title: What is the function of mitochondrial networks? A theoretical assessment of hypotheses and proposal for future research.
abstract: Mitochondria can change their shape from discrete isolated organelles to a large continuous reticulum. The cellular advantages underlying these fused networks are still incompletely understood. In this paper, we describe and compare hypotheses regarding the function of mitochondrial networks. We use mathematical and physical tools both to investigate existing hypotheses and to generate new ones, and we suggest experimental and modelling strategies. Among the novel insights we underline from this work are the possibilities that (i) selective mitophagy is not required for quality control because selective fusion is sufficient; (ii) increased connectivity may have non-linear effects on the diffusion rate of proteins; and (iii) fused networks can act to dampen biochemical fluctuations. We hope to convey to the reader that quantitative approaches can drive advances in the understanding of the physiological advantage of these morphological changes.
authors.affiliation: Department of Mathematics, Imperial College London, London, UK.
authors.forename: Hanne
authors.initials: H
authors.lastname: Hoitzing
authors.affiliation: Department of Mathematics, Imperial College London, London, UK.
authors.forename: Iain G
authors.initials: IG
authors.lastname: Johnston
authors.affiliation: Department of Mathematics, Imperial College London, London, UK.
authors.forename: Nick S
authors.initials: NS
authors.lastname: Jones
mesh_terms: D000818:Animals; D045222:Electron Transport Chain Complex Proteins / Q000502:physiology; D004734:Energy Metabolism; D006801:Humans; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D063306:Mitophagy
chemical_list: D045222:Electron Transport Chain Complex Proteins
keywords: hypotheses; mathematical biology; mitochondrial dynamics; mitochondrial networks; non-linearities; ultrastructure
references.citation: Am J Physiol Cell Physiol. 2006 Jul;291(1):C176-84
references.pmid: 16481372
references.citation: J Cell Biol. 1998 Feb 23;140(4):821-9
references.pmid: 9472034
references.citation: Science. 2012 Nov 9;338(6108):822-4
references.pmid: 23139336
references.citation: Cell Death Differ. 2003 Jun;10(6):709-17
references.pmid: 12761579
references.citation: Free Radic Biol Med. 2014 Oct;75:121-8
references.pmid: 25062828
references.citation: J Cell Sci. 2012 Dec 1;125(Pt 23):5745-57
references.pmid: 23015593
references.citation: Mol Cell. 2004 Oct 8;16(1):59-68
references.pmid: 15469822
references.citation: Biochem J. 1978 Dec 15;176(3):899-906
references.pmid: 218557
references.citation: Eur J Biochem. 1998 May 15;254(1):194-201
references.pmid: 9652414
references.citation: Trends Biochem Sci. 2001 Jan;26(1):23-9
references.pmid: 11165513
references.citation: FEBS Lett. 2003 Jul 10;546(2-3):355-8
references.pmid: 12832068
references.citation: Bull Math Biol. 2013 Sep;75(9):1636-51
references.pmid: 23760661
references.citation: EMBO J. 2014 Nov 18;33(22):2676-91
references.pmid: 25298396
references.citation: J Biol Chem. 2007 Aug 24;282(34):24525-37
references.pmid: 17591785
references.citation: Cell. 2010 Apr 16;141(2):280-9
references.pmid: 20403324
references.citation: Cell Metab. 2014 Apr 1;19(4):630-41
references.pmid: 24703695
references.citation: FEBS Lett. 1991 Dec 9;294(3):275-8
references.pmid: 1661688
references.citation: Mol Biol Cell. 2004 Nov;15(11):5001-11
references.pmid: 15356267
references.citation: Biochim Biophys Acta. 2001 Mar 1;1504(1):1-11
references.pmid: 11239480
references.citation: Hum Mol Genet. 2012 Mar 1;21(5):978-90
references.pmid: 22080835
references.citation: Int J Biochem Cell Biol. 2009 Oct;41(10):1914-27
references.pmid: 19549572
references.citation: Arch Biochem Biophys. 2007 Jun 15;462(2):245-53
references.pmid: 17475204
references.citation: J Biol Chem. 2011 Sep 2;286(35):30816-22
