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Structure paper

TitleStructural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.
Journal, issue, pagesNat Commun, Year 2026
Publish dateJan 10, 2026
AuthorsMinh Duc Nguyen / Ana Sierra-Magro / Vivek Singh / Anas Khawaja / Alba Timón-Gómez / Antoni Barrientos / Joanna Rorbach /
PubMed AbstractThe mitochondrial respiratory chain comprises four multimeric complexes (CI-CIV) that drive oxidative phosphorylation by transferring electrons to oxygen and generating the proton gradient required ...The mitochondrial respiratory chain comprises four multimeric complexes (CI-CIV) that drive oxidative phosphorylation by transferring electrons to oxygen and generating the proton gradient required for ATP synthesis. These complexes can associate into supercomplexes (SCs), such as the CI + CIII₂ + CIV respirasome, but how SCs form, by joining preassembled complexes or by engaging partially assembled intermediates, remains unresolved. Here, we use cryo-electron microscopy to determine high-resolution structures of native human CI + CIII₂ + CIV late-assembly intermediates. Together with biochemical analyses, these structures show that respirasome biogenesis concludes with the final maturation of CIV while it is associated with fully assembled CI and CIII₂. We identify HIGD2A as a placeholder factor within isolated and supercomplexed CIV that is replaced by subunit NDUFA4 during the last step of CIV and respirasome assembly. This mechanism suggests that placeholders such as HIGD2A act as molecular timers, preventing premature incorporation of NDUFA4 or its isoforms and ensuring the orderly progression of pre-SC particles into functional respirasomes. Since defects in CIV assembly, including NDUFA4 deficiencies, cause severe encephalomyopathies and neurodegenerative disorders, understanding the molecular architecture and assembly pathways of isolated and supercomplexed CIV offers insight into the pathogenic mechanisms underlying these conditions.
External linksNat Commun / PubMed:41519940
MethodsEM (single particle)
Resolution2.52 - 3.6 Å
Structure data

52525

9hzl

EMDB-52525, PDB-9hzl:
High resolution cryo-EM structure of human complex III in mitochondria
Method: EM (single particle) / Resolution: 2.52 Å

EMDB-52596: Initial respirasome complex map (consensus map)
Method: EM (single particle) / Resolution: 3.01 Å

EMDB-52612: Complex IV with HIGD2A density and incoming NDUFA4 (class 2)
Method: EM (single particle) / Resolution: 3.36 Å

EMDB-52613: NDUFA4 bound complex IV with weak density from HIGD2A
Method: EM (single particle) / Resolution: 3.6 Å

52654

9i6f

EMDB-52654, PDB-9i6f:
Cryo-EM structure of HIGD2A bound complex IV
Method: EM (single particle) / Resolution: 2.95 Å

52662

9i7u

EMDB-52662, PDB-9i7u:
Cryo-EM structure of NDUFA4 bound complex IV within the respirasome complex
Method: EM (single particle) / Resolution: 3.15 Å

EMDB-52664: Local refinement of complex IV (whole map)
Method: EM (single particle) / Resolution: 3.1 Å

54784

9ti4

EMDB-54784: local refinement map of human complex I
PDB-9ti4: High resolution Cryo-EM structure of human complex I in mitochondria
Method: EM (single particle) / Resolution: 2.66 Å

Chemicals

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM

ChemComp-FES:
FE2/S2 (INORGANIC) CLUSTER

ChemComp-PLX:
(9R,11S)-9-({[(1S)-1-HYDROXYHEXADECYL]OXY}METHYL)-2,2-DIMETHYL-5,7,10-TRIOXA-2LAMBDA~5~-AZA-6LAMBDA~5~-PHOSPHAOCTACOSANE-6,6,11-TRIOL / phospholipid*YM

ChemComp-HEC:
HEME C

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM

ChemComp-U10:
UBIQUINONE-10

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

ChemComp-CU:
COPPER (II) ION

ChemComp-MG:
Unknown entry

ChemComp-HEA:
HEME-A

ChemComp-PGV:
(1R)-2-{[{[(2S)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL (11E)-OCTADEC-11-ENOATE / phospholipid*YM

ChemComp-ZN:
Unknown entry

ChemComp-SF4:
IRON/SULFUR CLUSTER

ChemComp-FMN:
FLAVIN MONONUCLEOTIDE

ChemComp-8Q1:
S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate

ChemComp-NDP:
NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

ChemComp-DGT:
2'-DEOXYGUANOSINE-5'-TRIPHOSPHATE

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Human mitochondria / respirasome complex / cytochrome bc1 complex / CoQH2-cytochrome c reductase / complex III / assembly / cytochrome c oxidase / complex IV / HIGD2A / Mitochondria / human / respirasome / NDUFA4 / complex I / NADH dehydrogenase

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