Bacteria, yeast, worms, and flies: exploiting simple model organisms to investigate human mitochondrial diseases.
The extensive conservation of mitochondrial structure, composition, and function across evolution offers a unique opportunity to expand our understanding of human mitochondrial biology and disease. By investigating the biology of much simpler model organisms, it is often possible to answer questions that are unreachable at the clinical level. Here, we review the relative utility of four different model organisms, namely the bacterium Escherichia coli, the yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster, in studying the role of mitochondrial proteins relevant to human disease. E. coli are single cell, prokaryotic bacteria that have proven to be a useful model system in which to investigate mitochondrial respiratory chain protein structure and function. S. cerevisiae is a single-celled eukaryote that can grow equally well by mitochondrial-dependent respiration or by ethanol fermentation, a property that has proven to be a veritable boon for investigating mitochondrial functionality. C. elegans is a multicellular, microscopic worm that is organized into five major tissues and has proven to be a robust model animal for in vitro and in vivo studies of primary respiratory chain dysfunction and its potential therapies in humans. Studied for over a century, D. melanogaster is a classic metazoan model system offering an abundance of genetic tools and reagents that facilitates investigations of mitochondrial biology using both forward and reverse genetics. The respective strengths and limitations of each species relative to mitochondrial studies are explored. In addition, an overview is provided of major discoveries made in mitochondrial biology in each of these four model systems.
Rea
Shane L
SL
Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245-3207, USA. reas3@uthscsa.edu
Graham
Brett H
BH
Nakamaru-Ogiso
Eiko
E
Kar
Adwitiya
A
Falk
Marni J
MJ
D000818:Animals; D001419:Bacteria / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000235:genetics*; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics*; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics*; D008954:Models, Biological; D008957:Models, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics*
D004272:DNA, Mitochondrial
Eur J Biochem. 1993 Mar 15;212(3):727-35
8385010
Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11584-8
16855048
Aging Cell. 2010 Jun;9(3):433-47
20346072
Biochem Cell Biol. 1989 Sep;67(9):612-31
2679804
J Biol Chem. 2003 Nov 28;278(48):47602-9
12975362
Methods Mol Biol. 2007;372:51-66
18314717
Mech Ageing Dev. 2009 Jul;130(7):461-5
19442682
Biochim Biophys Acta. 2000 Aug 15;1459(2-3):274-83
11004440
Genetics. 2010 Jun;185(2):559-71
20382831
Ann N Y Acad Sci. 2007 Apr;1100:530-42
17460219
Antonie Van Leeuwenhoek. 1992 Aug;62(1-2):131-53
1444332
Mol Microbiol. 2004 Jan;51(1):149-58
14651618
Cell. 2008 Jul 11;134(1):112-23
18614015
J Mol Biol. 2006 Apr 28;358(2):396-405
16530220
Nature. 2010 May 27;465(7297):441-5
20505720
Neurology. 2004 Mar 9;62(5):818-20
15007142
J Biol Chem. 2009 Apr 24;284(17):11572-8
19244244
J Biol Chem. 2009 Apr 10;284(15):9814-23
19189973
PLoS One. 2010 Jan 06;5(1):e8549
20066047