references.pmid: 21757763
references.citation: J Biol Chem. 2003 Nov 7;278(45):44769-79
references.pmid: 12941956
references.citation: Cell Commun Signal. 2011 Sep 22;9:19
references.pmid: 21939514
references.citation: Trends Biochem Sci. 2002 Jan;27(1):27-33
references.pmid: 11796221
references.citation: EMBO J. 2014 Mar 3;33(5):418-36
references.pmid: 24431221
references.citation: Exp Neurol. 2009 Aug;218(2):247-56
references.pmid: 19332061
references.citation: Science. 2004 Sep 17;305(5691):1747-52
references.pmid: 15297626
references.citation: Mol Biol Cell. 2002 Dec;13(12):4343-54
references.pmid: 12475957
references.citation: Cell. 2006 Jul 14;126(1):163-75
references.pmid: 16839884
references.citation: Nat Genet. 2014 Feb;46(2):188-93
references.pmid: 24336167
references.citation: Nat Cell Biol. 2011 May;13(5):589-98
references.pmid: 21478857
references.citation: Phys Rev A Gen Phys. 1985 Aug;32(2):1072-1075
references.pmid: 9896162
references.citation: Front Neuroenergetics. 2013 Aug 12;5:7
references.pmid: 23964235
references.citation: Am J Physiol. 1997 Aug;273(2 Pt 1):C717-33
references.pmid: 9277370
references.citation: Bioessays. 2010 Nov;32(11):958-66
references.pmid: 20824657
references.citation: J Biol Chem. 2007 Aug 17;282(33):23788-98
references.pmid: 17537722
references.citation: PLoS Comput Biol. 2012;8(8):e1002649
references.pmid: 22916005
references.citation: FEBS J. 2011 Apr;278(6):941-54
references.pmid: 21232014
references.citation: J Cell Sci. 2013 Jan 1;126(Pt 1):103-16
references.pmid: 23038773
references.citation: J Biol Chem. 2012 Mar 16;287(12):9633-9
references.pmid: 22253434
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):E2967-76
references.pmid: 23878239
references.citation: Annu Rev Genet. 2012;46:265-87
references.pmid: 22934639
references.citation: Curr Biol. 2008 Jan 22;18(2):102-8
references.pmid: 18207745
references.citation: J Cell Biol. 2009 Dec 28;187(7):959-66
references.pmid: 20038677
references.citation: Curr Biol. 2006 Jul 25;16(14):R551-60
references.pmid: 16860735
references.citation: Bioessays. 2013 Nov;35(11):955-64
references.pmid: 23943303
references.citation: EMBO Rep. 2010 Feb;11(2):133-8
references.pmid: 20019757
references.citation: Nat Cell Biol. 2012 Feb;14(2):177-85
references.pmid: 22267086
references.citation: J Biol Chem. 2003 Mar 7;278(10):7743-6
references.pmid: 12509422
references.citation: J Alzheimers Dis. 2013;33 Suppl 1:S253-62
references.pmid: 22531428
references.citation: Cold Spring Harb Perspect Biol. 2013 Jun;5(6). pii: a011072. doi: 10.1101/cshperspect.a011072
references.pmid: 23732471
references.citation: Biophys J. 2014 Dec 2;107(11):2612-7
references.pmid: 25468340
references.citation: Eur J Biochem. 1999 Aug;263(3):671-85
references.pmid: 10469130
references.citation: Mol Cell Biochem. 1998 Jul;184(1-2):13-20
references.pmid: 9746309
references.citation: Bioessays. 2012 Apr;34(4):272-4
references.pmid: 22290641
references.citation: PLoS One. 2014;9(3):e91911
references.pmid: 24632851
references.citation: PLoS Comput Biol. 2012;8(10):e1002745
references.pmid: 23133350
references.citation: FEBS J. 2014 Jul;281(14):3095-112
references.pmid: 24841215
references.citation: J Cell Biol. 1988 Aug;107(2):481-95
references.pmid: 3417757
references.citation: Biochem J. 1972 Jun;128(1):161-3
references.pmid: 4343661
references.citation: Cell Death Differ. 2007 Jun;14(6):1086-94
references.pmid: 17332775
references.citation: Biochim Biophys Acta. 1978 Mar 13;501(3):349-69
references.pmid: 629958
references.citation: BMC Biol. 2013;11:71
references.pmid: 23800141
references.citation: PLoS One. 2008;3(9):e3257
references.pmid: 18806874
references.citation: Philos Trans R Soc Lond B Biol Sci. 2014 Jul 5;369(1646):20130442
references.pmid: 24864312
references.citation: J Neurosci. 2012 Jan 25;32(4):1233-43
references.pmid: 22279208
