Molecular Metabolism and Ageing Group

Research Overview

Cardiometabolic diseases including obesity, diabetes and cardiovascular disease are often considered to be heterogeneous, polygenic diseases. That is, these conditions develop as a result of numerous different environmental and genetic causes. However, ultimately these collectively lead to disruption of a common set of pathways that manifests a similar disease.
Several decades of research have been dedicated to determining what these common set of pathways are, with significant progress having been made. Our group has an interest in several of the well documented pathways identified, however much of our focus centres on the more recently identified dysfunction of mitochondrial activity.
Found in almost every cell type in our body, mitochondria are organelles whose primary function is to utilise glucose (sugar) and fatty acids (fats) to provide the cell with energy (ATP). Healthy mitochondria are more efficient and therefore many cell types, particularly post-mitotic cells such as muscle and neurons, have developed unique ways to maintain a healthy pool of mitochondria. This includes specific mechanisms to degrade old or damaged mitochondria (mitophagy) or to generate new mitochondria when necessary (biogenesis). However, the molecular networks that control efficient mitochondrial health, and indeed the cross-talk between them, are poorly characterised.
Moreover, even less is known about how these mitochondrial molecular networks are effected by, or causative for cardiometabolic disease. Therefore, our studies aim to elucidate key pathways involved in mitochondrial function, energy metabolism and tissue health with the aim of determining how they can be therapeutically manipulated to prevent or treat disease and ageing.

Research focus
Diabetes, obesity, heart failure, liver disease, neurodegeneration.
Integration of cutting-edge technologies and systems biology for the identification of novel regulators of mitochondrial function and energy metabolism.
Determine if genetic and pharmacological manipulation of mitochondrial health can prevent or reverse cardiometabolic disease and ageing.
Design and validation of targeted nanoparticles for the delivery of novel therapeutics.
Identification and validation of novel biomarkers and diagnostics for cardiometabolic disease and ageing.
Long non-coding (lnc)RNAs in cardiometabolic disease.

Staff

Dr Simon T Bond - Post Doctoral Scholar
Ms Yingying Liu - Lab Manager
Mr Tim Sikora - Research Assistant
Dr Yi Wang - Post Doctoral Scholar
Ms Christine Yang - Research Assistant
Dr Aowen Zhuang - Post Doctoral Scholar
Ms Shannen Walker - PhD Student
Mr Michael Keating - PhD Student

Collaborators

Funding

National Heart Foundation
Diabetes Australia Research Program

Research Outcomes

PATENTS: National Phase PCT (WO 2019/140488 A1): Modulatory agents for fatty liver US Provisional 530725PRV (pending PCT application); Modulatory agents for obesity

PUBLICATIONS:
1. Kevin Huynh; Pratishtha Chatterjee; Ian Martins; Kaushala Jayawardana; Corey Giles; Natalie Mellett; Simon Laws; Ashley Ian Bush; Christopher Rowe; Victor Luis Villemagne; David Ames; Brian G Drew; Colin Masters; Ralph Martins, Peter Meikle Relationships between plasma lipid species, gender, risk factors and Alzheimer's disease J Alzheimers Dis. 2020;76(1):303-315

2. Genders AJ, Connor T, Morrison S, Bond ST, Drew BG, Meikle PJ, Howlett KF, McGee SL. Reducing hepatic PKD activity lowers circulating VLDL cholesterol. J Endocrinol. 2020 Sep;246(3):265-276

3. Zhenqi Zhou*, Timothy M. Moore*, Brian G. Drew,Vicent Ribas, Mete Civelek, Frode Norheim, Marcus M. Seldin, Kate A. Whitney, Ellen Lester, Britany R. Reddish, Laurent Vergnes, Karen Reue, Prashant Rajbhandari, Peter Tontonoz, Jason Lee, Sushil K. Mahata, Sylvia C. Hewitt, Orian Shirihai, Kerrin Small, Markku Laakso, Sindre Lee, Christian A. Drevon, Kenneth S. Korach, Aldons J. Lusis, Andrea L. Hevener. (*contributed equally) Estrogen receptor-alpha controls energy homeostasis in white and brown adipose tissue by regulating Polg1 and mitochondrial remodeling. Science Transl Med, 2020 Aug 5;12(555):eaax8096 TEMPLATE FOR CONTENT FOR RESEARCH GROUP PAGE Page 6 of 13