J Biol Chem. 2010 Apr 9;285(15):11143-53
20110367
Physiol Rev. 2009 Jul;89(3):799-845
19584314
Biochim Biophys Acta. 2006 Oct;1762(10):873-89
17023146
Crit Rev Biochem Mol Biol. 2007 May-Jun;42(3):221-42
17562452
Genetics. 2006 Jul;173(3):1357-64
16648587
Biochim Biophys Acta. 2006 Feb;1757(2):115-22
16443191
Nat Genet. 2008 Mar;40(3):356-61
18246068
Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):832-8
20044972
Biochim Biophys Acta. 1998 Aug 14;1407(2):114-24
9685604
Curr Biol. 2006 May 23;16(10):982-9
16713954
J Biol Chem. 2008 May 16;283(20):13973-82
18343816
Hum Mol Genet. 2004 Feb 1;13(3):303-14
14662656
J Biophys Biochem Cytol. 1959 May 25;5(3):393-6
13664679
Methods Mol Biol. 2007;372:543-57
18314750
Ann N Y Acad Sci. 2002 Apr;959:466-74
11976220
Annu Rev Biochem. 2006;75:69-92
16756485
Int J Dev Biol. 1998;42(3):243-7
9654004
Nature. 2007 Jul 12;448(7150):151-6
17625558
J Biol Chem. 2008 Sep 19;283(38):25979-87
18603533
Biochim Biophys Acta. 1998 Dec 1;1409(2):107-12
9838069
Biochem Biophys Res Commun. 2002 Feb 15;291(1):8-16
11829454
Biochem J. 2002 May 15;364(Pt 1):317-22
11988106
J Biol Chem. 2006 Oct 27;281(43):32724-7
16950771
Genetics. 2007 Jun;176(2):937-46
17435251
Mol Biosyst. 2008 Jan;4(1):18-29
18075670
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3387-92
11248088
Biochim Biophys Acta. 1997 Feb 18;1344(3):286-99
9059519
Curr Protoc Hum Genet. 2009 Oct;Chapter 19:Unit19.5
19806592
Mech Ageing Dev. 2004 Jun;125(6):455-64
15178135
Cell. 2008 Jun 13;133(6):963-77
18555774
Annu Rev Biochem. 2000;69:1005-75
10966481
Mol Genet Metab. 2005 Aug;85(4):308-17
15886041
J Neurol Sci. 1983 Dec;62(1-3):327-55
6142097
Mol Genet Metab. 2008 Apr;93(4):388-97
18178500
Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2337-41
19164547
Exp Gerontol. 2006 Oct;41(10):974-91
16945497
BMC Cell Biol. 2009 Nov 26;10:83
19941651
J Biol Chem. 2007 Feb 16;282(7):4524-4532
17182618
Eur J Biochem. 1997 Dec 1;250(2):451-8
9428698
Biochem J. 2000 May 1;347 Pt 3:687-91
10769171
Int J Biochem Cell Biol. 2009 Oct;41(10):1817-27
19389485
J Mol Biol. 2009 Apr 3;387(3):559-69
19233206
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):346-52
16781662
Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18367-72
16344465
PLoS Genet. 2007 Dec 28;3(12):e234
18166084
Free Radic Res. 2000 Dec;33(6):857-64
11237107
Free Radic Biol Med. 2003 Feb 15;34(4):478-88
12566073
Biochim Biophys Acta. 2003 Jul 14;1638(2):91-105
12853115
J Biol Chem. 2005 Jan 7;280(1):301-7
15520003
J Neurosci. 2006 Jan 18;26(3):810-20
16421301
Gene. 2005 Jul 18;354:22-7
15890475
Eur J Biochem. 2004 Feb;271(3):494-508
14728676
J Biol Chem. 1993 Dec 5;268(34):25985-92
8245031
J Biol Chem. 1995 Aug 4;270(31):18264-70
7629145
Trends Biochem Sci. 1999 Jan;24(1):34-6
10087920
Biochim Biophys Acta. 2004 Dec 6;1659(2-3):212-20
15576054
Nat Genet. 2003 Jan;33(1):40-8
12447374
Biochim Biophys Acta. 2009 Jun;1787(6):626-34
19268423
Pediatrics. 2006 Aug;118(2):e337-46
16847078
Cell. 2009 Aug 21;138(4):628-44
19703392
J Biol Chem. 2003 Dec 19;278(51):51380-5
14551214
J Mol Biol. 2000 Sep 15;302(2):455-64
10970745
N Engl J Med. 2007 Feb 22;356(8):809-19
17314340
J Biol Chem. 2001 Aug 24;276(34):32240-6
11410594
Trends Endocrinol Metab. 2010 May;21(5):302-14
20060739
