MacFarlane Group

Molecular mechanisms of cell death

Prof Marion MacFarlane

Cell death is important as it controls the number of cells in our tissues, acting as a crucial counter-balance to cell division. We are studying cell death processes because adverse outcomes (toxicity) associated with therapeutic drugs or environmental agents are often mediated by the same proteins/pathways that control cell death.

Cell death is a fundamental cellular response that plays a crucial role both during development and in the removal of unwanted or damaged cells following stress, injury or infection. Consequently, cell death is tightly controlled and often occurs in an ordered manner by a process called ‘apoptosis’, or another more recently identified mode of regulated cell death termed ‘necroptosis’. Inappropriate cell death contributes to many human diseases, including cancer, autoimmune and neurodegenerative disorders. Proteins/pathways that control cell death have also been identified as defined nodes that form key decision points to regulate the response to toxic insult.

Our programme is aimed at understanding the fundamental mechanisms of cell death that regulate life/death decisions at the cellular level. By understanding the underlying molecular and cell biology of these processes, we aim to deliver field-changing mechanistic insights into toxicology and disease.

We are investigating:                     

1. Cell death pathways activated in response to a range of agents, with a focus on members of the Tumour Necrosis Factor (TNF) cytokine family 
2. Drugs or other xenobiotics that trigger mitochondrial-mediated cell death 
3. Cell death pathways induced by some Anti-Sense Oligonucleotide (ASO) /other nucleic acid-dependent therapeutics under development 

Our recent work places multiprotein signalling complexes triggered by members of the TNF cytokine family as key determinants of cell death (apoptosis or necroptosis) or survival (pro-inflammatory). We deploy strategies including novel in vitro reconstituted models, combined with an integrated molecular, cell biology, proteomics and structural biology-based approach to obtain novel insights into the assembly, regulation and molecular architecture of these multiprotein signalling complexes that direct cell fate. 

Off-target inhibition of mitochondrial function is a key contributor to drug attrition and a major driver of tissue-specific hepatotoxicity and cardiotoxicity.  We are investigating mechanisms of drug-induced mitochondrial toxicity or cell adaptation in translational models of hepatotoxicity/cardiotoxicity and, building on our recent work showing that drug ‘toxicophores’ result in off-target inhibition of the electron transport chain, we are integrating high-throughput analysis of drug/xenobiotic perturbation of mitochondrial health with active Machine Learning to identify novel features linked to mitochondrial toxicity. 

Data obtained via these integrated approaches will provide novel insights into the fundamental mechanisms of cell death, providing mechanistic frameworks to inform safer drug development and strategies for safer medicine use based on modelling individual variability.

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