4. Parker BL*, Calkin AC*#, Seldin MM*, Keating MF, Tarling EJ, Yang P, Moody SC, Liu Y, Zerenturk EJ, Needham EJ, Miller ML, Clifford BL, Morand P, Watt MJ, Meex RCR, Peng KY, Lee R, Jayawardana K, Pan C, Mellett NA, Weir JM, Lazarus R, Lusis AJ, Meikle PJ, James DE, de Aguiar Vallim TQ#, Drew BG#. (*contributed equally, # corresponding authors) An integrative systems genetic analysis of mammalian lipid metabolism. Nature, 2019, 567:187-193

5. Huynh K, Barlow CK, Jayawardana KS, Weir JM, Mellett NA, Cinel M, Magliano DJ, Shaw JE, Drew BG, Meikle PJ. High-throughput plasma lipidomics: Detailed mapping of the associations with cardiometabolic risk factors. Cell Chemical Biology, 2019;26:71-84

6. Bond ST, Moody SC, Liu Y, Civelek M, Villanueva CJ, Gregorevic P, Kingwell BA, Hevener AL, Lusis AJ, Henstridge DC, Calkin AC, Drew BG. The E3 ligase March5 is a PPARgamma target gene that regulates mitochondria and metabolism in adipocytes. American Journal of Physiology: Endocrinology and Metabolism. 2019;316:E293-E304

7. Bond ST, Kim J, Calkin AC, Drew BG. The antioxidant moiety of mitoq imparts minimal metabolic effects in adipose tissue of high fat fed mice. Frontiers Physiol. 2019 May 8;10:543

8. Zhou Z, Ribas V, Rajbhandari P, Drew BG, Moore TM, Fluitt AH, Reddish BR, Whitney KA, Georgia S, Vergnes L, Reue K, Liesa M, Shirihai O, van der Bliek AM, Chi NW, Mahata SK, Tiano JP, Hewitt SC, Tontonoz P, Korach KS, Mauvais-Jarvis F, Hevener AL. Estrogen receptor alpha protects pancreatic beta-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress. The Journal of Biological Chemistry. 2018;293:4735-4751

9. Marshall JPS, Estevez E, Kammoun HL, King EJ, Bruce CR, Drew BG, Qian H, Iliades P, Gregorevic P, Febbraio MA, Henstridge DC. Skeletal muscle-specific overexpression of heat shock protein 72 improves skeletal muscle insulin-stimulated glucose uptake but does not alter whole body metabolism. Diabetes, Obesity & Metabolism. 2018;20:1928-1936

10. Hoque A, Sivakumaran P, Bond ST, Ling NXY, Kong AM, Scott JW, Bandara N, Hernandez D, Liu GS, Wong RCB, Ryan MT, Hausenloy DJ, Kemp BE, Oakhill JS, Drew BG, Pebay A, Lim SY. Mitochondrial fission protein drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells. Cell Death Discovery. 2018;4:39

11. Hevener AL, Zhou Z, Moore TM, Drew BG, Ribas V. The impact of eralpha action on muscle metabolism and insulin sensitivity - strong enough for a man, made for a woman. Molecular Metabolism. 2018;15:20-34

12. Rosdah AA, Bond ST, Sivakumaran P, Hoque A, Oakhill JS, Drew BG, Delbridge LMD, Lim SY. Mdivi-1 protects human w8b2(+) cardiac stem cells from oxidative stress and simulated ischemia-reperfusion injury. Stem Cells and Development. 2017;26:1771-1780

13. Hevener AL, Zhou Z, Drew BG, Ribas V. The role of skeletal muscle estrogen receptors in metabolic homeostasis and insulin sensitivity. Advances in Experimental Medicine and Biology. 2017;1043:257-284

14. Ribas V*, Drew BG*, Zhou Z*, Phun J, Kalajian NY, Soleymani T, Daraei P, Widjaja K, Wanagat J, de Aguiar Vallim TQ, Fluitt AH, Bensinger S, Le T, Radu C, Whitelegge JP, Beaven SW, Tontonoz P, Lusis AJ, Parks BW, Vergnes L, Reue K, Singh H, Bopassa JC, Toro L, Stefani E, Watt MJ, Schenk S, Akerstrom T, Kelly M, Pedersen BK, Hewitt SC, Korach KS, Hevener AL. Skeletal muscle action of estrogen receptor alpha is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Sci Transl Med. 2016;8:334ra354 (* contributed equally)

