Mitochondrial creatine kinase in human health and disease

Abstract

Mitochondrial creatine kinase (MtCK), together with cytosolic creatine kinase isoenzymes and the highly diffusible CK reaction product, phosphocreatine, provide a temporal and spatial energy buffer to maintain cellular energy homeostasis. Mitochondrial proteolipid complexes containing MtCK form microcompartments that are involved in channeling energy in form of phosphocreatine rather than ATP into the cytosol. Under situations of compromised cellular energy state, which are often linked to ischemia, oxidative stress and calcium overload, two characteristics of mitochondrial creatine kinase are particularly relevant: its exquisite susceptibility to oxidative modifications and the compensatory up-regulation of its gene expression, in some cases leading to accumulation of crystalline MtCK inclusion bodies in mitochondria that are the clinical hallmarks for mitochondrial cytopathies. Both of these events may either impair or reinforce, respectively, the functions of mitochondrial MtCK complexes in cellular energy supply and protection of mitochondria form the so-called permeability transition leading to apoptosis or necrosis.

Dissociated Expression of Mitochondrial and Cytosolic Creatine Kinases in the Human Brain: A New Perspective on the Role of Creatine in Brain Energy Metabolism

“…26 Furthermore, the activity of uMtCK in the complex with ANT, porin, and cyclophilin D in the matrix reduces the formation of the apoptosis-inducing mitochondrial permeability transition. 24 Conversely, in the glycolytic astrocytic cells, BCK is expressed without uMtCK, which was also noted in the rat brain. 7 Functionally, the cytosolic localization of BCK means that there is no specific compartmentation of a CK enzyme to mitochondria, although BCK in the proximity of mitochondria can still integrate ATP produced by oxidative phosphorylation into the PCr/CK circuit once it has diffused out.…”

“…Coupling between this enzyme and adenine nucleotide translocator (ANT) in the inner mitochondrial membrane and porin in the outer mitochondrial membrane rapidly and specifically links ATP synthesized by oxidative phosphorylation with the PCr/CK system. 24 This improves the efficiency of oxidative phosphorylation by allowing the quick recycling of ADP, the principle driver of oxidative phosphorylation, back into the matrix. 24 With creatine, only micromolar concentrations of ADP are required to fully stimulate oxidative phosphorylation in permeabilized muscle cells, whereas without creatine, millimolar concentrations of ADP are required.…”

Mitochondrial Creatine Kinase Activity Prevents Reactive Oxygen Species Generation

“…3). Nevertheless, the reaction catalyzed by CK is reversible and this property is central to cellular energy buffering (59 …”

No death without life: vital functions of apoptotic effectors

“…3 Nevertheless, all these proteins are known to participate into a number of mitochondrial and extramitochondrial metabolic pathways, reinforcing the concept that proapoptotic effectors also exert vital functions (Table 3). Thus, (i) ANT mediates ATP/ADP exchange between the mitochondrial matrix and the cytosol, thereby ensuring an adequate cytosolic energy supply while maintaining high rates of oxidative phosphorylation (by releasing substrate inhibition); 135 (ii)VDAC is the most abundant OM protein and, in healthy cells, exists as a large, voltage-gated channel accounting for OM permeability properties; 136 (iii) CypD exhibits a peptidyl-prolyl cis-trans isomerase activity, which contributes to the correct folding of mitochondrial matrix proteins; 137 (iv) CK catalyzes the ATPdependent conversion of creatine into phosphocreatine, to constitute a highly diffusible intracellular energy buffer; 138 (v) PBR regulates cholesterol transport from OM to IM, the rate-limiting step in steroidogenesis; 139 and (vi) HK isoforms catalyze the production of glucose-6-phosphate, the first intermediate in glucose metabolism. 140 …”