PLoS One. 2009 Aug 12;4(8):e6607
19672299
Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1071-6
8577716
Development. 2008 Aug;135(15):2669-79
18599508
J Biol Chem. 2003 Oct 31;278(44):43089-94
12930833
Nucleic Acids Res. 2010 Jan;38(Database issue):D463-7
19910365
Mol Biol Cell. 2001 Feb;12(2):297-308
11179416
Genome Biol. 2001;2(1):RESEARCH0002
11178279
Mol Cell. 2004 Nov 5;16(3):487-96
15525520
Mol Biol Cell. 2002 Mar;13(3):847-53
11907266
Methods Cell Biol. 1994;44:655-81
7707974
Brief Funct Genomic Proteomic. 2003 Apr;2(1):57-71
15239944
Nature. 2006 Jun 29;441(7097):1162-6
16672981
Am J Hum Genet. 2008 Oct;83(4):468-78
18940309
Genetics. 2004 Jun;167(2):761-81
15238527
J Bacteriol. 1991 Mar;173(6):2026-34
2002005
Nature. 2006 Jun 29;441(7097):1157-61
16672980
EMBO J. 1999 Apr 1;18(7):1783-92
10202142
Nucleic Acids Res. 2003 Jul 1;31(13):3381-5
12824332
Genet Med. 2009 Jul;11(7):518-26
19546809
Science. 2002 Dec 20;298(5602):2398-401
12471266
Biochem J. 1990 Dec 15;272(3):589-95
2268287
Genetics. 1999 Dec;153(4):1809-24
10581287
Biochim Biophys Acta. 2010 Aug;1798(8):1465-73
20430008
Clin Med (Lond). 2003 May-Jun;3(3):285-6
12848268
Microbiol Rev. 1990 Sep;54(3):211-25
2215420
Nat Genet. 2004 Mar;36(3):283-7
14981521
Curr Genet. 1996 Nov;30(5):367-80
8929388
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):543-52
16631107
Genetics. 1977 Sep;87(1):105-28
17248753
J Lipid Res. 1999 Oct;40(10):1837-45
10508203
Neurology. 2001 Apr 10;56(7):849-55
11294920
Microbiol Mol Biol Rev. 1998 Dec;62(4):1046-78
9841665
Ann Neurol. 2004 Nov;56(5):631-41
15505787
J Clin Invest. 2005 Oct;115(10):2784-92
16200211
PLoS Biol. 2010 Mar 09;8(3):e1000328
20231875
Am J Hum Genet. 2008 Mar;82(3):623-30
18319072
Development. 2004 May;131(9):2183-94
15073152
Genetics. 1974 May;77(1):71-94
4366476
Biogerontology. 2010 Feb;11(1):31-43
19370397
Cell. 1987 Oct 23;51(2):165-73
3117373
Am J Physiol Cell Physiol. 2007 Jan;292(1):C33-44
16899548
J Biol Chem. 2002 Jan 18;277(3):1680-8
11704668
Antioxid Redox Signal. 2000 Summer;2(2):213-30
11229527
FEBS Lett. 2006 Oct 9;580(23):5450-5
16973164
Antioxid Redox Signal. 2010 Dec 15;13(12):1911-53
20568954
J Biol Chem. 1999 Oct 1;274(40):28598-605
10497226
Nat Genet. 1996 Apr;12(4):385-9
8630491
PLoS Genet. 2008 Apr 25;4(4):e1000061
18437205
Genome Res. 2000 May;10(5):703-13
10810093
Biochim Biophys Acta. 1997 Jul 4;1320(3):217-34
9230919
Science. 2000 Aug 4;289(5480):782-5
10926541
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16382-7
17056719
Am J Hum Genet. 1991 Nov;49(5):939-50
1928099
Biochim Biophys Acta. 1998 May 6;1364(2):125-33
9593856
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83
12642658
J Biol Chem. 2005 Dec 30;280(52):42655-42668
16239214
Curr Opin Chem Biol. 2002 Feb;6(1):106-11
11827833
FEMS Yeast Res. 2009 Dec;9(8):1283-92
19758332
Biochemistry. 2005 Mar 8;44(9):3562-71
15736965
N Engl J Med. 2003 Jun 26;348(26):2656-68
12826641
J Med Genet. 2010 Aug;47(8):507-12
19542079
J Biol Chem. 2003 Oct 31;278(44):43114-20
12923180
Adv Neurol. 1993;60:300-5
8380523
J Inherit Metab Dis. 2007 Oct;30(5):827
17703371
Biochim Biophys Acta. 1990 Sep 18;1046(2):214-22
2171667
Gene. 2001 Jan 24;263(1-2):103-12
11223248
Physiol Genomics. 2010 Mar 3;41(1):33-41
20009008
