Affinage

TIMMDC1

Complex I assembly factor TIMMDC1, mitochondrial · UniProt Q9NPL8

Length
285 aa
Mass
32.2 kDa
Annotated
2026-04-28
27 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIMMDC1 is a mitochondrial inner membrane assembly factor essential for biogenesis of the membrane arm of respiratory complex I. It physically associates with the MCIA complex (ACAD9, ECSIT, NDUFAF1, TMEM126B) and core complex I subunits, and its depletion selectively abolishes complex I activity while leaving complexes II–IV intact, thereby impairing oxidative phosphorylation and ATP production (PMID:24344204, PMID:30123074). TIMMDC1 protein stability is maintained by a C9orf72–prohibitin axis that prevents m-AAA protease-dependent degradation, and its expression is regulated post-transcriptionally by miR-450a and METTL3-mediated m6A methylation (PMID:33545050, PMID:31101765, PMID:40409178). A deep intronic TIMMDC1 variant (c.597-1340A>G) causes aberrant splicing and loss of protein, resulting in mitochondrial complex I deficiency, a phenotype rescuable by splice-switching antisense oligonucleotides (PMID:28604674, PMID:35091571).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2013 High

    Establishing TIMMDC1 as a complex I assembly factor resolved its unknown mitochondrial function by showing it physically engages the MCIA complex and core complex I subunits, and that its depletion reduces complex I activity and cellular respiration.

    Evidence AP-MS, reciprocal co-IP, siRNA knockdown with complex I activity assays and respiration measurement in human cells; independently, BN-PAGE/MS identification of TIMMDC1 on 550/815 kDa complex I subcomplexes

    PMID:24191001 PMID:24344204

    Open questions at the time
    • Precise step in the complex I assembly pathway at which TIMMDC1 acts was not defined
    • Topology and transmembrane domain contributions to function were not characterized
    • No structural model of TIMMDC1 within the MCIA complex
  2. 2016 Medium

    Complexome profiling confirmed TIMMDC1 as a stable MCIA complex component, anchoring it alongside ACAD9, ECSIT, NDUFAF1, and TMEM126B in the complex I assembly pathway.

    Evidence Complexome profiling and viral rescue in patient cell lines

    PMID:27374774

    Open questions at the time
    • Stoichiometry and direct contact partners within the MCIA complex not resolved
    • Whether TIMMDC1 loss destabilizes the entire MCIA complex or only selected subunits was not tested
  3. 2017 Medium

    Discovery of a deep intronic TIMMDC1 variant causing aberrant splicing and complex I deficiency established TIMMDC1 as a Mendelian disease gene, linking its loss of function to human mitochondrial disease.

    Evidence RNA-seq and protein analysis in patient-derived fibroblasts carrying c.597-1340A>G

    PMID:28604674

    Open questions at the time
    • Single family report; genetic confirmation in additional kindreds was lacking
    • Clinical spectrum and genotype–phenotype correlations were not fully defined
  4. 2018 Medium

    Demonstrating that TIMMDC1 knockdown selectively impairs complex I (not II–IV), suppresses respiration and glycolysis, and reduces AKT/GSK-3β/β-catenin signaling linked TIMMDC1-dependent bioenergetics to downstream oncogenic signaling.

    Evidence siRNA knockdown in gastric cancer cells, Seahorse metabolic analysis, complex activity assays, western blotting, in vivo xenograft

    PMID:30123074

    Open questions at the time
    • Whether AKT pathway effects are a direct consequence of reduced ATP or a parallel TIMMDC1 function is unresolved
    • Cancer context generalizability beyond gastric cancer not tested
  5. 2019 Medium

    Identifying miR-450a as a direct post-transcriptional repressor of TIMMDC1 and showing that a C-terminal truncation (p.Arg225*) retains partial assembly function defined regulatory and structural boundaries of TIMMDC1 activity.

