Redox regulation is emerging as an important modulator of cellular pathways, integrating signals from metabolic status and reactive oxygen species (ROS) production. Redox signalling is mediated by reversible changes in the ratios of redox couples (such as glutathione, thioredoxin and NAD(P)H), or in the levels of ROS (such as H2O2). Target proteins are changed by reversible modification of particular redox-sensitive thiols, altering their function, location or interactions, and hence their biological activity (Figure 1). Critically, redox signalling operates as a reversible “redox switch” on a protein, and is distinct from irreversible oxidative damage.
Figure 1: Summary of redox signalling.
The goals of our lab are: firstly, to investigate the importance of redox metabolism in physiology and pathology; and secondly, to develop novel molecular techniques to probe redox biology in vivo. We use the fruit fly Drosophila melanogaster as a model organism, which has many advantages including the availability of powerful genetic tools and the strong evolutionary conservation to mammals. Flies are an excellent, tractable system to study complex processes in vivo, since we can easily control their nutrition and environment, as well as treat with drugs. For instance, we can deliver compounds to living flies, either through the diet or by microinjection (Figure 2).
Figure 2: Delivering probes or drugs into living flies via microinjection (labelled with a blue dye).
We aim to identify, characterise and manipulate redox-sensitive targets using a combination of biochemical, genetic and proteomic approaches, in order to unravel the physiological and metabolic effects of redox signalling. Many interventions can improve health and extend lifespan in Drosophila melanogaster, such as manipulating nutrient-sensing pathways either pharmacologically or genetically. However, the underlying molecular mechanisms are still largely unclear. Therefore we are researching whether altered redox metabolism can explain these longevity benefits, and conversely whether the dysregulation of redox signalling networks contributes to the pathophysiology of diseases such as diabetes and to the ageing process.
van Dam E, van Leeuwen LAG, dos Santos E, James J, Best L, Lennicke C, Vincent AJ, Marinos G, Foley A, Buricova M, Mokochinski JB, Kramer HB, Lieb W, Laudes M, Franke A, Kaleta C and Cocheme HM. (2020). Sugar-induced obesity and insulin resistance are uncoupled from shortened survival in Drosophila. Cell Metabolism; 31(4), 710-725.
Lennicke C and Cocheme HM. (2020). Redox signalling and ageing: insights from Drosophila. Biochemical Society Transactions; doi.org/10.1042/BST20190052.
Cochemé HM, Bjedov I, Grönke S, Menger KE, James AM, Castillo-Quan JI, Foley A, Lennicke C, Buricova M, Adcott J, Cabreiro F, Murphy MP, Partridge L. (2019). Enhancing autophagy by redox regulation extends lifespan in Drosophila BioRxiv 790378.
Pryor R, Norvaisas P, Marinos G, Best L, Thingholm LB, Quintaneiro LM, De Haes W, Esser D, Waschina S, Lujan C, Smith RL, Scott TA, Martinez-Martinez D, Woodward O, Bryson K, Laudes M, Lieb W, Houtkooper RH, Franke A, Temmerman L, Bjedov I, Cochemé HM, Kaleta C, Cabreiro F. (2019). Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy Cell 178:1299-1312.
van Leeuwen LAG, Hinchy EC, Murphy MP, Robb EL, Cochemé HM. (2017). Click-PEGylation – A mobility shift approach to assess the redox state of cysteines in candidate proteins Free Radical Biology & Medicine Vol 108, 374-382.
Menger KE, James AM, Cochemé HM, Harbour ME, Chouchani ET, Ding S, Fearnley IM, Partridge L, Murphy MP. (2015). Fasting, but Not Aging, Dramatically Alters the Redox Status of Cysteine Residues on Proteins in Drosophila melanogaster. Cell Reports 11, 1856-65.
Cochemé HM, Quin C, McQuaker SJ, Cabreiro F, Logan A, Prime TA, Abakumova I, Patel JV, Fearnley IM, James AM, Porteous CM, Smith RA, Saeed S, Carré JE, Singer M, Gems D, Hartley RC, Partridge L, Murphy MP. (2011). Measurement of H2O2 within living drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix. Cell Metabolism 13(3), 340–350.