TMEM186

TMEM186 is a mitochondrial inner membrane protein and bona fide subunit of the MCIA (mitochondrial complex I intermediate assembly) complex, which includes NDUFAF1, ECSIT, ACAD9, and TMEM126B; loss of TMEM186 disrupts MCIA complex integrity and impairs complex I assembly (PMID:32320651). TMEM186 enriches with newly translated ND3, establishing a direct role in biogenesis of the ND2-module of respiratory chain complex I (PMID:32320651). TMEM186 belongs to the TMEM70/TMEM186/TMEM223 protein family, which is restricted to species possessing OXPHOS complexes, consistent with a conserved function in oxidative phosphorylation assembly (PMID:32275929).

1. 2020 Medium

   Establishing that TMEM186 is a mitochondrial inner membrane protein belonging to an OXPHOS-associated family resolved its subcellular localization and placed it in an evolutionary context consistent with a role in respiratory chain biogenesis.

   Evidence BioID proximity labeling, subcellular localization experiments, and evolutionary coevolution analyses in human cells

   PMID:32275929

   Open questions at the time

   • Study was primarily focused on TMEM70; functional role of TMEM186 itself was not directly dissected
   • No structural data for TMEM186 or its topology within the inner membrane
2. 2020 High

   Identifying TMEM186 as a bona fide MCIA complex subunit whose knockout disrupts complex I assembly and whose association with nascent ND3 defines its specific role in ND2-module biogenesis answered the key question of what TMEM186 does mechanistically in mitochondria.

   Evidence Cell knockout studies, co-immunoprecipitation, complexome profiling, and metabolic labeling of newly translated mitochondrial subunits in human cells

   PMID:32320651

   Open questions at the time

   • Precise molecular mechanism by which TMEM186 facilitates ND3 incorporation into the ND2-module is unknown
   • Whether TMEM186 loss causes human disease has not been reported
   • No reconstitution of TMEM186 function with purified MCIA components

• It remains unknown how TMEM186 biochemically contributes to ND3/ND2-module assembly within the MCIA complex, whether it has enzymatic or purely structural roles, and whether TMEM186 mutations cause mitochondrial disease in humans.
• No structural model of TMEM186 within the MCIA complex
• No patient mutations or disease association reported
• Catalytic versus scaffolding role undetermined