Three-dimensional network of creatine metabolism: From intracellular energy shuttle to systemic metabolic regulatory switch

Abstract

Background: Creatine serves as an intracellular shuttle for high-energy phosphate bonds, enabling rapid ATP transfer from energy-producing to energy-consuming cellular compartments. In skeletal muscle, creatine coordinates energy distribution among mitochondrial oxidative phosphorylation, glycolysis, and the phosphagen system. Consequently, creatine supplementation acutely enhances muscular performance and is widely utilized as an ergogenic aid in power-based sports. Recent studies demonstrate that enhanced creatine metabolism in adipose tissue promotes brown adipocyte renewal and boosts energy expenditure in cold environments or sedentary conditions, thereby improving overall systemic metabolism. Beyond its traditional role as an exercise supplement, the creatine metabolic network has emerged as a promising therapeutic target for metabolic disorders.

Scope of review: This review begins by revisiting the history and latest advancements in creatine research, and ultimately proposes three dimensions for the current explanation of creatine metabolism: (1) subcellular energy transport; (2) muscle-fat metabolic axis; (3) systemic energy sensing and metabolic reprogramming.

Major conclusions: The creatine cycle enables directed energy flow through mitochondrial supercomplexes (VDAC/ANT-CK) and resets systemic metabolism via subcellular energy tunnels and inter-organ interactions. Creatine kinase (CK) condensates, through liquid-liquid phase separation, can rapidly meet energy demands during exercise. Therefore, targeting the dynamics of the CK phase may be promising for enhancing athletic performance and improving metabolic diseases.

Keywords: Creatine; Energy metabolism; Exercise; Metabolic diseases; Phase separation; Thermogenesis.

Figure 1

The BLSA Metabolic Axis Model of Creatine. Creatine synthesized by the liver is distributed to various tissues and organs through the bloodstream, entering the intracellular creatine cycle. The creatine cycle in skeletal muscle is coupled with ATP synthesis, consuming energy in the form of work output (exercise); the creatine cycle in adipose tissue is coupled with thermogenesis, consuming energy in the form of heat. The creatine cycle in the brain can sense the system energy metabolic status and subsequently regulate the energy expenditure relationship between tissues and organs through neural and endocrine mechanisms. This model defines creatine as the core regulator of systemic energy distribution, enabling diverse energy allocation through creatine cycles in different tissues. This model not only reveals how creatine coordinates energy distribution among different tissues but also suggests that regulating creatine metabolism could be a new strategy for treating metabolic diseases. By controlling creatine cycle, it may be possible to achieve fine-tuned management of energy metabolism, thereby reversing pathological processes of obesity, diabetes, and other metabolic diseases.

Figure 2

Putative topology of the VDAC/ANT-CK supramolecular machine. The cubic homooligomer umtCK (red surface) and its direct interaction partner VDAC (yellow surface) are embedded in phospholipid cardiolipin (CL, white surface) within the mitochondrial outer membrane (MOM) and inner membrane (MIM). ANT (magenta surface) is located near this complex in the MIM, and functional data and co-purification experiments indicate a close proximity between them, suggesting they reside within the same MIM phosphatidyl carnitine patch. Note that this figure only shows the interaction of one CL molecule and one VDAC dimer with one dimer of the umtCK octamer; however, each mtCK dimer may participate in such interactions, including additional interactions with other anionic phospholipids in the MOM. Additionally, VDAC and ANT likely form dimers (as shown) or higher-order oligomers in vivo, and this figure only depicts the crystal structure of the dimer (Schlattner et al. ,2018). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Figure 3

Phase separation of CK condensates. This spatiotemporal mechanism allows creatine kinase CK to form dynamic condensates, temporarily coupling CK kinase with its substrate ADP, creating localized ‘energy reaction containers’. Molecular dynamics simulations show that when PCr concentration exceeds 25 mM, CK undergoes liquid–liquid phase separation and assembles into membrane-associated condensates within mitochondrial inner membrane microdomains rich in ANT and CK-MT. These protein-lipid platforms composed of phosphatidylcholine, phosphatidylethanolamine, and cardiolipin rapidly increase local ATP regeneration through substrate channels. Given the significant reliance of this process on physical phase transitions, it is markedly faster than complex biochemical reactions, making it more suitable for the sudden energy demands encountered during exercise.