15. McMullen JR, Drew BG. Long non-coding rnas (lncrnas) in skeletal and cardiac muscle: Potential therapeutic and diagnostic targets? Clinical Science. 2016;130:2245-2256

16. McCurdy CE, Schenk S, Hetrick B, Houck J, Drew BG, Kaye S, Lashbrook M, Bergman BC, Takahashi DL, Dean TA, Nemkov T, Gertsman I, Hansen KC, Philp A, Hevener AL, Chicco AJ, Aagaard KM, Grove KL, Friedman JE. Maternal obesity reduces oxidative capacity in fetal skeletal muscle of japanese macaques. JCI Insight. 2016;1:e86612

17. Coughlan MT, Higgins GC, Nguyen TV, Penfold SA, Thallas-Bonke V, Tan SM, Ramm G, Van Bergen NJ, Henstridge DC, Sourris KC, Harcourt BE, Trounce IA, Robb PM, Laskowski A, McGee SL, Genders AJ, Walder K, Drew BG, Gregorevic P, Qian H, Thomas MC, Jerums G, Macisaac RJ, Skene A, Power DA, Ekinci EI, Wijeyeratne XW, Gallo LA, Herman-Edelstein M, Ryan MT, Cooper ME, Thorburn DR, Forbes JM. Deficiency in apoptosis-inducing factor recapitulates chronic kidney disease via aberrant mitochondrial homeostasis. Diabetes. 2016;65:1085-1098

18. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015;21:443-454

19. Drew BG, Hamidi H, Zhou Z, Villanueva CJ, Krum SA, Calkin AC, Parks BW, Ribas V, Kalajian NY, Phun J, Daraei P, Christofk HR, Hewitt SC, Korach KS, Tontonoz P, Lusis AJ, Slamon DJ, Hurvitz SA, Hevener AL. Estrogen receptor (er)alpha-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression. The Journal of Biological Chemistry. 2015;290:5566-5581

20. Henstridge DC, Bruce CR, Drew BG, Tory K, Kolonics A, Estevez E, Chung J, Watson N, Gardner T, Lee-Young RS, Connor T, Watt MJ, Carpenter K, Hargreaves M, McGee SL, Hevener AL, Febbraio MA. Activating hsp72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance. Diabetes. 2014;63:1881-1894

21. Drew BG, Ribas V, Le JA, Henstridge DC, Phun J, Zhou Z, Soleymani T, Daraei P, Sitz D, Vergnes L, Wanagat J, Reue K, Febbraio MA, Hevener AL. Hsp72 is a mitochondrial stress sensor critical for parkin action, oxidative metabolism, and insulin sensitivity in skeletal muscle. Diabetes. 2014;63:1488-1505

22. Wend K, Wend P, Drew BG, Hevener AL, Miranda-Carboni GA, Krum SA. ERalpha regulates lipid metabolism in bone through ATGL and perilipin. Journal of Cellular Biochemistry. 2013;114:1306-1314

23. Villanueva CJ, Vergnes L, Wang J, Drew BG, Hong C, Tu Y, Hu Y, Peng X, Xu F, Saez E, Wroblewski K, Hevener AL, Reue K, Fong LG, Young SG, Tontonoz P. Adipose subtype-selective recruitment of TLE3 or PRDM16 by PPARgamma specifies lipid storage versus thermogenic gene programs. Cell Metabolism. 2013;17:423-435

24. Drew BG, Hevener AL. The impact of estrogen receptor α expression in the pathogenesis of the metabolic syndrome. In: E E, ed. Integrative biology of women’s health. Spangenburg; 2013.

25. Carey AL, Siebel AL, Reddy-Luthmoodoo M, Natoli AK, D'Souza W, Meikle PJ, Sviridov D, Drew BG, Kingwell BA. Skeletal muscle insulin resistance associated with cholesterol-induced activation of macrophages is prevented by high density lipoprotein. PloS one. 2013;8:e56601

26. Beaven SW, Matveyenko A, Wroblewski K, Chao L, Wilpitz D, Hsu TW, Lentz J, Drew B, Hevener AL, Tontonoz P. Reciprocal regulation of hepatic and adipose lipogenesis by liver x receptors in obesity and insulin resistance. Cell Metabolism. 2013;18:106-117

27. Hoang A, Drew BG, Low H, Remaley AT, Nestel P, Kingwell BA, Sviridov D. Mechanism of cholesterol efflux in humans after infusion of reconstituted high-density lipoprotein. European Heart Journal. 2012;33:657-665

