Mitochondrial complex I: An intricate energy-converting machine, a cornerstone of mitochondrial metabolism, and a locus of mitochondrial dysfunction and disease

Dysfunctions of mitochondrial complex I, the first of four energy-converting complexes that power the cell to produce ATP by oxidative phosphorylation, cause many mitochondrial diseases. Following the ‘resolution revolution’ in cryo-electron microscopy (cryoEM) the structure of mammalian complex I has been solved, but many key aspects of how the enzyme works remain unknown. It is further unclear how it is regulated, repaired or replaced; how its structure, function or assembly are affected by clinically-identified mutations; or how reactive oxygen species, drugs or toxins affect its catalysis and function in the cell. Even when a mutation in a well-characterised complex I gene is established as the direct cause of a mitochondrial disease, the pathological mechanisms that define the pathways from the molecular defect to the clinical symptoms are poorly understood.

The aims of the Mitochondrial Complex I programme are to define and understand the molecular structure, function and dysfunction of mammalian complex I, and to exploit and apply this basic knowledge to understand complex I in vivo, elucidate disease mechanisms, support clinical diagnoses, and contribute to the development of therapeutic strategies against both primary diseases and complex multifactorial disorders involving complex I.

Mitochondrial complex I (NADH:ubiquinone oxidoreductase) powers ATP synthesis by oxidative phosphorylation, exploiting the energy from reduction of ubiquinone by NADH to drive protons across the energy-transducing inner membrane. Being also required to maintain the redox status of the mitochondrial NAD+ pool to keep the tricarboxylic acid cycle and ß-oxidation running, it is a keystone of mitochondrial metabolism and crucial for the survival of human cells. Consequently, mutations in its subunits and assembly factors that impact on its structure, function or biogenesis cause mitochondrial diseases, it is a drug target in diabetes, ischaemia-reperfusion (IR) injury and cancer, and complex I-linked drug toxicity compromises drug discovery programmes. Understanding the function and dysfunction of complex I in these contexts is an intellectual and scientific challenge for both medical and basic scientists that must be tackled on multiple levels. Basic molecular knowledge of the enzyme’s structure, mechanism and assembly is required to underpin biomedical studies of complex I in mitochondrial and cellular systems of greater complexity. The Mitochondrial Complex I group aims to develop and apply this basic knowledge to understand and address the role of complex I in genetically, environmentally and pharmacologically-linked mitochondrial dysfunctions.