Affinage

TIMM17A

Mitochondrial import inner membrane translocase subunit Tim17-A · UniProt Q99595

Length
171 aa
Mass
18.0 kDa
Annotated
2026-06-10
25 papers in source corpus 14 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIMM17A (Tim17) is an essential, stoichiometrically required membrane subunit of the TIM23 presequence translocase of the mitochondrial inner membrane, where it drives import of preproteins bearing presequences into the matrix and laterally sorts inner-membrane precursors (PMID:37527780, PMID:10393182). Conserved negative charges near the intermembrane-space face of Tim17 initiate translocation along a distinct Tim17 transmembrane cavity for both matrix-targeted and laterally-released precursors, and control preprotein-induced gating of the translocase (PMID:37527780, PMID:15618217). Its transmembrane segments perform separable tasks: TM1/TM2 mediate interaction with the Tim23 channel while TM3 and matrix-facing residues bind the PAM import motor, allowing Tim17 to hand preproteins from channel to motor and to govern the dynamic switch between the TOM-tethered/sorting (Tim21-containing) and PAM-bound forms of the translocase via conserved G/AXXXG/A TM motifs (PMID:28165323, PMID:27994013). Beyond its constitutive import role, Tim17A acts as a stress-regulated rheostat: stress-induced eIF2α phosphorylation lowers Tim17A levels through the inner-membrane protease YME1L, attenuating TIM23-dependent import and inducing mitochondrial proteostasis (UPR) genes (PMID:24315374). Tim17A also suppresses mtDNA instability, with its overexpression stabilizing mutant mtDNA in a human cellular disease model (PMID:18826960, PMID:27994013). The short-lived Tim17A protein is supported by an HSF1–HSPD1/HSPE1 chaperonin axis that sustains mitochondrial biogenesis and energy production in cancer cells, and its loss causes mitochondrial iron overload, oxidative stress, and parthanatos, linking import capacity to iron homeostasis and tumor cell viability (PMID:40463013, PMID:38949950).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 High

    Established that metazoan Tim17 orthologs are functionally conserved, addressing whether human/Drosophila Tim17 use the same targeting and assembly mechanism as yeast.

    Evidence In vitro import of human and Drosophila Tim17 into isolated yeast mitochondria with topology and assembly analysis

    PMID:8893850

    Open questions at the time
    • Did not define Tim17 function within the translocase
    • Heterologous yeast system, not native human mitochondria
  2. 1998 High

    Defined Tim17's own biogenesis route, showing its import signal lies in the C-terminal half and requires the carrier (Tim22) translocase and membrane potential, not Tim23.

    Evidence In vitro import assays in isolated yeast mitochondria with ΔΨ depletion and ts-Tim22 mutants

    PMID:9501078

    Open questions at the time
    • Did not resolve Tim17 functional contribution to preprotein translocation
    • Structural basis of topology unaddressed
  3. 1999 Medium

    Showed Tim17 is a stoichiometric, indispensable component of the TIM17.23 translocase, establishing it as part of a defined complex rather than an accessory factor.

    Evidence Biochemical fractionation, Co-IP and stoichiometry analysis of yeast mitochondria

    PMID:10393182

    Open questions at the time
    • No Tim17-lacking sub-complex tested functionally
    • Single lab, no structural model
  4. 2004 High

    Identified conserved IMS-facing negative charges as critical for import and proposed they control preprotein-induced gating, beginning to define the molecular mechanism of Tim17 action.

    Evidence Truncation, alanine-scanning and charge-reversal mutagenesis with import assays and ΔΨ measurements in yeast

    PMID:15618217

    Open questions at the time
    • Gating model inferred from genetics, not structurally resolved at the time
    • Single lab
  5. 2005 High

    Resolved that Tim17 has two separable functions—membrane insertion and Pam18/PAM binding—and is the switch between sorting and motor-bound translocase states.

