📒 Schlattner 2006

Mitochondrial creatine kinase in human health and disease1



  • Creatine kinase (CK) is a central controller of cellular energy homeostasis: PCr + ADP <=> Cr + ATP

Mitochondrial creatine kinase (mtCK) —an enzyme central to cellular energetics

  • @ cristae and intermembrane space
  • phosphocreatine: buffer
  • (In the cmpartments) metabolite channeling or functional coupling
    • high local ATP/ADP ratios in the vicinity of cellular ATPases
    • low at ATP synthase

Dual localization of creatine kinase microcompartments in mitochondria

  • IMS is a microcompartment for adenylates
    • IMS height = 9nm. (Could fit mtCK octamer)
    • Cristae junctions (pendiculi) <= 10–15 nm
    • VDAC is a rate-limiting diffusion barrier

MtCK proteolipid complexes in contact sites

  • channeling of ‘‘high-energy’’ phosphates, regulated by the energy state
  • Proteolipid complexes
    • adenine translocator (ANT) in IMM
    • VDAC in OMM
    • Kinases (e.g. mtCK, NDP kinase @ IMS, mtHK @ OMM)
    • apoptotic proteins: cyt c, Bcl-2,
    • protective effect on mitochondrial permeability transition (MPT)
  • Only octameric MtCK shows a high affinity to cardiolipin and other anionic phospholipids and stucks in the membrane
  • Calcium is yet another signal that seems to regulate MtCK complexes

Function of MtCK proteolipid complexes in metabolite channeling and apoptosis

  • Streamlined metabolite exchange (fusing rxn of VDAC, mtCK, & ANT): ATP(m) + Cr(i) <=> ADP(m) + PCr(i)
  • The degree of such metabolite channeling seems to vary among different tissues, species, and developmental states
  • MtCK could play the role of an energy sensor, coupling cellular energy state to programmed cell death

Mitochondrial creatine kinase—from molecular damage to pathological states

MtCK—a prime target of oxidative and radical-induced molecular damage

  • All CK isoenzymes are extremely susceptible to damage by ROS and RNS (superoxide anions (O2-), hydrogen peroxide (H2O2), hydroxyl radicals (OH), nitrogen monoxide (NO) and peroxynitrite (PN, ONOO*)
  • Mitochondrial ROS can also be generated by pharmacological interventions, e.g., with anthracyclines, a prominent class of anti-cancer drugs
  • Enzyme inactivation (active site) & interfere with oligomeric state and membrane binding capacity of mtCK (dimer/dimer interface)
  • CK inactivation is irreversible, especially at higher ROS concentrations
    • MtCK is particularly susceptible to PN treatment (μM range)
    • sMtCK (heart, muscle) octamers are more susceptible to PN than those of uMtCK (brain)

Impairment of MtCK in ischemia and cardiomyopathy

  • “stability paradox” in heart: metabolic homeostasis despite large fluctuations in work load
    • Relies on CK shuttle running by mtCK, esp. sMtCK (sMtCK isoenzyme can make up to 25% of total CK activity in rat heart)
    • mitochondrial volume ~40% of cellular volume
    • Lack in Cr or mtCK => reduced performance and cardiomyopathy in KO rats
  • vicious cycle from ROS: ischemia/reperfusion injury => increased ROS => inactivation of mtCK => less cytosolic ATP => Ca overload => more ROS/RNS => … => mitochondrial permeability transition, apoptosis and/or necrosis
  • ischemic preconditioning => protection to sMtCK and ANT complex => higher energy flux through CK

Involvement of MtCK in anthracycline-induced cardiotoxicity

  • severe acute and chronic cardiotoxicity still represent serious complications of anthracycline (e.g. doxorubicin) therapy
  • oxidative damage and functional impairment of MtCK in a dose-, time-, and drug-dependent manner in vitro and in vivo
  • MtCK as well as ANT are preferentially hit by the drug (competition for cardiolipin)
  • 10–30μM doxorubicin complexed with iron induced sMtCK inactivation within several tens of minutes
  • Dimerization and inhibition of sMtCK membrane binding could also destabilize mitochondrial contact sites
  • Organs that lack MtCK (liver) or express high levels of uMtCK (e.g., kidney and brain) do not show severe anthracycline toxicity

Impairment of MtCK in neurodegenerative disorders

  • ROS => inactivation of uMtCK in the brain
  • uMtCK inacitvation observed in AD and ALS
  • Creatine supplementation?

Up-regulation of mitochondrial creatine kinase in human health and disease

  • sMtCK expression follows the simultaneous induction of mitochondria,
  • in situations of high aerobic workload, the energy transport function of sMtCK is important
  • up-regulation of the mitochondrial transcription factor A (mtTFA) => expression of sMtCK
  • Creatine depletion by β-GPA feeding => energy cirsis => crystalline inclusions (mtCK) in the mitochondria due to compensatory overexpression. Also seen in mitochondrial cytopathies.
  • Overexpression of uMtCK in cancer (protection against apoptosis)


  1. Schlattner U, Tokarska-Schlattner M, Wallimann T. Mitochondrial creatine kinase in human health and disease. Biochim. Biophys. Acta 2006;1762(2):164-180. doi:10.1016/j.bbadis.2005.09.004. ↩︎