title: CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex.
abstract: The permeability transition pore (PT-pore) mediates cell death through the dissipation of the mitochondrial membrane potential (ΔΨm). 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' PT-pore 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.
authors: Division of Experimental Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors: Christoph
authors: C
authors: Datler
authors: Evangelos
authors: E
authors: Pazarentzos
authors: Anne-Laure
authors: AL
authors: Mahul-Mellier
authors: Wanwisa
authors: W
authors: Chaisaklert
authors: Ming-Shih
authors: MS
authors: Hwang
authors: Foy
authors: F
authors: Osborne
authors: Stefan
authors: S
authors: Grimm
mesh_terms: D017209:Apoptosis; D001865:Bongkrekic Acid / Q000494:pharmacology; D053453:Caspase 9 / Q000378:metabolism; D003402:Creatine Kinase / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D010539:Permeability; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D054875:Ubiquitination; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
chemical_list: C540562:ASB9 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D050826:Suppressor of Cytokine Signaling Proteins; C494762:VDAC1 protein, human; D001865:Bongkrekic Acid; D050995:Voltage-Dependent Anion Channel 1; C519581:CKMT1A protein, human; D003402:Creatine Kinase; C506433:CASP9 protein, human; D053453:Caspase 9
keywords: Apoptosis; Creatine kinase; Mitochondrial membrane potential; Permeability transition pore