DNAJC11

DNAJC11 is a mitochondrial outer membrane protein that functions as a peripheral component of the mitochondrial intermembrane space bridging (MIB) complex, the extended assembly that joins the core MICOS complex to the SAM50/metaxin machinery and is required for organizing the inner membrane and its cristae (PMID:17624330, PMID:26477565). It was first identified in a mitofilin-anchored complex alongside SAM50, metaxins 1/2, CHCHD3, and CHCHD6 (PMID:17624330), and its abundance depends on mitofilin and SAM50, consistent with stable incorporation into this complex (PMID:25111180). Its modular architecture partitions function: the J-domain directs mitochondrial localization while the DUF3395 domain mediates the bulk of its protein-protein interactions, which include MICOS members, the outer-membrane channels VDACs, ribosomal subunits, and Hsp70 chaperones, with a preference for synaptic proteins in neural tissue (PMID:31550165). Beyond structural roles, DNAJC11 acts upstream of the distribution regulator ARMC1, facilitating ARMC1 release from mitochondria to tune steady-state mitochondrial distribution (PMID:40203102). Loss of DNAJC11 function in mice causes mitochondrial inner-membrane disorganization, cristae loss, and motor neuron vacuolation that is rescued by the human ortholog (PMID:25111180). It is also co-opted by SARS-CoV-2, where it stabilizes NSP3 and promotes NSP3–NSP4-driven double-membrane vesicle formation (PMID:40872740).

1. 2007 Medium

   Established DNAJC11 as a physical member of a mitochondrial inner-membrane-associated multiprotein assembly rather than an isolated chaperone, by co-purifying it with the mitofilin/MICOS machinery.

   Evidence Anti-mitofilin monoclonal antibody immunocapture and protein identification

   PMID:17624330

   Open questions at the time

   • Single co-IP without domain mapping or reciprocal pulldown
   • Did not define which subunit DNAJC11 directly contacts
   • No functional consequence assayed
2. 2014 High

   Resolved DNAJC11's submitochondrial position and demonstrated a causal requirement in cristae/inner-membrane architecture, linking its loss to motor neuron pathology.

   Evidence ENU forward genetics, subcellular fractionation, human-ortholog rescue, mitofilin/SAM50 siRNA epistasis, and EM in mice and HeLa cells

   PMID:25111180

   Open questions at the time

   • Mechanism by which a peripheral OMM protein controls inner-membrane organization unresolved
   • Roles of additional isoforms not defined
   • J-domain chaperone activity not biochemically tested
3. 2015 Medium

   Distinguished DNAJC11 as a peripheral subunit of the complete MIB complex rather than the core MICOS, and tied its evolutionary presence to cristae-bearing organisms.

   Evidence BN-PAGE/MS complexome profiling and phylogenomic co-occurrence analysis

   PMID:26477565

   Open questions at the time

   • Phylogenomic correlation does not prove a cristae-forming function
   • Stoichiometry and direct binding interface within MIB unresolved
4. 2019 Medium

   Mapped DNAJC11's interactome and assigned domain functions, separating localization (J-domain) from interaction (DUF3395), and revealing tissue-specific partners.

   Evidence FLAG affinity purification–MS in HEK293FT cells and transgenic mouse cerebrum with domain-deletion analysis

   PMID:31550165

   Open questions at the time

   • Direct versus indirect interactions not discriminated
   • Functional consequence of VDAC, ribosomal, and synaptic partner binding not tested
   • Single-lab interactome
5. 2025 Medium

   Placed DNAJC11 upstream of ARMC1 mito-cytoplasmic shuttling, giving it an active role in tuning mitochondrial distribution beyond structural scaffolding.

   Evidence Co-IP, interaction-disrupting mutants, and fluorescence microscopy of mitochondrial distribution

   PMID:40203102

   Open questions at the time

   • Molecular mechanism of ARMC1 release not defined
   • Single lab; not independently replicated
6. 2025 Medium

   Showed DNAJC11 can be hijacked by SARS-CoV-2 to stabilize NSP3 and support replication-organelle (DMV) biogenesis.

   Evidence MS, co-IP, siRNA knockdown, ectopic expression, and EM of DMV morphology

   PMID:40872740

   Open questions at the time

   • Whether this co-opts the normal MIB/cristae function is unknown
   • Single study, not independently confirmed

• It remains unresolved how a peripheral outer-membrane protein mechanistically drives inner-membrane/cristae organization and whether its J-domain confers genuine co-chaperone activity toward the Hsp70 partners observed.
• No demonstrated chaperone/folding activity for the J-domain
• Direct binding interface within MIB not structurally defined
• Link between cytoskeletal/podocyte phenotype and mitochondrial function unestablished