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Creatine metabolism: energy homeostasis, immunity and cancer biology


Perturbations in metabolic processes are associated with diseases such as obesity, type 2 diabetes mellitus, certain infections and some cancers. A resurgence of interest in creatine biology is developing, with new insights into a diverse set of regulatory functions for creatine. This resurgence is primarily driven by technological advances in genetic engineering and metabolism as well as by the realization that this metabolite has key roles in cells beyond the muscle and brain. Herein, we highlight the latest advances in creatine biology in tissues and cell types that have historically received little attention in the field. In adipose tissue, creatine controls thermogenic respiration and loss of this metabolite impairs whole-body energy expenditure, leading to obesity. We also cover the various roles that creatine metabolism has in cancer cell survival and the function of the immune system. Renewed interest in this area has begun to showcase the therapeutic potential that lies in understanding how changes in creatine metabolism lead to metabolic disease.

Key points

  • Mitochondria in brown adipose tissue are capable of normal oxidative phosphorylation, with P:O ratios similar to those of other tissues.

  • Atypical actions of creatine involve phosphocreatine transport into colorectal cancer cells, super-stoichiometric ADP liberation to trigger respiration in thermogenic adipocytes and chromatin remodelling to modulate macrophage polarity.

  • Cyclocreatine and creatine can both inhibit tumour progression, suggesting that the pro-cancer role of creatine is independent of its function in energy buffering.

  • The mitochondrial network transduces energy over long distances, thus minimizing the requirement for metabolite diffusion, whereas cells with a disrupted mitochondrial network might buffer energy via the creatine kinase–phosphocreatine circuit.

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Fig. 1: Pathway of endogenous creatine synthesis.
Fig. 2: UCP1-dependent thermogenesis.
Fig. 3: Creatine biology in various cell types.


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The authors apologize for being unable to cite papers that have contributed to the progress of this field owing to space limitations. The authors acknowledge support by the Canadian Institutes of Health Research (CIHR; grant PJT-159529) and Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant (to L.K.).

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Creatine kinase–phosphocreatine circuit

Also known as the phosphocreatine shuttle, this system mediates the stoichiometric (1:1) transphosphorylation of phosphate from mitochondrial or glycolytic ATP to phosphocreatine, which is then used by creatine kinase to maintain high local ATP:ADP ratios.


A mitochondrial inner membrane protein that dissipates the proton gradient across the lipid bilayer, effectively decreasing the proton-motive force and minimizing ATP synthesis; the energy dissipated across the mitochondrial inner membrane results in a considerable increase in the rate of respiration, substrate oxidation and release of heat.

Proton-motive force

The potential energy stored as a combination of the electrical and concentration (electrochemical) gradient across the mitochondrial inner membrane due to the extrusion of protons into the intermembrane space by the electron transport chain.

Congenic background

An inbred strain of mouse where the control and experimental animals only differ from one another by a small genetic region (typically a single gene).


The ambient temperature where the metabolic rate is at a minimum, when temperature regulation is achieved by non-evaporative physical processes alone.

Creatine-dependent thermogenesis

The phosphorylation of creatine by creatine kinase and subsequent dephosphorylation of phosphocreatine (or downstream phosphometabolite) that regenerates creatine and dissipates the high-energy phosphate to generate heat; also known as futile creatine cycling.

P:O ratio

The number of moles of ADP phosphorylated to ATP for every two electrons that reduce oxygen to water.

Thymocyte selection

During T cell differentiation, thymocytes can undergo expansion, differentiation (positive selection) or cell death (negative selection).

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Kazak, L., Cohen, P. Creatine metabolism: energy homeostasis, immunity and cancer biology. Nat Rev Endocrinol 16, 421–436 (2020).

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