Professor Judy Hirst

I studied chemistry at St. John’s College, Oxford and obtained a D. Phil. in chemistry from Lincoln College, Oxford, carrying out research in the group of Fraser Armstrong on mechanisms of electron transport in complex enzymes. 

Following postdoctoral work at The Scripps Research Institute, La Jolla, California, in the group of David Goodin, supported by a  Wellcome Trust Prize International Research Fellowship, I joined the MRC Mitochondrial Biology Unit to establish my research group to study mitochondrial complex I. 

I am now Professor of Biological Chemistry, Director of the MBU, and a Fellow of Corpus Christi College. I was elected Fellow of the Royal Society (FRS) in 2018 and Fellow of the Academy of Medical Sciences (FMedSci) in 2019, and awarded a Royal Society of Chemistry Interdisciplinary Prize in 2018 and the Keilin Memorial Lecture and Medal in 2020. 

I am also an advocate for sustainability and have recently taken on the role of Head of Sustainability at the School of Clinical Medicine.  

Project/study information

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 β-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 requires molecular, cellular, mechanistic and clinical information to be brought together: basic molecular knowledge of the enzyme’s structure, mechanism and assembly is required to underpin biomedical studies of the enzyme in mitochondrial and cellular systems of greater complexity. 

The Hirst group aims to develop this basic knowledge, and to understand and address the role of complex I in genetically, environmentally and pharmacologically-linked mitochondrial dysfunctions. 

To do this we combine cryo-electron microscopy (cryoEM) to study the structure of complex I, with biochemical and physical methods to study its function and dysfunction. We study the interactions of the complex with reactive oxygen species, drugs and toxins, and how they affect its catalysis and cellular functions. 

We study the complex in cultured human cells and mitochondria isolated from mammalian tissues, and use model organisms from mouse to yeast to bacterial species to manipulate it genetically. 

We therefore aim to discover how complex I works (and doesn’t work), how it is regulated, how it is affected by clinically-identified mutations, drugs and toxins, and to help to elucidate its role in both primary mitochondrial diseases and complex multifactorial disorders.