title: Cristae remodeling causes acidification detected by integrated graphene sensor during mitochondrial outer membrane permeabilization.
abstract: The intrinsic apoptotic pathway and the resultant mitochondrial outer membrane permeabilization (MOMP) via BAK and BAX oligomerization, cytochrome c (cytc) release, and caspase activation are well studied, but their effect on cytosolic pH is poorly understood. Using isolated mitochondria, we show that MOMP results in acidification of the surrounding medium. BAK conformational changes associated with MOMP activate the OMA1 protease to cleave OPA1 resulting in remodeling of the cristae and release of the highly concentrated protons within the cristae invaginations. This was revealed by utilizing a nanomaterial graphene as an optically clear and ultrasensitive pH sensor that can measure ionic changes induced by tethered mitochondria. With this platform, we have found that activation of mitochondrial apoptosis is accompanied by a gradual drop in extra-mitochondrial pH and a decline in membrane potential, both of which can be rescued by adding exogenous cytc. These findings have importance for potential pharmacological manipulation of apoptosis, in the treatment of cancer.
authors: Department of Biomedical Engineering, University of California, Irvine, CA, USA.
authors: Ted D
authors: TD
authors: Pham
authors: Department of Chemical Engineering and Materials Science, University of California, Irvine, CA, USA.
authors: Phi Q
authors: PQ
authors: Pham
authors: Department of Chemical Engineering and Materials Science, University of California, Irvine, CA, USA.
authors: Jinfeng
authors: J
authors: Li
authors: Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA.
authors: Anthony G
authors: AG
authors: Letai
authors: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Douglas C
authors: DC
authors: Wallace
authors: Department of Biomedical Engineering, University of California, Irvine, CA, USA.|Department of Chemical Engineering and Materials Science, University of California, Irvine, CA, USA.|Department of Electrical Engineering and Computer Science, University of California, Irvine, CA, USA.
authors: Peter J
authors: PJ
authors: Burke
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism; D015374:Biosensing Techniques; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006108:Graphite; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008666:Metalloendopeptidases / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism*; D049329:Nanostructures; D010539:Permeability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: C494772:BAK1 protein, human; D000072224:Bcl-2-Like Protein 11; D033681:Mitochondrial Membrane Transport Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C581062:RTL10 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D006108:Graphite; D045304:Cytochromes c; D008666:Metalloendopeptidases; C477817:molecule metalloprotease-related protein-1, human; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human