    Evidence AGO-PAR-CLIP and RNA-seq in ovarian cancer cells; TIMMDC1-KO complementation assay with truncation mutant

    PMID:30981218 PMID:31101765

    Open questions at the time
    • Physiological relevance of miR-450a regulation of TIMMDC1 outside cancer context unknown
    • Minimal functional domain of TIMMDC1 not mapped
  6. 2021 High

    Revealing that C9orf72 recruits the prohibitin complex to shield TIMMDC1 from m-AAA protease degradation uncovered a dedicated protein quality-control mechanism governing complex I assembly factor stability.

    Evidence Co-IP, proximity ligation, KO cell lines, protease inhibitor experiments, complex I assays, patient-derived neuron analysis

    PMID:33545050

    Open questions at the time
    • Whether this protective mechanism operates on other MCIA subunits was not addressed
    • Structural basis of the C9orf72–prohibitin–TIMMDC1 interaction is unknown
  7. 2021 Medium

    Genetic epistasis in Drosophila placed TIMMDC1 downstream of NDUFAF3/NDUFAF4 in complex I biogenesis, specifying its role in Q-, N-, and PP-b-module assembly steps.

    Evidence Drosophila genetic epistasis, BN-PAGE, immunoblotting of assembly intermediates

    PMID:34386730

    Open questions at the time
    • Whether the same epistatic hierarchy holds in mammalian systems is unconfirmed
    • Mechanism by which NDUFAF3/4 loss destabilizes TIMMDC1 is unclear
  8. 2022 High

    Splice-switching antisense oligonucleotides correcting the TIMMDC1 intronic variant restored protein levels and mitochondrial function, providing proof-of-concept for therapeutic rescue of TIMMDC1 deficiency.

    Evidence ASO treatment of patient fibroblasts with quantitative proteomics and real-time metabolic analysis

    PMID:35091571

    Open questions at the time
    • In vivo efficacy and delivery to affected tissues (brain, muscle) not demonstrated
    • Long-term stability of rescue not assessed
  9. 2025 Medium

    Demonstrating METTL3-mediated m6A methylation of TIMMDC1 mRNA as a repressive mechanism added an epitranscriptomic layer of TIMMDC1 regulation with consequences for cell proliferation and immune polarization.

    Evidence Me-RIP, RIP, METTL3 knockdown/overexpression with TIMMDC1 rescue in airway smooth muscle cells