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10190-5
references.pmid: 21646527
references.citation: Cancer Res. 2013 Nov 15;73(22):6700-10
references.pmid: 24080278
references.citation: PLoS Comput Biol. 2010 Jan;6(1):e1000632
references.pmid: 20052270
references.citation: EMBO J. 2009 Oct 21;28(20):3074-89
references.pmid: 19745815
references.citation: Rejuvenation Res. 2005 Spring;8(1):3-5
references.pmid: 15798367
references.citation: Heart Lung Circ. 2014 Jul;23(7):602-9
references.pmid: 24657282
references.citation: J Biol Chem. 2014 Mar 28;289(13):9182-94
references.pmid: 24554722
references.citation: Physiol Rev. 1999 Oct;79(4):1127-55
references.pmid: 10508231
references.citation: Nat Rev Mol Cell Biol. 2011 Jan;12(1):9-14
references.pmid: 21179058
references.citation: Trends Biochem Sci. 2012 Jul;37(7):284-92
references.pmid: 22410198
references.citation: EMBO J. 2009 Jun 3;28(11):1589-600
references.pmid: 19360003
references.citation: J Cell Sci. 2013 May 15;126(Pt 10):2187-97
references.pmid: 23525002
references.citation: J Cell Biol. 2009 Dec 28;187(7):1023-36
references.pmid: 20038678
references.citation: PLoS One. 2012;7(12):e52830
references.pmid: 23300790
references.citation: J Biol Chem. 2011 Feb 11;286(6):4772-82
references.pmid: 21041314
references.citation: EMBO J. 2008 Jan 23;27(2):433-46
references.pmid: 18200046
references.citation: J Biol Chem. 1982 Mar 25;257(6):2754-7
references.pmid: 7061448
references.citation: Semin Cancer Biol. 2009 Feb;19(1):50-6
references.pmid: 19138741
references.citation: Biophys J. 2003 Apr;84(4):2734-55
references.pmid: 12668482
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2013 Dec;88(6):062723
references.pmid: 24483502
references.citation: J Mol Cell Cardiol. 2013 May;58:125-33
references.pmid: 23306007
references.citation: Science. 2011 Oct 21;334(6054):358-62
references.pmid: 21885730
references.citation: Nat Genet. 2001 Jul;28(3):272-5
references.pmid: 11431699
references.citation: Science. 1998 Jun 12;280(5370):1763-6
references.pmid: 9624056
references.citation: J Biol Chem. 1989 Aug 15;264(23):13430-9
references.pmid: 2503501
references.citation: Nat Med. 2001 Aug;7(8):934-40
references.pmid: 11479626
references.citation: J Cell Biol. 2008 Dec 1;183(5):795-803
references.pmid: 19029340
references.citation: Hum Mol Genet. 2012 Sep 1;21(17):3858-70
references.pmid: 22678058
references.citation: Biochem J. 1979 Jun 15;180(3):533-44
references.pmid: 39549
references.citation: PLoS Biol. 2010;8(12):e1000560
references.pmid: 21179497
references.citation: Circulation. 2010 May 11;121(18):2012-22
references.pmid: 20421521
references.citation: PLoS Comput Biol. 2005 Sep;1(4):e36
references.pmid: 16163394
references.citation: Am J Physiol Regul Integr Comp Physiol. 2013 Mar 15;304(6):R393-406
references.pmid: 23364527
references.citation: J Biol Chem. 2005 Jul 15;280(28):26185-92
references.pmid: 15899901
references.citation: Cell. 2006 Jul 14;126(1):177-89
references.pmid: 16839885
references.citation: PLoS Comput Biol. 2012;8(6):e1002576
references.pmid: 22761564
references.citation: PLoS Comput Biol. 2013;9(7):e1003108
references.pmid: 23874166
references.citation: Science. 1993 Oct 29;262(5134):744-7
references.pmid: 8235595
references.citation: Physiol Rev. 2009 Jul;89(3):799-845
references.pmid: 19584314
references.citation: J Cell Sci. 2014 Feb 15;127(Pt 4):719-26
references.pmid: 24338369
references.citation: Biophys J. 2009 May 6;96(9):3509-18
references.pmid: 19413957
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10237-42
references.pmid: 21646529
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11960-5
references.pmid: 19617534
references.citation: Hum Mol Genet. 2009 Oct 15;18(R2):R169-76
references.pmid: 19808793
references.citation: J Cell Sci. 2010 Mar 15;123(Pt 6):917-26
references.pmid: 20179104
references.citation: J Membr Biol. 1990 Mar;114(2):97-112
references.pmid: 2111408