TMEM14C

TMEM14C is an inner mitochondrial membrane protein that functions as the importer of protoporphyrinogen IX into the mitochondrial matrix, constituting an essential step in the terminal heme biosynthesis pathway (PMID:25157825). TMEM14C deficiency in mice causes porphyrin accumulation, erythroid maturation arrest, and embryonic lethality from severe anemia, a phenotype partially rescued by a protoporphyrin IX analog (PMID:25157825). In SF3B1-mutant myelodysplastic syndromes, hotspot mutations induce aberrant splicing of TMEM14C that alters its 5′ UTR and reduces protein expression through impaired translation; combined functional rescue of TMEM14C and ABCB7 nearly abolishes ring sideroblast formation, establishing coordinated missplicing of these mitochondrial transporters as the mechanism of mitochondrial iron sequestration in this disease (PMID:34861039, PMID:38759096).

1. 2014 High

   The fundamental question of what transports protoporphyrinogen IX into the mitochondrial matrix was answered: TMEM14C was identified as this importer, establishing its essential role in terminal heme synthesis and erythropoiesis.

   Evidence Loss-of-function mouse model, subcellular fractionation to inner mitochondrial membrane, and porphyrin analog rescue in erythroid cells

   PMID:25157825

   Open questions at the time

   • No direct transport assay with reconstituted TMEM14C in liposomes
   • Structural basis of substrate recognition for protoporphyrinogen IX unknown
   • Whether TMEM14C transports additional porphyrin intermediates not tested
2. 2016 Medium

   The absence of TMEM14C missplicing in Sf3b1-K700E knock-in mice—which lack ring sideroblasts despite anemia—provided epistatic evidence that aberrant TMEM14C splicing is specifically required for ring sideroblast formation in SF3B1-mutant disease.

   Evidence Hematopoietic-specific Sf3b1-K700E knock-in mouse with genome-wide RNA-seq splicing analysis

   PMID:27604819

   Open questions at the time

   • Indirect evidence from species difference rather than direct manipulation of TMEM14C splicing
   • Does not distinguish contribution of TMEM14C missplicing from ABCB7 missplicing individually
3. 2020 Low

   Conservation of TMEM14C function in porphyrin/heme metabolism was extended to apicomplexan parasites, where disruption of a Tmem14c homolog in Toxoplasma gondii increased artemisinin susceptibility.

   Evidence Genome-scale CRISPR screen in Toxoplasma gondii with dihydroartemisinin selection

   PMID:32968076

   Open questions at the time

   • Non-mammalian system with limited direct mechanistic validation of transport activity
   • No biochemical demonstration of substrate specificity in Toxoplasma
   • Relevance to mammalian TMEM14C mechanism not directly tested
4. 2022 High

   The mechanism by which SF3B1 mutations cause ring sideroblasts was resolved: mutant SF3B1 missplices TMEM14C to alter its 5′ UTR, reducing protein via impaired translation; combined rescue of TMEM14C and ABCB7 nearly abolished ring sideroblast formation, proving coordinated loss of these transporters drives mitochondrial iron sequestration.

   Evidence SF3B1-mutant iPSC-derived erythroid differentiation model with RNA-seq, polysome profiling, western blot, and functional rescue experiments

   PMID:34861039

   Open questions at the time

   • Quantitative contribution of TMEM14C versus ABCB7 missplicing individually to RS formation not fully delineated
   • Whether additional SF3B1 missplicing targets contribute to the MDS phenotype beyond RS
5. 2024 Medium

   Natural variant analysis confirmed the specificity of the TMEM14C missplicing–RS link: the SF3B1 E592K variant retains normal TMEM14C splicing and lacks ring sideroblasts, distinguishing it from canonical hotspot mutations.

   Evidence RNA splicing analysis and clinical phenotype correlation in patient samples with SF3B1 E592K versus canonical mutations

   PMID:38759096

   Open questions at the time

   • Single-study observation without functional validation of E592K in an experimental model
   • Mechanism by which E592K spares TMEM14C splicing while other hotspot mutations do not is unexplained

• The structural basis of TMEM14C-mediated protoporphyrinogen IX transport and the precise mechanism by which specific SF3B1 mutations selectively target TMEM14C splicing remain unresolved.
• No structure of TMEM14C or reconstituted transport assay exists
• Mechanism of selective branch-point usage by different SF3B1 mutations at the TMEM14C locus unknown
• Whether TMEM14C has additional substrates or interacting partners in the heme synthesis machinery is untested