CellularBioenergetics

Key Research Areas

• Cardiometabolic disease
• Diabetes and obesity
• Mitochondrial biology
• Cancer cell metabolism

Research Overview

Every cell requires a constant supply of nutrients to provide the energy and ‘building blocks’ needed for cellular function and maintenance. Disruption of the fundamental processes involved in nutrient metabolism has a major impact on the fidelity and survival of cells and can ultimately precipitate disease. The goal of the Cellular Bioenergetics Laboratory is to understand how metabolic dysfunction at the whole-body, cellular and molecular level contributes to the pathogenesis of cardiometabolic disease and cancer, and to leverage this knowledge to identify and test potential new strategies to treat these conditions.

There are 4 key projects underway in the Cellular Bioenergetics Laboratory, led by Prof Nigel Turner:

1. Preventing the buildup of toxic lipids to improve cellular metabolism

Excess intracellular accumulation of specific types of lipids leads to cellular dysfunction and impairs the actions of insulin to appropriately regulate carbohydrate and lipid metabolism. This project explores approaches for limiting the accumulation of toxic lipid species, with a goal of improving insulin action and overall cellular metabolism.

2. Boosting NAD+ biosynthesis to prevent cardiometabolic disease

NAD+ is an important co-factor for many different enzymes which are critical for regulating metabolism and lifespan. This project uses genetic and pharmacological approaches to examine the potential therapeutic effect of promoting NAD+ biosynthesis in pre-clinical models of cardiometabolic disease.

3. Understanding mitochondrial stress signaling

Mitochondria have a well described role as the powerhouse of the cell, but also participate in many other critical processes. Given their key role in cellular homeostasis, one emerging question is how mitochondria respond to stress. This project will examine the intercellular signaling pathways activated in response to mitochondrial bioenergetic stress, with a goal of identifying bioactive molecules with roles in nutrient metabolism and stress resistance.

4. Targeting metabolism to treat cancer

Cancer cells reprogram their metabolism to channel fuel (fat, protein and glucose) into pathways that allow them to proliferate and thrive, even under stressful conditions such as in response to hypoxia or chemotherapy treatment. This project uses advanced techniques to map metabolic changes in specific cancers, with a goal of identifying novel anti-cancer strategies to improve treatment outcomes.