28. Drew BG, Rye KA, Duffy SJ, Barter P, Kingwell BA. The emerging role of hdl in glucose metabolism. Nature reviews. Endocrinology. 2012;8:237-245

29. Chao LC, Wroblewski K, Ilkayeva OR, Stevens RD, Bain J, Meyer GA, Schenk S, Martinez L, Vergnes L, Narkar VA, Drew BG, Hong C, Boyadjian R, Hevener AL, Evans RM, Reue K, Spencer MJ, Newgard CB, Tontonoz P. Skeletal muscle nur77 expression enhances oxidative metabolism and substrate utilization. Journal of Lipid Research. 2012;53:2610-2619

30. Ribas V*, Drew BG*, Le JA, Soleymani T, Daraei P, Sitz D, Mohammad L, Henstridge DC, Febbraio MA, Hewitt SC, Korach KS, Bensinger SJ, Hevener AL. Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development. Proc Nat Acad Sci 2011;108:16457-16462. (* contributed equally)

31. Gao XM, Liu Y, White D, Su Y, Drew BG, Bruce CR, Kiriazis H, Xu Q, Jennings N, Bobik A, Febbraio MA, Kingwell BA, Bucala R, Fingerle-Rowson G, Dart AM, Morand EF, Du XJ. Deletion of macrophage migration inhibitory factor protects the heart from severe ischemiareperfusion injury: A predominant role of anti-inflammation. Journal of Molecular and Cellular Cardiology. 2011;50:991-999

32. Drew BG, Carey AL, Natoli AK, Formosa MF, Vizi D, Reddy-Luthmoodoo M, Weir JM, Barlow CK, van Hall G, Meikle PJ, Duffy SJ, Kingwell BA. Reconstituted high-density lipoprotein infusion modulates fatty acid metabolism in patients with type 2 diabetes mellitus. Journal of Lipid Research. 2011;52:572-581

33. Coughlan MT, Yap FY, Tong DC, Andrikopoulos S, Gasser A, Thallas-Bonke V, Webster DE, Miyazaki J, Kay TW, Slattery RM, Kaye DM, Drew BG, Kingwell BA, Fourlanos S, Groop PH, Harrison LC, Knip M, Forbes JM. Advanced glycation end products are direct modulators of beta-cell function. Diabetes. 2011;60:2523-2532

34. Yuen DY, Dwyer RM, Matthews VB, Zhang L, Drew BG, Neill B, Kingwell BA, Clark MG, Rattigan S, Febbraio MA. Interleukin-6 attenuates insulin-mediated increases in endothelial cell signaling but augments skeletal muscle insulin action via differential effects on tumor necrosis factor-alpha expression. Diabetes. 2009;58:1086-1095

35. Patel S*, Drew BG*, Nakhla S, Duffy SJ, Murphy AJ, Barter PJ, Rye KA, Chin-Dusting J, Hoang A, Sviridov D, Celermajer DS, Kingwell BA. Reconstituted high-density lipoprotein increases plasma high-density lipoprotein antiinflammatory properties and cholesterol efflux capacity in patients with type 2 diabetes. J American Coll Card. 2009;53:962-971 (* contributed equally)

36. Henstridge DC, Drew BG, Formosa MF, Natoli AK, Cameron-Smith D, Duffy SJ, Kingwell BA. The effect of the nitric oxide donor sodium nitroprusside on glucose uptake in human primary skeletal muscle cells. Nitric oxide. 2009;21:126-131

37. Drew BG, Duffy SJ, Formosa MF, Natoli AK, Henstridge DC, Penfold SA, Thomas WG, Mukhamedova N, de Courten B, Forbes JM, Yap FY, Kaye DM, van Hall G, Febbraio MA, Kemp BE, Sviridov D, Steinberg GR, Kingwell BA. High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus. Circulation. 2009;119:2103-2111

38. Calkin AC, Drew BG, Ono A, Duffy SJ, Gordon MV, Schoenwaelder SM, Sviridov D, Cooper ME, Kingwell BA, Jackson SP. Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux. Circulation. 2009;120:2095-2104

39. Soro-Paavonen A, Watson AM, Li J, Paavonen K, Koitka A, Calkin AC, Barit D, Coughlan MT, Drew BG, Lancaster GI, Thomas M, Forbes JM, Nawroth PP, Bierhaus A, Cooper ME, Jandeleit-Dahm KA. Receptor for advanced glycation end products (rage) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes. 2008;57:2461-2469

