title: Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration.
abstract: MCL-1, an anti-apoptotic BCL-2 family member that is essential for the survival of multiple cell lineages, is also among the most highly amplified genes in cancer. Although MCL-1 is known to oppose cell death, precisely how it functions to promote survival of normal and malignant cells is poorly understood. Here, we report that different forms of MCL-1 reside in distinct mitochondrial locations and exhibit separable functions. On the outer mitochondrial membrane, an MCL-1 isoform acts like other anti-apoptotic BCL-2 molecules to antagonize apoptosis, whereas an amino-terminally truncated isoform of MCL-1 that is imported into the mitochondrial matrix is necessary to facilitate normal mitochondrial fusion, ATP production, membrane potential, respiration, cristae ultrastructure and maintenance of oligomeric ATP synthase. Our results provide insight into how the surprisingly diverse salutary functions of MCL-1 may control the survival of both normal and cancer cells.
authors.affiliation: Department of Biochemistry, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Perciavalle
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Stewart
authors.forename: Brian
authors.initials: B
authors.lastname: Koss
authors.forename: John
authors.initials: J
authors.lastname: Lynch
authors.forename: Sandra
authors.initials: S
authors.lastname: Milasta
authors.forename: Madhavi
authors.initials: M
authors.lastname: Bathina
authors.forename: Jamshid
authors.initials: J
authors.lastname: Temirov
authors.forename: Megan M
authors.initials: MM
authors.lastname: Cleland
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pelletier
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Opferman
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis; D019069:Cell Respiration; D002478:Cells, Cultured; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000378:metabolism
chemical_list: C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases