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.