title: Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy.
abstract: Defects in mitochondrial fusion or fission are associated with many pathologies, raising the hope that pharmacological manipulation of mitochondrial dynamics may have therapeutic benefit. This approach assumes that organ physiology can be restored by rebalancing mitochondrial dynamics, but this concept remains to be validated. We addressed this issue by analyzing mice deficient in Mff, a protein important for mitochondrial fission. Mff mutant mice die at 13 wk as a result of severe dilated cardiomyopathy leading to heart failure. Mutant tissue showed reduced mitochondrial density and respiratory chain activity along with increased mitophagy. Remarkably, concomitant deletion of the mitochondrial fusion gene Mfn1 completely rescued heart dysfunction, life span, and respiratory chain function. Our results show for the first time that retuning the balance of mitochondrial fusion and fission can restore tissue integrity and mitochondrial physiology at the whole-organ level. Examination of liver, testis, and cerebellum suggest, however, that the precise balance point of fusion and fission is cell type specific.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
authors.forename: Hsiuchen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.affiliation: Broad Institute, Cambridge, MA 02142.
authors.forename: Clary
authors.initials: C
authors.lastname: Clish
authors.affiliation: Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02115.
authors.forename: Mohit
authors.initials: M
authors.lastname: Jain
authors.affiliation: Broad Institute, Cambridge, MA 02142 Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02115.
authors.forename: Vamsi
authors.initials: V
authors.lastname: Mootha
authors.affiliation: Integrated Imaging Center, Department of Biology, Johns Hopkins University, Baltimore, MD 21218.
authors.forename: J Michael
authors.initials: JM
authors.lastname: McCaffery
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125 dchan@caltech.edu.
authors.forename: David C
authors.initials: DC
authors.lastname: Chan
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D058685:Genetic Pleiotropy; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000502:physiology*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics*; D017186:Titrimetry
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C000603499:mitochondrial fission factor, mouse