    PMID:40409178

    Open questions at the time
    • Specific m6A sites on TIMMDC1 mRNA were not mapped
    • Whether m6A regulation affects TIMMDC1 in non-disease contexts is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structural model of TIMMDC1 within the MCIA complex and the precise mechanism by which TIMMDC1 facilitates membrane-arm subunit insertion remain unresolved.
  • No cryo-EM or crystal structure of TIMMDC1 alone or in complex
  • Precise contacts between TIMMDC1 transmembrane domains and complex I subunits unknown
  • Whether TIMMDC1 has catalytic activity or functions purely as a scaffold is undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-1430728 Metabolism 3
Partners
ACAD9C9ORF72ECSITMETTL3NDUFAF1TMEM126B
Complex memberships
MCIA complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 TIMMDC1 (C3orf1) is a membrane-embedded mitochondrial complex I assembly factor that localizes to the mitochondrial inner membrane, physically associates with multiple members of the MCIA complex (ACAD9, ECSIT, NDUFAF1, TMEM126B) and core complex I subunits, and its depletion results in reduced complex I activity and cellular respiration. Quantitative proteomics demonstrated a role for TIMMDC1 in assembly of both membrane-embedded and soluble arms of complex I. Interaction proteomics (AP-MS), reciprocal co-immunoprecipitation, subcellular fractionation/localization, siRNA knockdown with complex I activity assay and cellular respiration measurement, quantitative proteomics Molecular and cellular biology High 24344204
2013 TIMMDC1 (C3orf1) is associated with subcomplexes of complex I (550 kDa and 815 kDa) that accumulate when NDUFA11 expression is suppressed, identifying it as one of several extrinsic assembly factors participating in constructing the membrane arm of complex I. Blue-native PAGE of subcomplexes after siRNA suppression of NDUFA11, mass spectrometry identification of subcomplex components Proceedings of the National Academy of Sciences of the United States of America High 24191001
2021 C9orf72 directly stabilizes TIMMDC1 protein in the mitochondrial inner membrane by recruiting the prohibitin complex to inhibit m-AAA protease-dependent degradation of TIMMDC1, thereby maintaining complex I assembly and oxidative phosphorylation. Co-immunoprecipitation, proximity ligation, siRNA/knockout cell lines, protease inhibitor experiments, complex I activity assays, patient-derived neuron analysis Cell metabolism High 33545050
2017 A deep intronic variant in TIMMDC1 (c.597-1340A>G) causes aberrant splicing with inclusion of a cryptic exon, leading to loss of TIMMDC1 protein and mitochondrial complex I deficiency, establishing TIMMDC1 as a disease-associated complex I assembly factor. RNA sequencing, aberrant splicing analysis, protein analysis in patient-derived fibroblasts Nature communications Medium 28604674
2022 Splice-switching antisense oligonucleotides (SSOs) targeting the deep intronic TIMMDC1 variant c.597-1340A>G restore normal TIMMDC1 mRNA processing and protein levels in patient fibroblasts, rescuing complex I subunit abundance and mitochondrial function as confirmed by quantitative proteomics and real-time metabolic analysis. Antisense oligonucleotide treatment, RNA analysis, quantitative proteomics, real-time mitochondrial metabolic analysis in patient fibroblasts NPJ genomic medicine High 35091571
2021 TIMMDC1 is destabilized in complex I assembly intermediates when either NDUFAF3 or NDUFAF4 is disrupted in Drosophila, placing TIMMDC1 downstream of these assembly factors in the complex I biogenesis pathway, specifically in Q-, N-, and PP-b-module assembly. Genetic epistasis analysis in Drosophila, blue-native PAGE, immunoblotting of assembly intermediates iScience Medium 34386730
2019 TIMMDC1 is a direct target of miR-450a as identified by AGO-PAR-CLIP combined with RNA-seq, placing TIMMDC1 within a set of mitochondrial energy metabolism genes regulated post-transcriptionally in ovarian cancer cells. AGO-PAR-CLIP, RNA-seq, miRNA overexpression with target validation Cancer research Medium 31101765
2019 TIMMDC1 C-terminal truncation (p.Arg225*) acts as a hypomorphic variant that still allows partial complex I assembly rescue in TIMMDC1 knockout cells, demonstrating that the C-terminus of TIMMDC1 is not absolutely required for its assembly factor function. TIMMDC1 knockout cell complementation assay, complex I activity measurement, protein analysis Human mutation Medium 30981218
2018 TIMMDC1 knockdown in gastric cancer cells selectively reduces mitochondrial complex I activity (but not complexes II–IV), inhibits mitochondrial respiration and glycolysis, reduces ATP production, and decreases phosphorylation of AKT (Ser473) and GSK-3β (Ser9) with downstream reduction of β-catenin and c-Myc. siRNA knockdown, Seahorse mitochondrial respiration assay, complex activity assays, western blotting, in vivo xenograft International journal of biological sciences Medium 30123074
2014 TIMMDC1 (C3orf1) localizes to the mitochondrial inner membrane and its depletion in 95D lung carcinoma cells reduces mitochondrial viability, membrane potential, and ATPase activity, inhibiting cell growth and migration with upregulation of cell-cycle arrest genes (CCNG2, PTEN) and migration-inhibiting genes (TIMP3, COL3A1) and downregulation of NUPR1. siRNA knockdown, mitochondrial localization confirmation, mitochondrial membrane potential assay, ATPase activity assay, microarray gene expression analysis, cell migration and proliferation assays International journal of molecular sciences Medium 25391042
2025 METTL3 methyltransferase suppresses TIMMDC1 expression via m6A methylation of TIMMDC1 mRNA, as confirmed by Me-RIP assay and RIP showing METTL3-TIMMDC1 mRNA interaction, thereby inhibiting PDGF-BB-induced airway smooth muscle cell proliferation, migration, and M2 macrophage polarization. Me-RIP assay, RIP assay, METTL3 knockdown/overexpression, TIMMDC1 knockdown/overexpression, cell proliferation and migration assays, flow cytometry Immunobiology Medium 40409178
2016 TIMMDC1 (TMEM126B complex member) is identified as a component of the MCIA complex (alongside ACAD9, ECSIT, NDUFAF1, TMEM126B) by complexome profiling, and TMEM126B loss disrupts MCIA complex integrity and complex I assembly. Complexome profiling, viral rescue in patient cell lines American journal of human genetics Medium 27374774

