title: Mitochondrial morphological features are associated with fission and fusion events.
abstract: Mitochondria are dynamic organelles that undergo constant remodeling through the regulation of two opposing processes, mitochondrial fission and fusion. Although several key regulators and physiological stimuli have been identified to control mitochondrial fission and fusion, the role of mitochondrial morphology in the two processes remains to be determined. To address this knowledge gap, we investigated whether morphological features extracted from time-lapse live-cell images of mitochondria could be used to predict mitochondrial fate. That is, we asked if we could predict whether a mitochondrion is likely to participate in a fission or fusion event based on its current shape and local environment. Using live-cell microscopy, image analysis software, and supervised machine learning, we characterized mitochondrial dynamics with single-organelle resolution to identify features of mitochondria that are predictive of fission and fusion events. A random forest (RF) model was trained to correctly classify mitochondria poised for either fission or fusion based on a series of morphological and positional features for each organelle. Of the features we evaluated, mitochondrial perimeter positively correlated with mitochondria about to undergo a fission event. Similarly mitochondrial solidity (compact shape) positively correlated with mitochondria about to undergo a fusion event. Our results indicate that fission and fusion are positively correlated with mitochondrial morphological features; and therefore, mitochondrial fission and fusion may be influenced by the mechanical properties of mitochondrial membranes.
authors.affiliation: Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America; Van Andel Institute Graduate School, Grand Rapids, Michigan, United States of America.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Westrate
authors.affiliation: Center for Nonlinear Studies, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America; Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Drocco
authors.affiliation: Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
authors.forename: Katie R
authors.initials: KR
authors.lastname: Martin
authors.affiliation: Center for Nonlinear Studies, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America; Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: William S
authors.initials: WS
authors.lastname: Hlavacek
authors.affiliation: Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America; Van Andel Institute Graduate School, Grand Rapids, Michigan, United States of America.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: MacKeigan
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D020558:GTP Phosphohydrolases / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D009154:Mutation / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human
references.citation: J Biol Chem. 2005 Jul 15;280(28):26185-92
references.pmid: 15899901
references.citation: J Cell Sci. 2012 Dec 1;125(Pt 23):5745-57
references.pmid: 23015593
references.citation: PLoS Comput Biol. 2011 Oct;7(10):e1002212
references.pmid: 21998575
references.citation: Mol Biol Cell. 2011 Jul 1;22(13):2235-45
references.pmid: 21551073
references.citation: Annu Rev Genet. 2012;46:265-87
references.pmid: 22934639
references.citation: J Biochem. 2011 Mar;149(3):241-51
references.pmid: 21233142
references.citation: Nat Genet. 2000 Oct;26(2):211-5
references.pmid: 11017080
references.citation: Cell. 2006 Jun 30;125(7):1241-52
references.pmid: 16814712
references.citation: PLoS One. 2012;7(5):e19879
references.pmid: 22649485
references.citation: J Am Heart Assoc. 2012 Oct;1(5):e003012
references.pmid: 23316298
references.citation: Mol Biol Cell. 2002 Dec;13(12):4343-54
references.pmid: 12475957
references.citation: Transl Neurodegener. 2013 May 27;2(1):12
references.pmid: 23711354
references.citation: Dev Cell. 2001 Oct;1(4):515-25
references.pmid: 11703942
references.citation: EMBO J. 2008 Jan 23;27(2):433-46
references.pmid: 18200046
references.citation: J Cell Biol. 2004 Nov 22;167(4):661-72
references.pmid: 15545319
references.citation: J Am Coll Cardiol. 2013 Feb 12;61(6):599-610
references.pmid: 23219298
references.citation: J Cell Biol. 2005 Sep 26;170(7):1021-7
references.pmid: 16186251
references.citation: J Biol Chem. 2003 Mar 7;278(10):7743-6
references.pmid: 12509422
references.citation: Nat Genet. 2001 Jul;28(3):272-5
references.pmid: 11431699
references.citation: Mol Biol Cell. 2003 May;14(5):1953-63
references.pmid: 12802067
references.citation: J Cell Biol. 2003 Jan 20;160(2):189-200
references.pmid: 12527753
references.citation: Am J Physiol Cell Physiol. 2010 Aug;299(2):C477-87
references.pmid: 20445168
references.citation: Drug Discov Today. 2008 Mar;13(5-6):268-74
references.pmid: 18342804
references.citation: Science. 2012 Aug 31;337(6098):1062-5
references.pmid: 22936770
references.citation: Cell Death Differ. 2008 Jul;15(7):1147-52
references.pmid: 18437161
references.citation: J Cell Sci. 2001 Mar;114(Pt 5):867-74
references.pmid: 11181170
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11960-5
references.pmid: 19617534
references.citation: Nat Cell Biol. 1999 Sep;1(5):298-304
references.pmid: 10559943
references.citation: Annu Rev Biochem. 2007;76:751-80
references.pmid: 17362197
references.citation: Nat Rev Mol Cell Biol. 2005 Aug;6(8):657-63
references.pmid: 16025099
references.citation: Science. 2011 Oct 21;334(6054):358-62
references.pmid: 21885730