    Evidence Reciprocal Co-IP, import assays and genetic dissection of TIM23 sub-complexes in yeast

    PMID:15797382

    Open questions at the time
    • Which TM segments mediate each function not yet assigned
    • Switch dynamics not directly visualized
  6. 2008 Medium

    Demonstrated TIMM17A can suppress mtDNA loss, linking the import subunit to genome maintenance in a human disease model.

    Evidence Overexpression in A3243G cybrid cells with mtDNA quantification plus yeast multicopy suppressor screen

    PMID:18826960

    Open questions at the time
    • Mechanism connecting import to mtDNA stability unresolved
    • Overexpression phenotype only
  7. 2013 High

    Established Tim17A as a stress-regulated rheostat, showing eIF2α phosphorylation triggers YME1L-dependent Tim17A degradation that attenuates import and induces a protective UPR.

    Evidence Stress induction, YME1L KD/KO, import and UPR gene assays in C. elegans and mammalian cells

    PMID:24315374

    Open questions at the time
    • Direct YME1L cleavage site on Tim17A not mapped
    • How import attenuation triggers UPR genes not fully resolved
  8. 2017 High

    Assigned distinct TM segments to specific partner interactions (TM1/TM2–Tim23, TM3–PAM) and identified G/AXXXG/A motifs governing the assembly switch, refining the structural logic of channel-to-motor handoff.

    Evidence Systematic alanine/glycine TM mutagenesis with Co-IP, BN-PAGE and import/mtDNA assays in yeast

    PMID:27994013 PMID:28165323

    Open questions at the time
    • Atomic structure of the switch states not determined
    • mtDNA instability link mechanistically incomplete
  9. 2023 High

    Resolved the translocation path itself, mapping a distinct Tim17 transmembrane cavity and IMS-side negative charges that initiate translocation and enable lateral release of sorted precursors.

    Evidence Crosslinking/interaction mapping with translocating preproteins in native membrane plus mutagenesis and structural analysis

    PMID:37527780

    Open questions at the time
    • Dynamics of lateral gate opening during sorting not time-resolved
    • Coupling to PAM during matrix import not structurally captured
  10. 2024 Medium

    Connected Tim17A to iron homeostasis and a druggable vulnerability, showing its loss (or NMT inhibition) drives mitochondrial iron overload and parthanatos in lung cancer cells.

    Evidence siRNA KD, NMT inhibitor treatment, iron/oxidative stress/PAR measurements and tumor assays

    PMID:38949950

    Open questions at the time
    • Mechanism linking import loss to ferrous iron accumulation unresolved
    • Role of Tim17A myristoylation status not directly demonstrated
  11. 2025 Medium

    Placed Tim17A within an HSF1–HSPD1/HSPE1 chaperonin axis sustaining its short-lived protein and within a DNAJC15-regulated import bottleneck for OXPHOS biogenesis.

    Evidence CRISPR epistasis screen and DNAJC15/OMA1/AFG3L2 genetic manipulation with import, respiration and UPR readouts (preprints)

