Structure of the human respiratory complex II

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Human complex II links the tricarboxylic acid cycle and oxidative phosphorylation, essential for cellular energy production.
• Mutations in complex II are implicated in mitochondrial diseases and certain cancers.
• The precise structure of human complex II remained unresolved, limiting functional and disease mechanism understanding.

Purpose of the Study:

• To determine the high-resolution structure of human complex II.
• To elucidate the electron transfer pathway within the complex.
• To map disease-associated mutations onto the structure for molecular insights.

Main Methods:

• Cryoelectron microscopy (cryo-EM) was employed to determine the structure.
• The structure was resolved at 2.86 Å resolution in the presence of ubiquinone.
• Subunit composition (SDHA, SDHB, SDHC, SDHD) was identified.

Main Results:

• The structure reveals human complex II comprises two soluble (SDHA, SDHB) and two membrane-spanning (SDHC, SDHD) subunits.
• A proposed route for electron transfer through the complex is presented.
• Clinically relevant mutations were mapped onto the determined structure.

Conclusions:

• The resolved structure provides a molecular basis for understanding human complex II function.
• Mapping mutations offers insights into the molecular mechanisms underlying complex II-related diseases.
• This structural information is vital for future research into mitochondrial disorders and cancer therapies.