1. Metcalfe LK, Shepherd PR, Smith GC, Turner N. (2022). Limited Metabolic Effect of the CREBRFR457Q Obesity Variant in Mice. Cells 11:497 https://www.mdpi.com/2073...
2. Jayashankar V, Selwan E, Hancock SE, Verlande A, Goodson MO, Eckenstein KH, Milinkeviciute G, Hoover BM, Chen B, Fleischman AG, Cramer KS, Hanessian S, Masri S, Turner N, Edinger AL. (2021). Drug-like sphingolipid SH-BC-893 opposes ceramide-induced mitochondrial fission and corrects diet-induced obesity. EMBO Molecular Medicine 13:e13086 https://doi.org/10.15252/emmm....
3. Alexopoulos SJ, Chen SY, Brandon AE, Salamoun JM, Byrne FL, Garcia CJ, Beretta M, Olzomer EM, Shah DP, Philp AM, Hargett SR, Lawrence RT, Lee B, Sligar J, Carrive P, Tucker SP, Philp A, Lackner C, Turner N, Cooney GJ, Santos WL & Hoehn KL (2020). Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice, Nature Communications 11:2397 https://www.nature.com/articles/s41467...
4. Liu M, Hancock SE, Sultani G, Wilkins BP, Ding E, Osborne B, Quek LE, Turner N. (2019). Snail-Overexpression Induces Epithelial-mesenchymal Transition and Metabolic Reprogramming in Human Pancreatic Ductal Adenocarcinoma and Non-tumorigenic Ductal Cells. Journal of Clinical Medicine 8:822 https://www.mdpi.com/2077-0383...
5. Montgomery MK, Osborne B, Brandon AE, O’Reilly L, Fiveash CE, Brown SHJ, Wilkins BP, Samsudeen A, Yu J, Devanapalli B, Hertzog A, Tolun AA, Kavanagh T, Cooper AA, Mitchell TW, Biden TJ, Smith NJ, Cooney GJ, Turner N. (2019). Regulation of mitochondrial metabolism in murine skeletal muscle by the medium chain fatty acid receptor Gpr84. FASEB Journal 33: 12264-12276 https://doi.org/10.1096/fj.201...
6. Turner N (co-corresponding author), Lim XY, Toop HD, Osborne B, Brandon AE, Taylor EN, Fiveash CE, Govindaraju H, Teo JD, McEwen HP, Couttas TA, Butler SM, Das A, Kowalski GM, Bruce CR, Hoehn KL, Fath T, Schmitz-Peiffer C, Cooney GJ, Montgomery MK, Morris JC, Don AS. (2018). A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism. Nature Communications 9:3165 https://doi.org/10.1038/s41467...
7. Das A, Huang GX, Bonkowski MS, Longchamp A, Li C, Schultz MB, Kim LJ, Osborne B, Joshi S, Lu Y, Treviño-Villarreal JH, Kang MJ, Hung T, Lee B, Williams EO, Igarashi M, Mitchell JR, Wu LE, Turner N, Arany Z, Guarente L, Sinclair DA. (2018). Impairment of an endothelial NAD+-H2S signaling network is a reversible cause of vascular aging. Cell 173:74-89 https://www.cell.com/cell/fulltext/S0092...
8. Montgomery MK, Brown SH, Lim XY, Fiveash CE, Osborne B, Bentley NL, Braude JP, Mitchell TW, Coster AC, Don AS, Cooney GJ, Schmitz-Peiffer C, Turner N. (2016). Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: A beneficial role for very long-chain sphingolipid species. Biochimica et Biophysica Acta. Molecular & Cell Biology of Lipids 1861:1828-1839 https://doi.org/10.1016/j.bbal...
9. Liu M, Quek LE, Sultani G & Turner N. (2016). Epithelial-mesenchymal transition induction is associated with augmented glucose uptake and lactate production in pancreatic ductal adenocarcinoma. Cancer Metabolism 4:19 https://cancerandmetabolism.biomedcentral.com/articles/10.118...
10. Montgomery MK and Turner N. (2015). Mitochondrial dysfunction and insulin resistance: an update. Endocrine Connections 4:1-15 https://www.heartlungcirc.org/article/S1443...
11. Montgomery MK, Hallahan NL, Brown SH, Liu M, Mitchell TW, Cooney GJ & Turner N. (2013). Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding. Diabetologia 56:1129-1139 https://link.springer.com/article/10.1007...
12. Turner N, Kowalski GM, Leslie SJ, Risis S, Yang C, Lee-Young RS, Babb JR, Meikle PJ, Lancaster GI, Henstridge DC, White PJ, Kraegen EW, Marette A, Cooney GJ, Febbraio MA & Bruce CR. (2013). Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding. Diabetologia 56:1638-1648 https://link.springer.com/article/10.1007/s00125...
13. Gomes AP, Price NL, Ling AJY, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Kaelin Jr. WG, Turner N, Bell EL & Sinclair DA. (2013). Declining NAD+ induces a pseudohypoxic state that disrupts nuclear-mitochondrial communication during aging. Cell 155:1624-38 https://doi.org/10.1016/j.cell...
14. Wright LE, Brandon AE, Hoy AJ, Forsberg G-B, Lelliott CJ, Reznick J, Löfgren L, Oscarsson J, Strömstedt M, Cooney GJ & Turner N. (2011). Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress. Diabetologia 54:1417-1426 https://link.springer.com/article/10.1007...
15. Hoehn KL, Turner N (co-first author), Swarbrick MM, Wilks D, Preston E, Phua Y, Joshi H, Furler SM, Larance M, Hegarty BD, Leslie SJ, Pickford R, Hoy AJ, Kraegen EW, James DE & Cooney GJ. (2010). Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole body energy expenditure or adiposity. Cell Metabolism 11: 70-76 https://www.cell.com/cell-metabolism..
16. Turner N, Hariharan K, TidAng J, Frangioudakis G, Beale SM, Wright LE, Zeng XY, Leslie SJ, Li J, Kraegen EW, Cooney GJ & Ye J. (2009). Enhancement of muscle mitochondrial oxidative capacity and alterations in insulin action are lipid species-dependent: Potent tissue-specific effects of medium chain fatty acids. Diabetes 58:2547-2554 https://doi.org/10.2337/db09-0...
17. Turner N, Bruce CR, Beale SM, Hoehn KL, So T, Rolph MS & Cooney GJ. (2007). Excess lipid availability increases mitochondrial fatty acid oxidative capacity in skeletal muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. Diabetes 56: 2085–2092 https://doi.org/10.2337/db07-0...