conclusions
Supplementary Materials
Funding
Conflicts of Interest
References
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Protein | Pathogenic/Likely Pathogenic Mutation * | Symptoms | ClinVar Accession No. | First Deposited in ClinVar | Reference |
---|---|---|---|---|---|
TIM23 core components | |||||
Tim23 | NA | ||||
Tim17A | NA | ||||
Tim17B | NA | ||||
Tim50 | NM_001001563.5(TIMM50):c.26C>A (p.Ser9Ter) | Mitochondrial encephalopathy, Reduced TIMM50 mRNA levels, OXPHOS malfunction, Failure to thrive, Lactic acidosis | RCV000677434.1, RCV001328000.2 | 24 August 2018 | [75] |
NM_001001563.5(TIMM50):c.260G>C (p.Gly87Ala) | Mitochondrial encephalopathy, Reduced TIMM50 mRNA levels, OXPHOS malfunction, Failure to thrive, Lactic acidosis | RCV000677433.1, RCV001328001.1 | 24 August 2018 | [75] | |
NM_001001563.5(TIMM50):c.341G>A (p.Arg114Gln) | Encephalopathy, Decreased complex I, II, IV and V levels, Abnormality of visual evoked potentials, Strabismus, Scoliosis | RCV001812628.1, RCV003120700.4 | 19 January 2022 | [79] | |
NM_001001563.5(TIMM50):c.340C>T (p.Arg114Trp) | Epileptic encephalopathy, Decreased complex V activity, Elevated CSF lactate levels, Myoclonic jerks, Cachectic | RCV000509033.3, RCV001367110.6 | 9 October 2017 | [74] | |
NM_001001563.5(TIMM50):c.446C>T (p.Thr149Met) | Epileptic spasms, Hypsarrhythmia, Bilateral optic atrophy, Abnormal EEG, Developmental delay | RCV000509024.3 | 9 October 2017 | [74,80] | |
NM_001001563.5(TIMM50):c.664G>A (p.Ala222Thr) | 3-methylglutaconic aciduria type 9 | RCV000578358.5 | 8 February 2018 | [81] | |
NM_001001563.5(TIMM50):c.715C>T (p.Arg239Trp) | 3-methylglutaconic aciduria type 9 | RCV000578437.5, RCV002529040.2 | 8 February 2018 | [82] | |
NM_001001563.5(TIMM50):c.805G>A (p.Gly269Ser) | Encephalopathy, Failure to thrive, Spastic tetraparesia with dystonia, Piramidalism, Elevated CSF lactate levels | RCV000190713.5, RCV001812182.1 | 14 September 2015 | [79] | |
TIM23 lateral-sorting components | |||||
Tim21 | NA | ||||
Mgr2 | NA | ||||
TIM23 motor components/PAM complex | |||||
Tim44 | NA | ||||
Tim14 (Isoform 1) | NM_145261.4(DNAJC19):c.51del (p.Phe17fs) | Dilated cardiomyopathy with ataxia, Lipidosis, 3-methylglutaconic aciduria type 5 | RCV001231277.9 | 16 July 2020 | [83,84,85] |
NM_145261.4(DNAJC19):c.63del (p.Arg20_Tyr21insTer) | Dilated cardiomyopathy with ataxia, 3-methylglutaconic aciduria type 5 | RCV001780991.5 | 29 November 2021 | [84,85] | |
NM_145261.4(DNAJC19):c.63C>G (p.Tyr21Ter) | Dilated cardiomyopathy with ataxia, Failure to thrive, Optic atrophy, 3-methylglutaconic aciduria type 5, 3-methylglutaconic aciduria type 3 | RCV001206673.7, RCV001824933.1 | 16 July 2020 | [84,85] | |
NM_145261.4(DNAJC19):c.62dup (p.Tyr21Ter) | Dilated cardiomyopathy with ataxia, 3-methylglutaconic aciduria type 5 | RCV001729987.3 | 16 October 2021 | [84,85,86] | |
NM_145261.4(DNAJC19):c.158G>A (p.Gly53Glu) | Dilated cardiomyopathy with ataxia, 3-methylglutaconic aciduria type 5 | RCV001283818.1 | 26 January 2021 | [76] | |
NM_145261.4(DNAJC19):c.300del (p.Ala101fs) | Dilated cardiomyopathy with ataxia, Noncompaction cardiomyopathy, 3-methylglutaconic aciduria type 5 | RCV000106304.5 | 24 March 2014 | [87] | |
Tim14 (Isoform 2) | NA | ||||
Pam16 | NM_016069.11(PAM16):c.221A>C (p.Gln74Pro) | Autosomal recessive spondylometaphyseal dysplasia, Megarbane type, Macrocephaly, Developmental delay, Hypotonia, Narrow spinal cord | RCV000788051.3 | 22 July 2019 | [77] |
NM_016069.11(PAM16):c.226A>G (p.Asn76Asp) | Autosomal recessive spondylometaphyseal dysplasia, Megarbane type, Developmental delay, Prominent abdomen, Square iliac bones, Respiratory insufficiency | RCV000167551.4 | 29 March 2015 | [88] | |
mHsp70 | NM_004134.7(HSPA9):c.376C>T (p.Arg126Trp) | EVEN-plus syndrome (EVPLS) [Epiphyseal and vertebral dysplasia, microtia, and flat nose, plus associated malformations] | RCV000210028.3 | 14 March 2016 | [78] |
NM_004134.7(HSPA9):c.383A>G (p.Tyr128Cys) | EVEN-plus syndrome (EVPLS) [Epiphyseal and vertebral dysplasia, microtia, and flat nose, plus associated malformations], Premature termination predicted to abolish half the protein | RCV000209966.4 | 14 March 2016 | [78] | |
NM_004134.7(HSPA9):c.409_410del (p.Asp136_Ile137insTer) | Autosomal dominant sideroblastic anemia, 50% of HSPA9 mRNA and 80% of HSPA9 protein | RCV000209839.4 | 12 March 2016 | [89,90] | |
NM_004134.7(HSPA9):c.882_883del (p.Gly295_Val296insTer) | EVEN-plus syndrome (EVPLS) [Epiphyseal and vertebral dysplasia, microtia, and flat nose, plus associated malformations], Predicted to result in premature protein termination, Developmental delay | RCV000209995.6, RCV001781629.4, RCV003387515.2 | 12 March 2016 | [78] | |
NM_004134.7(HSPA9):c.1373_1378del (p.Ile458_Asn459del) | Autosomal dominant sideroblastic anemia, 50% of HSPA9 mRNA and 80% of HSPA9 protein | RCV000209862.4 | 12 March 2016 | [89] | |
Mge 1 (Isoform 1) | NA | ||||
Mge 1 (Isoform 2)_ | NA |
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Jain, S.; Paz, E.; Azem, A. Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex. Genes 2024, 15, 1534. https://doi.org/10.3390/genes15121534
Jain S, Paz E, Azem A. Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex. Genes. 2024; 15(12):1534. https://doi.org/10.3390/genes15121534
Chicago/Turabian StyleJain, Sahil, Eyal Paz, and Abdussalam Azem. 2024. "Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex" Genes 15, no. 12: 1534. https://doi.org/10.3390/genes15121534
APA StyleJain, S., Paz, E., & Azem, A. (2024). Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex. Genes, 15(12), 1534. https://doi.org/10.3390/genes15121534