Mitochondrial Creatine Kinase and Mitochondrial Outer Membrane Porin Show a Direct Interaction That Is Modulated by Calcium

Schlattner, Uwe; Dolder, Max; Wallimann, Theo; Tokarska‐Schlattner, Malgorzata

doi:10.1074/jbc.m106524200

Cited by 99 publications

(81 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5E,F; data not shown). It has been suggested that CKMT1 and VDAC1 are constituents of the PT-pore (Beutner et al, 1998), and they have been shown to directly interact (Schlattner et al, 2001). Therefore, we speculated that this interaction cells was verified by using western blotting.…”

Section: Depletion Of Ckmt1 Results In Mptmentioning

confidence: 99%

CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex

Datler

Pazarentzos

Mahul‐Mellier

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

The permeability transition pore (PT-pore) mediates cell death through the dissipation of the mitochondrial membrane potential (DY m ). Because the exact composition of the PT-pore is controversial, it is crucial to investigate the actual molecular constituents and regulators of this complex. We found that mitochondrial creatine kinase-1 (CKMT1) is a universal and functionally necessary gatekeeper of the PT-pore, as its depletion induces mitochondrial depolarization and apoptotic cell death. This can be inhibited efficiently by bongkrekic acid, a compound that is widely used to inhibit the PT-pore. However, when the 'classical' PTpore subunits cyclophilin D and VDAC1 are pharmacologically inhibited or their expression levels reduced, mitochondrial depolarization by CKMT1 depletion remains unaffected. At later stages of drug-induced apoptosis, CKMT1 levels are reduced, suggesting that CKMT1 downregulation acts to reinforce the commitment of cells to apoptosis. A novel high-molecular-mass CKMT1 complex that is distinct from the known CKMT1 octamer disintegrates upon treatment with cytotoxic drugs, concomitant with mitochondrial depolarization. Our study provides evidence that CKMT1 is a key regulator of the PT-pore through a complex that is distinct from the classical PT-pore.

show abstract

Section: Depletion Of Ckmt1 Results In Mptmentioning

confidence: 99%

CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex

Datler

Pazarentzos

Mahul‐Mellier

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Only recently, we provided evidence for a physical interaction between octameric MtCK and VDAC that is enhanced by physiological concentrations of Ca 2ϩ (23). The latter is characteristic for a lowered cellular energy state and thus of potential regulatory importance.…”

mentioning

confidence: 94%

C-terminal Lysines Determine Phospholipid Interaction of Sarcomeric Mitochondrial Creatine Kinase

Schlattner

Gehring

Vernoux

et al. 2004

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

High affinity interaction between octameric mitochondrial creatine kinase (MtCK) and the phospholipid cardiolipin in the inner mitochondrial membrane plays an important role in metabolite channeling between MtCK and inner membrane adenylate translocator, which itself is tightly bound to cardiolipin. Three Cterminal basic residues revealed as putative cardiolipin anchors in the x-ray structures of MtCK and corresponding to lysines in human sarcomeric MtCK (sMtCK) were exchanged by in vitro mutagenesis (K369A/E, K379Q/A/E, K380Q/A/E) to yield double and triple mutants. sMtCK proteins were bacterially expressed, purified to homogeneity, and verified for structural integrity by enzymatic activity, gel filtration chromatography, and CD spectroscopy. Interaction with cardiolipin and other acidic phospholipids was quantitatively analyzed by light scattering, surface plasmon resonance, and fluorescence spectroscopy. All mutant sMtCKs showed a strong decrease in vesicle cross-linking, membrane affinity, binding capacity, membrane ordering capability, and binding-induced changes in protein structure as compared with wild type. These effects did not depend on the nature of the replacing amino acid but on the number of exchanged lysines. They were moderate for Lys-379/Lys-380 double mutants but pronounced for triple mutants, with a 30-fold lower membrane affinity and an entire lack of alterations in protein structure compared with wild-type sMtCK. However, even triple mutants partially maintained an increased order of cardiolipin-containing membranes. Thus, the three Cterminal lysines determine high affinity sMtCK/cardiolipin interaction and its effects on MtCK structure, whereas low level binding and some effect on membrane fluidity depend on other structural components. These results are discussed in regard to MtCK microcompartments and evolution.

show abstract

“…In heart, rhythmic contraction is the consequence of transient changes in [Ca 2ϩ ] i . Furthermore, there is now increasing evidence that Ca 2ϩ has multiple effects on other intracellular processes and particularly on several mitochondrial functions (19,23,32), including dehydrogenases, ATP synthase, and, more recently, the binding of PCr-kinase with mitochondrial membranes (34). Thus, activation of mitochondrial oxidative phosphorylation during Ca 2ϩ transient may now also be considered as an important mechanism in excitation-contraction coupling in heart (25)(26)(27) (Fig.…”

mentioning

confidence: 99%

Modular regulation analysis of heart contraction: application to in situ demonstration of a direct mitochondrial activation by calcium in beating heart

Diolez¹,

Deschodt-Arsac²,

Raffard³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

show abstract

Mitochondrial Creatine Kinase and Mitochondrial Outer Membrane Porin Show a Direct Interaction That Is Modulated by Calcium

Cited by 99 publications

References 38 publications

CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex

CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex

C-terminal Lysines Determine Phospholipid Interaction of Sarcomeric Mitochondrial Creatine Kinase

Modular regulation analysis of heart contraction: application to in situ demonstration of a direct mitochondrial activation by calcium in beating heart

Contact Info

Product

Resources

About