    PMID:40307502 PMID:40463013

    Open questions at the time
    • Preprint, not peer-reviewed
    • Direct biochemical link between chaperonins and Tim17A folding/stability not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How constitutive import function, stress-driven YME1L degradation, mtDNA maintenance, and iron homeostasis are mechanistically unified through a single Tim17A subunit remains unresolved.
  • No structural model of human TIMM17A translocase states
  • Mechanistic basis of mtDNA stabilization undefined
  • Causal chain from import loss to iron overload/parthanatos uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140104 molecular carrier activity 4 GO:0008289 lipid binding 1
Pathway
R-HSA-9609507 Protein localization 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
PAM18TIMM21TIMM23TIMM44YME1L
Complex memberships
TIM23 presequence translocaseTIM23-PAM import motor complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 Tim17 contains conserved negative charges close to the intermembrane space side of the bilayer that are essential to initiate presequence protein translocation along a distinct transmembrane cavity of Tim17 for both matrix-targeted and inner membrane-sorted preproteins; direct lateral release of transmembrane segments of inner membrane-sorted precursors into the lipid bilayer occurs via this Tim17-dependent mechanism. Crosslinking/interaction mapping of Tim17 with translocating preproteins in the native membrane environment; mutagenesis of conserved negative charges; structural analysis Nature High 37527780
2005 Tim17 (yeast) performs two separable functions in the TIM23 complex: it promotes inner membrane insertion of preproteins and binds Pam18 to form the functional TIM23–PAM complex. Tim17 is crucial for the switch between TOM-tethered (Tim21-containing) and PAM-bound forms of the presequence translocase during the import reaction cycle. Biochemical co-immunoprecipitation, protein import assays, genetic dissection of TIM23 sub-complexes in yeast Cell High 15797382
2013 Human TIMM17A protein levels are decreased downstream of stress-induced eIF2α phosphorylation (translational attenuation) through a mechanism dependent on the mitochondrial protease YME1L; this Tim17A degradation attenuates TIM23-dependent mitochondrial protein import and induces mitochondrial UPR-associated proteostasis genes, conferring stress resistance. eIF2α phosphorylation stress induction, YME1L knockdown/KO, protein import assays, UPR gene induction assays, C. elegans and mammalian cell experiments Cell metabolism High 24315374
2017 Tim17 (yeast) TM1 and TM2 mutations impair interaction with Tim23 (the translocation channel), while TM3 mutations compromise binding to the PAM import motor; residues in the matrix-facing region of Tim17 are directly involved in binding the import motor, establishing functionally distinct roles for different Tim17 transmembrane segments in handing preproteins from the channel to the motor. Alanine-scanning mutagenesis of all four TM segments of Tim17; co-immunoprecipitation of Tim17 mutants with Tim23 and PAM components; protein import assays in yeast eLife High 28165323
2004 Two conserved negative charges in the N-terminal IMS-exposed stretch of Tim17 (yeast) are critical for preprotein import function; truncation of the first 11 residues impairs preprotein import without destabilizing the TIM23 complex; replacing these negative charges with positive residues causes growth defects that can be suppressed by converting positive charges between TM2 and TM3 to aspartates, suggesting charged residues control preprotein-induced gating of the TIM23 translocase. Truncation and alanine-scanning mutagenesis of Tim17 N-terminus; charge-reversal mutagenesis; protein import assays; membrane potential measurements; genetic growth assays in yeast The Journal of biological chemistry High 15618217
1999 The TIM17.23 complex contains Tim17, Tim23, and Tim44 in equimolar amounts; Tim44 is peripherally associated at the matrix side and forms dimers that recruit two molecules of mt-Hsp70 to import sites; no sub-complex lacking Tim17 was detected, indicating Tim17 is stoichiometrically essential for the full translocase assembly. Biochemical fractionation, co-immunoprecipitation, protein stoichiometry analysis of the TIM17.23 complex from yeast mitochondria The EMBO journal Medium 10393182