40. Drew BG, Kingwell BA. Acadesine, an adenosine-regulating agent with the potential for widespread indications. Expert opinion on Pharmacotherapy. 2008;9:2137-2144

41. Drew BG, Calkin AC. Drug evaluation: K-111, an insulin-sensitizing peroxisome proliferator-activated receptor alpha agonist. Current Opinion in Investigational Drugs. 2007;8:324-330

42. Natoli AK, Medley TL, Ahimastos AA, Drew BG, Thearle DJ, Dilley RJ, Kingwell BA. Sex steroids modulate human aortic smooth muscle cell matrix protein deposition and matrix metalloproteinase expression. Hypertension. 2005;46:1129-1134

43. Henstridge DC, Kingwell BA, Formosa MF, Drew BG, McConell GK, Duffy SJ. Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes. Diabetologia. 2005;48:2602-2608

44. Ferrier KE, Nestel P, Taylor A, Drew BG, Kingwell BA. Diet but not aerobic exercise training reduces skeletal muscle tnf-alpha in overweight humans. Diabetologia. 2004;47:630-637

45. Drew BG, Fidge NH, Gallon-Beaumier G, Kemp BE, Kingwell BA. High-density lipoprotein and apolipoprotein AI increase endothelial NO synthase activity by protein association and multisite phosphorylation. Proc Nat Acad Sci. 2004;101:6999- 7004

Research Publications

Parker BL*, Calkin AC*#, Seldin MM*, Keating MF, Tarling EJ, Yang P, Moody SC, Liu Y, Zerenturk EJ, Needham EJ, Miller ML, Clifford BL, Morand P, Watt MJ, Meex RCR, Peng KY, Lee R, Jayawardana K, Pan C, Mellett NA, Weir JM, Lazarus R, Lusis AJ, Meikle PJ, James DE, de Aguiar Vallim TQ#, Drew BG#. (*contributed equally, # corresponding authors) An integrative systems genetic analysis of mammalian lipid metabolism. Nature, 2019, 567:187-193

Bond ST, Moody SC, Liu Y, Civelek M, Villanueva CJ, Gregorevic P, Kingwell BA, Hevener AL, Lusis AJ, Henstridge DC, Calkin AC, Drew BG. The E3 ligase March5 is a PPARgamma target gene that regulates mitochondria and metabolism in adipocytes. American Journal of Physiology: Endocrinology and Metabolism. 2019;316:E293-E304

Ribas V*, Drew BG*, Zhou Z*, Phun J, Kalajian NY, Soleymani T, Daraei P, Widjaja K, Wanagat J, de Aguiar Vallim TQ, Fluitt AH, Bensinger S, Le T, Radu C, Whitelegge JP, Beaven SW, Tontonoz P, Lusis AJ, Parks BW, Vergnes L, Reue K, Singh H, Bopassa JC, Toro L, Stefani E, Watt MJ, Schenk S, Akerstrom T, Kelly M, Pedersen BK, Hewitt SC, Korach KS, Hevener AL. Skeletal muscle action of estrogen receptor alpha is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Sci Transl Med. 2016;8:334ra354 (* contributed equally)

Drew BG, Ribas V, Le JA, Henstridge DC, Phun J, Zhou Z, Soleymani T, Daraei P, Sitz D, Vergnes L, Wanagat J, Reue K, Febbraio MA, Hevener AL. Hsp72 is a mitochondrial stress sensor critical for parkin action, oxidative metabolism, and insulin sensitivity in skeletal muscle. Diabetes. 2014;63:1488-1505

Drew BG, Rye KA, Duffy SJ, Barter P, Kingwell BA. The emerging role of hdl in glucose metabolism. Nature Reviews Endocrinology. 2012;8:237-245 Bond ST, Kim J, Calkin AC, Drew BG. The antioxidant moiety of MitoQ imparts minimal metabolic effects in adipose tissue of high fat fed mice. Frontiers Physiol. 2019 May 8;10:543

Research Projects

This Research Group doesn't currently have any projects


School Research Themes

Cardiometabolic



Key Contact

For further information about this research, please contact Head of Laboratory Associate Professor Brian Drew

Department / Centre

Baker Department of Cardiometabolic Health

Unit / Centre

Molecular Imaging and Theranostics Group Molecular Metabolism and Ageing Group

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