Life Sciences Research for Lifelong Health

Michael Wakelam

Research Summary

We aim to understand the essential physiological functions of lipids. Lipids are highly dynamic structures with structural, metabolic and signalling roles. To fully understand the roles that lipids have in cell function during ageing we need the ability to determine their individual changes.

The cellular lipidome is extremely complex, with distinct classes of lipids each containing many molecular species that can differ both in the length of each acyl chain present and in the number and position of double bonds.

In our lab we have pioneered the use of high-sensitivity liquid chromatography-mass spectrometry (LC-MS) technology to rapidly and comprehensively measure the levels of lipids in a wide range of cell types, tissues and tumours. The lipidome of a cell typically comprises of ~ 1500 distinct lipid species measurable with current LC-MS technology. However, this number is most likely an underestimate since there are theoretically closer to 10 000 distinct lipid species in the lipidome.

The principal aim of our laboratory is to better understand how the distinct lipid species of a cell’s lipidome function during the healthy ageing of the whole animal.

​To achieve this we use a multidisciplinary approach combining LC-MS analysis, protein biochemistry, cell biology and genetic manipulation of model organisms. This allows us to identify the cellular signalling pathways and processes that individual lipid species regulate, and to investigate how the enzymes that determine the composition of the lipidome are regulated in response to changes in the environment.

Latest Publications

Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism.
Hahn O, Grönke S, Stubbs TM, Ficz G, Hendrich O, Krueger F, Andrews S, Zhang Q, Wakelam MJ, Beyer A, Reik W, Partridge L

Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time.

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Genome biology, 18, 1474-760X, 56, 2017

PMID: 28351387

Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication.
Farquhar MJ, Humphreys IS, Rudge SA, Wilson GK, Bhattacharya B, Ciaccia M, Hu K, Zhang Q, Mailly L, Reynolds GM, Aschcroft M, Balfe P, Baumert TF, Roessler S, Wakelam MJ, McKeating JA

Chronic hepatitis C is a global health problem with an estimated 170 million HCV infected individuals at risk of progressive liver disease and hepatocellular carcinoma (HCC). Autotaxin (ATX) is a phospholipase with diverse roles in physiological and pathological processes including inflammation and oncogenesis. Clinical studies have reported increased ATX expression in chronic hepatitis C, however, the pathways regulating ATX and its role in the viral life cycle are not well understood.

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Journal of hepatology, , 1600-0641, , 2017

PMID: 28126468

Phospholipase D activity couples plasma membrane endocytosis with retromer dependent recycling.
Thakur R, Panda A, Coessens E, Raj N, Yadav S, Balakrishnan S, Zhang Q, Georgiev P, Basak B, Pasricha R, Wakelam MJ, Ktistakis NT, Padinjat R

During illumination, the light sensitive plasma membrane (rhabdomere) of Drosophila photoreceptors undergoes turnover with consequent changes in size and composition. However the mechanism by which illumination is coupled to rhabdomere turnover remains unclear. We find that photoreceptors contain a light-dependent phospholipase D (PLD) activity. During illumination, loss of PLD resulted in an enhanced reduction in rhabdomere size, accumulation of Rab7 positive, rhodopsin1-containing vesicles (RLVs) in the cell body and reduced rhodopsin protein. These phenotypes were associated with reduced levels of phosphatidic acid, the product of PLD activity and were rescued by reconstitution with catalytically active PLD. In wild type photoreceptors, during illumination, enhanced PLD activity was sufficient to clear RLVs from the cell body by a process dependent on Arf1-GTP levels and retromer complex function. Thus, during illumination, PLD activity couples endocytosis of RLVs with their recycling to the plasma membrane thus maintaining plasma membrane size and composition.

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eLife, 5, 2050-084X, , 2016

PMID: 27848911

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Keywords

ageing
cell biology
lipids
signalling

Group Members

Latest Publications

Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication.

Farquhar MJ, Humphreys IS, Rudge SA

Journal of hepatology
1600-0641: (2017)

PMID: 28126468

Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.

Huang-Doran I, Tomlinson P, Payne F

JCI insight
1 :e88766 (2016)

PMID: 27766312

The Phospholipase D2 Knock Out Mouse Has Ectopic Purkinje Cells and Suffers from Early Adult-Onset Anosmia.

Vermeren MM, Zhang Q, Smethurst E

PloS one
11 1932-6203:e0162814 (0)

PMID: 27658289

C13orf31 (FAMIN) is a central regulator of immunometabolic function.

Cader MZ, Boroviak K, Zhang Q

Nature immunology
1529-2916: (2016)

PMID: 27478939

Purification, characterization and crystallization of the F-ATPase from Paracoccus denitrificans.

Morales-Rios E, Watt IN, Zhang Q

Open biology
5 2046-2441: (2015)

PMID: 26423580

Phosphoinositide 3-kinase-related overgrowth: cellular phenotype and future therapeutic options.

Parker VE, Knox RG, Zhang Q

Lancet (London, England)
385 Suppl 1 1474-547X:S77 (2015)

PMID: 26312899

Phosphatidylinositolphosphate Phosphatase Activities and Cancer.

Rudge SA, Wakelam MJ

Journal of lipid research
0022-2275: (2015)

PMID: 26302980