1998 Tim17 (yeast) lacks a hydrophilic N-terminal domain; its import signal resides in the C-terminal half and requires membrane potential (ΔΨ); insertion into the inner membrane requires the Tim22 complex but not functional Tim23, establishing Tim17 biogenesis as dependent on the carrier translocase pathway. In vitro import assays with isolated yeast mitochondria, ΔΨ depletion, temperature-sensitive Tim22 mutants, deletion/chimeric constructs of Tim17 and Tim23 The EMBO journal High 9501078
1996 Human and Drosophila Tim17 orthologs are functionally conserved: both are targeted to yeast mitochondria via Tom70 on the outer membrane surface, insert into the inner membrane in a ΔΨ-dependent step, adopt a characteristic topology, and assemble with Tim23, demonstrating high evolutionary conservation of Tim17 targeting and assembly mechanisms. In vitro import assays of human and Drosophila Tim17 into isolated yeast mitochondria; topology analysis; assembly assays Journal of molecular biology High 8893850
2008 Overexpression of human TIMM17A in NT2 cybrid cells carrying the A3243G mutant mtDNA significantly increases the proportion of clones maintaining mtDNA and provides long-term mtDNA stabilization for several months, identifying TIMM17A as a suppressor of mtDNA loss in a human cellular model of mitochondrial disease. Overexpression of human TIM17A in NT2 teratocarcinoma cybrid cells; quantification of mtDNA maintenance over time; multicopy suppressor screen in yeast Human molecular genetics Medium 18826960
2017 Tim17 (yeast) harbors conserved G/AXXXG/A motifs within its transmembrane regions that are essential for interaction with Tim23 and translocase assembly; these motifs regulate the dynamic switch between TIM23(PAM)-complex and TIM23(SORT)-complex by recruiting either PAM machinery or Tim21; tim17 TM mutants also display mtDNA instability and membrane potential loss. Alanine/glycine substitutions in TM G/AXXXG/A motifs; co-immunoprecipitation; BN-PAGE analysis of complex assembly; protein import assays; mtDNA stability assays in yeast Molecular and cellular biology Medium 27994013
2025 HSF1 promotes mitochondrial biogenesis, respiration, and ATP production in cancer cells via TIMM17A; HSF1 upregulates the steady-state level of the short-lived TIMM17A protein through its direct target genes HSPD1 and HSPE1 (mitochondrial chaperonin subunits responsible for refolding imported proteins in the matrix); the HSF1–HSPD1/HSPE1–TIMM17A axis remodels the mitochondrial proteome to promote mitochondrial translation and energy production. Genome-wide CRISPR epistasis screen; genetic knockdown/KO of TIMM17A, HSPD1, HSPE1; measurement of mitochondrial biogenesis, respiration, ATP production; western blot for TIMM17A levels bioRxivpreprint Medium 40463013
2024 TIM17A is a critical target of N-myristoyltransferase (NMT) inhibitors in lung carcinoma cells; TIM17A silencing recapitulates NMT inhibition by inducing mitochondrial ferrous iron overload, oxidative stress, and cell death by parthanatos, revealing a functional connection between protein myristoylation, the mitochondrial import machinery, and iron homeostasis. siRNA knockdown of TIMM17A; NMT inhibitor treatment; measurement of mitochondrial ferrous iron, oxidative stress markers, poly(ADP-ribose) levels; viability assays; in vivo tumor growth assays Cancer research communications Medium 38949950
2025 Loss of DNAJC15 (cleaved and degraded by OMA1/AFG3L2 under stress) reduces import of OXPHOS-related proteins specifically via the TIMM23–TIMM17A translocase, limiting OXPHOS biogenesis; non-imported preproteins accumulate at the ER and induce ATF6-related UPR, establishing TIMM17A-containing translocase as a stress-regulated bottleneck for OXPHOS protein import. DNAJC15 KO; OMA1/AFG3L2 genetic manipulation; protein import assays through TIM23–TIMM17A complex; measurement of OXPHOS biogenesis; ATF6-UPR reporter assays bioRxivpreprint Medium 40307502
2010 Overexpression of TIMM17A in breast cancer cells promotes oncogenic activity; siRNA knockdown of TIMM17A reduces breast cancer cell proliferation and invasion in vitro, establishing a functional role for TIMM17A in cancer cell aggressiveness. TIMM17A overexpression and siRNA knockdown in breast cancer cell lines; proliferation and invasion assays Proteomics Low 20198662
2024 miR-593-3p directly targets TIMM17A mRNA (validated by dual luciferase reporter assay); miR-593-3p overexpression reduces TIMM17A protein levels and suppresses breast cancer cell proliferation and invasion, while TIMM17A overexpression counteracts these inhibitory effects. Dual luciferase reporter assay; western blot; miRNA overexpression; CCK-8, colony formation, Annexin V/PI, Transwell invasion assays in MDA-MB-231 cells Biochemical genetics Low 40307502

