Redox signalling is an important modulator of diverse biomedically relevant metabolic pathways (Figure 1). Consequently, dysregulation of redox homeostasis is implicated in the pathophysiology of many age-related diseases, as well as in the ageing process itself. However, the underlying mechanisms remain largely unclear, which hampers the development of effective therapeutic strategies. To address this challenge, our group leverages the fruit fly Drosophila as a powerful and tractable in vivo system, with its combination of short lifespan and strong evolutionary conservation of central signalling pathways and druggable targets regulating energy metabolism and lifespan.
Figure 1: Redox signalling operates through the specific post-translational modification of key redox-sensitive cysteine residues on target proteins. This reversible ‘redox switch’ integrates signals from oxidative, nutritional and environmental cues to selectively regulate cellular function (Lennicke & Cochemé 2020, Biochem Soc Trans).
Our research is focused on the following complementary questions:
(1) How does redox signalling regulate metabolic homeostasis and ageing? We aim to identify, characterise and manipulate redox-sensitive targets using a combination of biochemical, proteomic and genetic knock-in approaches, in order to unravel the physiological importance of redox signalling in vivo in the context of metabolic diseases and ageing (e.g. van Leeuwen et al. 2017, Free Rad Biol Med; Cochemé* et al. 2019, BioRxiv).
(2) How do diets and drugs impact on survival? We perform dietary and drug interventions shedding light on the complex interplay between redox balance, metabolic dysfunction and ageing. For instance, we recently showed that sugar-induced obesity and insulin resistance can be uncoupled from shortened lifespan, and identified dysregulation of purine catabolism as underlying the pathophysiology of high sugar diets in Drosophila (Figure 2). Furthermore, we extended our study to humans, and found that the association between dietary sugar intake and circulating purines was conserved in a population cohort (van Dam et al. 2020, Cell Metab). We are also interested in exploring evolutionary conserved pharmacological interventions that extend lifespan (e.g. Pryor et al. 2019, Cell).
Ultimately, our goal is to uncover novel pathways and potential therapeutic targets for health and longevity benefits.
Figure 2: A high-sugar diet shortens survival independently of obesity and insulin resistance. Sugar-induced dysregulation of purine catabolism leads to the development of stones in the renal tubules (van Dam et al. 2020, Cell Metab).
Lennicke C and Cochemé HM. (2021) Redox metabolism: ROS as specific molecular regulators of cell signaling and function Molecular Cell 81(18) 3691-3707. https://doi.org/10.1016/j.molcel.2021.08.018
Lennicke C and Cochemé HM. (2021) Redox regulation of the insulin signalling pathway. Redox Biology 42, 101964.
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 Cochemé HM. (2020). Sugar-induced obesity and insulin resistance are uncoupled from shortened survival in Drosophila. Cell Metabolism 31(4), 710-725.
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. (*co-corresponding)
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 108, 374-382.
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.