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Review
. 2022 Jan 26;14(3):529.
doi: 10.3390/nu14030529.

Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review

Robert Percy Marshall  1 , Jan-Niklas Droste  1 , Jürgen Giessing  2 , Richard B Kreider  3
Affiliations
Review

Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review

Robert Percy Marshall et al. Nutrients. .

Abstract

Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some chronic and traumatic diseases. Creatine supplementation has been reported to improve high-energy phosphate availability as well as have antioxidative, neuroprotective, anti-lactatic, and calcium-homoeostatic effects. These characteristics may have a direct impact on mitochondrion's survival and health particularly during stressful conditions such as ischemia and injury. This narrative review discusses current scientific evidence for use or supplemental CrM as a therapeutic agent during conditions associated with mitochondrial dysfunction. Based on this analysis, it appears that CrM supplementation may have a role in improving cellular bioenergetics in several mitochondrial dysfunction-related diseases, ischemic conditions, and injury pathology and thereby could provide therapeutic benefit in the management of these conditions. However, larger clinical trials are needed to explore these potential therapeutic applications before definitive conclusions can be drawn.

Keywords: cardiac infarction; chronic fatigue syndrome; hypoxia; ischemia; long COVID; mitochondriopathia; neurodegenerative diseases; noncommunicable disease; oxidative stress; stroke.

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Conflict of interest statement

R.P.M. received financial support for presenting on creatine at industry sponsored scientific conferences. J.N.D. declares there is no financial and no non-financial conflict of interest. J.G. reports no conflict of interest. R.B.K. has conducted industry sponsored research on creatine, received financial support for presenting on creatine at industry sponsored scientific conferences, and has served as an expert witness on cases related to creatine. Additionally, he serves as Chair of the Scientific Advisory Board for AlzChem who sponsored this special issue.

Figures

Figure 1
Figure 1
General overview of the metabolic role of creatine in the creatine kinase/phosphocreatine (CK/PCr) system [1]. The diagram depicts connected subcellular energy production and cellular mechanics of creatine metabolism. This chemo-mechanical energy transduction network involves structural and functional coupling of the mitochondrial reticulum (mitochondrial interactosome and oxidative metabolism), phosphagen and glycolytic system (extramitochondrial ATP production), the linker of nucleoskeleton and cytoskeleton complex (nesprins interaction with microtubules, actin polymerization, β-tubulins), motor proteins (e.g., myofibrillar ATPase machinery, vesicles transport), and ion pumps (e.g., SERCA, Na+/K+-ATPase). The cardiolipin-rich domain is represented by parallel black lines. Green sparkled circles represent the subcellular processes where the CK/PCr system is important for functionality. Several proteins of the endoplasmic reticulum–mitochondria organizing network (ERMIONE), the SERCA complex, the TIM/TOM complex, the MICOS complex, the linker of nucleoskeleton and cytoskeleton complex, and the architecture of sarcomere and cytoskeleton are not depicted for readability. ANT: adenine nucleotide translocase; CK: creatine kinase; Cr: creatine; Crn: creatinine; CRT: Na+/Cl−-dependent creatine transporter; ERMES: endoplasmic reticulum-mitochondria encounter structure; ETC: electron transport chain; GLUT-4: glucose transporter type 4; HK: hexokinase; mdm10: mitochondrial distribution and morphology protein 10; MICOS: mitochondrial contact site and cristae organizing system; NDPK: nucleoside-diphosphate kinase; NPC: nuclear pore complex; PCr: phosphocreatine; SAM: sorting and assembly machinery; SERCA: Sarco/Endoplasmic Reticulum Ca2+ ATPase; TIM: translocase of the inner membrane complex; TOM: translocase of the outer membrane complex; UCP: uncoupling protein; VDAC: voltage-dependent anion channel. Reprinted with permission. See Bonilla et al. [1] for more details about the metabolic basis of creatine in energy production and disease.
Figure 2
Figure 2
Panel A: Intracellular cascade after injury, infarction or contusion leads to mitochondrial dysfunction. Panel B: Impact of creatine on mitochondrial dysfunction. Green shows direct increase/stimulation of Cr/PCr, red shows direct decrease/inhibition of Cr/PCr, dotted line represents indirect impact of Cr/PCr on cellular pathways. ATP is adenosine triphosphate; Cr is creatine; PCr is phosphocreatine; ROS is reactive oxygen species; mPTP is mitochondrial permeability transition pore. Adapted from Dean et al. [55].
Figure 3
Figure 3
Warburg Effect: glycolysis produces 2 ATP instead of 36 ATP, in pathological tissues even despite aerobic conditions. Glc is glucose, Oxy is oxygen, ATP is adenosine triphosphate. Adapted from Vander Heiden et al. [91].
Figure 4
Figure 4
Mitochondrial dysfunction and non-communicable diseases. Adapted from Diaz-Vegas et al. [90].
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