Energy production in living organisms must always run smoothly

Mutations can lead to serious diseases

December 18, 2019

NADH:ubiquinone oxidoreductase, complex I, is one of the largest membrane protein assemblies known and has a central role in energy production by the mitochondrial respiratory chain, providing about 40% of the proton motive force required for the synthesis of adenosine triphosphate (ATP) that is the energy storage form of the cells. The structure of complex I was determined by electron cryo-microscopy in collaboration with the universities of Frankfurt, Helsinki and Graz and the Max Planck Institute of Biophysics.

Complex I is the first enzyme of the respiratory chain and has a central role in cellular energy production, coupling electron transfer between NADH and quinone to proton translocation by an unknown mechanism. Dysfunction of complex I has been implicated in many human neurodegenerative diseases. Complex I has also been suggested to be a major source of reactive oxygen species in mitochondria, which can damage mitochondrial DNA and may be one of the causes of Parkinson’s disease and ageing.

The Proton Pump Respiratory Complex I<br><br>

Proton pump I_mpibp

The Proton Pump Respiratory Complex I

Structure of complex I

In this study, the structure of complex I from the aerobic yeast Yarrowia lipolytica was solved by electron cryo-microscopy (cryo-EM) at high resolution of 3.2 Å. Thus, a substrate molecule could be identified in the access path to the active center and the structure indicated an unusual lipid-protein arrangement at the membrane transition. Furthermore, the structure of a complex I assembly intermediate and mutant (structure solved at 4.0 Å resolution) provide detailed molecular insights into complex I assembly and the cause of a hereditary complex I–linked disease, which has been shown to cause the Leigh's disease in humans with various types of mutations. Patients have a homogeneous phenotype characterized by early onset of the disease and clinical presentation of hypotension, psychomotor regression, abnormal eye movements and respiratory failure in combination with brain stem and basal ganglia lesions leading to death, see also the review: J. D. Ortigoza-Escobar et al.: Ndufs4 related Leigh syndrome: A case report and review of the literature. Mitochondrion 28 73-78 (2016).

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