title: Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death.
abstract: The B-cell lymphoma-2 (Bcl-2) family proteins are critical regulators of apoptosis and consist of both proapoptotic and antiapoptotic factors. Within this family, the myeloid cell leukemia factor 1 (Mcl-1) protein exists in two forms as the result of alternative splicing. The long variant (Mcl-1L) acts as an antiapoptotic factor, whereas the short isoform (Mcl-1S) displays proapoptotic activity. In this study, using splice-switching antisense oligonucleotides (ASOs), we increased the synthesis of Mcl-1S, which induced a concurrent reduction of Mcl-1L, resulting in increased sensitivity of cancer cells to apoptotic stimuli. The Mcl-1 ASOs also induced mitochondrial hyperpolarization and a consequent increase in mitochondrial calcium (Ca(2+)) accumulation. The high Mcl-1S/L ratio correlated with significant hyperfusion of the entire mitochondrial network, which occurred in a dynamin-related protein (Drp1)-dependent manner. Our data indicate that the balance between the long and short variants of the Mcl-1 gene represents a key aspect of the regulation of mitochondrial physiology. We propose that the Mcl-1L/S balance is a novel regulatory factor controlling the mitochondrial fusion and fission machinery.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Morciano
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giorgi
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, FE 44121 Ferrara, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Balestra
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies.
authors.forename: Saverio
authors.initials: S
authors.lastname: Marchi
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, FE 44121 Ferrara, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Perrone
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, FE 44121 Ferrara, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Pinotti
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies paolo.pinton@unife.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
mesh_terms: D017398:Alternative Splicing; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D064550:Death-Associated Protein Kinases / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D063154:Mitochondrial Dynamics / Q000502:physiology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D012333:RNA, Messenger; D064550:Death-Associated Protein Kinases; D002118:Calcium