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Genetic diagnosis of Mendelian disorders via RNA sequencing. Nature communications 429 28604674
2021 C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly. Cell metabolism 117 33545050
2013 Assembly factors for the membrane arm of human complex I. Proceedings of the National Academy of Sciences of the United States of America 116 24191001
2013 TIMMDC1/C3orf1 functions as a membrane-embedded mitochondrial complex I assembly factor through association with the MCIA complex. Molecular and cellular biology 72 24344204
2016 Evolution of the Tim17 protein family. Biology direct 56 27760563
2016 Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype. American journal of human genetics 54 27374774
2019 miR-450a Acts as a Tumor Suppressor in Ovarian Cancer by Regulating Energy Metabolism. Cancer research 53 31101765
2012 Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13. Arthritis and rheumatism 51 22354554
2018 Long non-coding RNA TCF7 contributes to the growth and migration of airway smooth muscle cells in asthma through targeting TIMMDC1/Akt axis. Biochemical and biophysical research communications 29 30528236
2019 POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33. Scientific reports 21 30643196
2018 TIMMDC1 Knockdown Inhibits Growth and Metastasis of Gastric Cancer Cells through Metabolic Inhibition and AKT/GSK3β/β-Catenin Signaling Pathway. International journal of biological sciences 18 30123074
2013 Independent replication analysis of genetic loci with previous evidence of association with juvenile idiopathic arthritis. Pediatric rheumatology online journal 17 23506417
2022 Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder. NPJ genomic medicine 14 35091571
2021 Dissecting the concordant and disparate roles of NDUFAF3 and NDUFAF4 in mitochondrial complex I biogenesis. iScience 12 34386730
2016 Shared Genetic Etiology of Autoimmune Diseases in Patients from a Biorepository Linked to De-identified Electronic Health Records. Frontiers in genetics 12 27812365
2014 Depletion of C3orf1/TIMMDC1 inhibits migration and proliferation in 95D lung carcinoma cells. International journal of molecular sciences 11 25391042
2023 Neuropathological hallmarks of antenatal mitochondrial diseases with a corpus callosum defect. Brain : a journal of neurology 10 36349561
2016 Lens transcriptome profile during cataract development in Mip-null mice. Biochemical and biophysical research communications 10 27524245
2024 Multi-omics characterization of esophageal squamous cell carcinoma identifies molecular subtypes and therapeutic targets. JCI insight 6 38652547
2019 A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein-truncating variant. Human mutation 6 30981218
2000 Identification and expression analysis of C3orf1, a novel human gene homologous to the Drosophila RP140-upstream gene. DNA sequence : the journal of DNA sequencing and mapping 5 11092749
2020 Deep intronic TIMMDC1 variant delays diagnosis of rapidly progressive complex I deficiency. European journal of medical genetics 4 33278652
2025 Integrated bioinformatics and experiment validation reveal cuproptosis-related biomarkers and therapeutic targets in sepsis-induced myocardial dysfunction. BMC infectious diseases 2 40165133
2020 Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes. Human mutation 2 32196808
2025 METTL3 regulates ASMCs proliferation and M2 macrophage polarization via mediating the m6A methylation of TIMMDC1 in asthma. Immunobiology 1 40409178
2025 Corticosterone induces fatty liver syndrome in chickens via glucocorticoid receptor and inhibition of mitochondrial supercomplex formation. American journal of physiology. Regulatory, integrative and comparative physiology 0 40408241
2025 Comprehensive study of W06A7.4 and TMEM144 mediated pathways in aging: insights from Caenorhabditis elegans to human. Molecular genetics and genomics : MGG 0 41026247