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Mitochondrial presequence translocase: switching between TOM tethering and motor recruitment involves Tim21 and Tim17. Cell 281 15797382
2013 Stress-regulated translational attenuation adapts mitochondrial protein import through Tim17A degradation. Cell metabolism 167 24315374
1999 The TIM17.23 preprotein translocase of mitochondria: composition and function in protein transport into the matrix. The EMBO journal 78 10393182
1998 Biogenesis of Tim23 and Tim17, integral components of the TIM machinery for matrix-targeted preproteins. The EMBO journal 65 9501078
2004 Conserved N-terminal negative charges in the Tim17 subunit of the TIM23 translocase play a critical role in the import of preproteins into mitochondria. The Journal of biological chemistry 62 15618217
2016 Evolution of the Tim17 protein family. Biology direct 56 27760563
2010 Quantitative proteomics study of breast cancer cell lines isolated from a single patient: discovery of TIMM17A as a marker for breast cancer. Proteomics 56 20198662
2008 Characterization of the mitochondrial inner membrane protein translocator Tim17 from Trypanosoma brucei. Molecular and biochemical parasitology 52 18325611
1996 The preprotein translocase of the inner mitochondrial membrane: evolutionary conservation of targeting and assembly of Tim17. Journal of molecular biology 51 8893850
2023 Central role of Tim17 in mitochondrial presequence protein translocation. Nature 46 37527780
2017 Role of Tim17 in coupling the import motor to the translocation channel of the mitochondrial presequence translocase. eLife 34 28165323
2010 High TIMM17A expression is associated with adverse pathological and clinical outcomes in human breast cancer. Breast cancer (Tokyo, Japan) 31 20972741
2020 Tim17 Updates: A Comprehensive Review of an Ancient Mitochondrial Protein Translocator. Biomolecules 19 33297490
2017 Role of Tim17 Transmembrane Regions in Regulating the Architecture of Presequence Translocase and Mitochondrial DNA Stability. Molecular and cellular biology 18 27994013
2015 Functional complementation analyses reveal that the single PRAT family protein of trypanosoma brucei is a divergent homolog of Tim17 in saccharomyces cerevisiae. Eukaryotic cell 17 25576485
2008 The conserved translocase Tim17 prevents mitochondrial DNA loss. Human molecular genetics 15 18826960
2016 The Impact of TIMM17A on Aggressiveness of Human Breast Cancer Cells. Anticancer research 11 26977020
2024 N-Myristoytransferase Inhibition Causes Mitochondrial Iron Overload and Parthanatos in TIM17A-Dependent Aggressive Lung Carcinoma. Cancer research communications 9 38949950
2017 The divergent N-terminal domain of Tim17 is critical for its assembly in the TIM complex in Trypanosoma brucei. Molecular and biochemical parasitology 6 28965880
2021 A TIMM17A Regulatory Network Contributing to Breast Cancer. Frontiers in genetics 5 34421983
2024 Distinct structural motifs are necessary for targeting and import of Tim17 in Trypanosoma brucei mitochondrion. mSphere 3 38193679
2025 Identification of TRAF2, CAMK2G, and TIMM17A as biomarkers distinguishing mechanical asphyxia from sudden cardiac death base on 4D-DIA Proteomics: A pilot study. Journal of pharmaceutical and biomedical analysis 1 39921950
2025 MicroRNA-593-3p Inhibits Growth and Metastasis of Human Breast Cancer Cells by Regulating TIMM17A Expression. Biochemical genetics 0 40307502
2025 HSF1 remodels mitochondrial biogenesis and function in cancer cells via TIMM17A. bioRxiv : the preprint server for biology 0 40463013
2023 Distinct structural motifs are necessary for targeting and import of Tim17 in Trypanosoma brucei mitochondrion. bioRxiv : the preprint server for biology 0 37461662

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