Mitochondrion. 2010 Mar;10(2):125-36
19900588
Nat Genet. 2002 Aug;31(4):400-4
12134146
Biochim Biophys Acta. 2003 Jul 10;1604(3):135-50
12837546
Hum Mol Genet. 2005 Oct 15;14(20):3079-88
16155110
J Clin Invest. 2007 Mar;117(3):587-9
17332886
J Biol Chem. 2004 Oct 22;279(43):44394-9
15304507
Mitochondrion. 2001 Aug;1(2):181-9
16120277
Mitochondrion. 2007 Jun;7 Suppl:S62-71
17482885
Development. 1993 Jun;118(2):401-15
8223268
PLoS Biol. 2007 Oct 2;5(10):e259
17914900
Biochemistry. 1994 Jan 18;33(2):494-9
8286379
Mol Gen Genet. 1980;177(4):553-65
6770227
Nature. 2000 Nov 2;408(6808):101-6
11081516
J Biol Chem. 2009 Mar 6;284(10):6425-35
19074434
J Biol Chem. 2007 Dec 21;282(51):36914-22
17977822
Curr Biol. 1997 Aug 1;7(8):R465-6
9259571
J Neurobiol. 2004 Sep 5;60(3):328-47
15281071
J Biol Chem. 2001 Jun 8;276(23):20551-8
11278828
IUBMB Life. 2003 Feb;55(2):83-95
12749690
J Biol Chem. 2003 May 2;278(18):15514-22
12600982
Philos Trans R Soc Lond B Biol Sci. 1980 Aug 11;290(1040):329-39
6106247
Curr Biol. 2006 Aug 22;16(16):1641-5
16920626
Nature. 1996 Feb 15;379(6566):589-90
8628392
Bioessays. 2006 Jun;28(6):595-605
16700064
Genetics. 2003 Nov;165(3):1243-53
14668379
Mol Aspects Med. 2010 Jun;31(3):227-85
20346371
Biochim Biophys Acta. 2009 Jan;1791(1):69-75
19022396
J Biol Chem. 2003 Jun 13;278(24):22031-6
12672828
Mol Genet Genomics. 2003 Oct;270(1):1-8
12928865
J Bioenerg Biomembr. 2001 Jun;33(3):259-66
11695836
J Lipid Res. 2003 Mar;44(3):441-9
12562848
Biochemistry. 2001 May 22;40(20):6124-31
11352750
Biochemistry. 1998 Aug 25;37(34):11792-6
9718301
Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4483-8
11917141
FEBS Lett. 2005 Jun 6;579(14):3164-8
15922336
Biochim Biophys Acta. 1998 May 6;1364(2):134-46
9593861
IUBMB Life. 2001 Jul;52(1-2):49-53
11795593
Neuron. 2005 Aug 4;47(3):365-78
16055061
J Proteome Res. 2006 Jul;5(7):1543-54
16823961
Cell. 2006 Dec 29;127(7):1335-47
17190598
Brain. 2007 Aug;130(Pt 8):2037-44
17412732
Mol Cell Endocrinol. 2008 Oct 10;293(1-2):25-31
18374475
J Membr Biol. 1995 Nov;148(2):169-76
8606365
Biochim Biophys Acta. 1998 May 6;1364(2):147-65
9593868
PLoS Genet. 2008 Jan;4(1):e6
18193945
Dev Cell. 2001 Nov;1(5):633-44
11709184
Biochim Biophys Acta. 2007 May;1772(5):533-42
17320357
J Struct Biol. 2007 Aug;159(2):238-42
17360196
J Biol Chem. 2002 Mar 29;277(13):10973-81
11788608
Genetics. 2006 Sep;174(1):525-33
16849596
Mol Gen Genet. 2000 Sep;264(1-2):37-46
11016831
J Alzheimers Dis. 2010;20 Suppl 2:S281-92
20421691
Dev Cell. 2003 Aug;5(2):197-203
12919672
Microbiol Mol Biol Rev. 2000 Jun;64(2):281-315
10839818
Biochim Biophys Acta. 2009 Oct;1788(10):2003-14
19619503
JAMA. 1971 Nov 15;218(7):1015-22
4942064
J Mol Biol. 2007 Nov 30;374(3):837-63
17959197
Nature. 1998 Aug 13;394(6694):694-7
9716135
Science. 2006 Mar 10;311(5766):1430-6
16469879
Biofactors. 2008;32(1-4):113-8
19096106
Genetics. 2001 Sep;159(1):241-54
11560901
Biotechnol J. 2006 Mar;1(3):270-81
16897707
Biochim Biophys Acta. 1995 Mar 22;1234(2):214-20
7696296
Mech Ageing Dev. 2001 Aug;122(11):1187-201
11389932
Mitochondrion. 2009 Nov;9(6):394-401
19616643
Trends Biochem Sci. 2005 Jul;30(7):396-404
15951180
Annu Rev Pathol. 2009;4:315-42
18842101
Yeast. 2000 Nov;16(15):1421-7
11054823
Dis Model Mech. 2009 Jul-Aug;2(7-8):336-40
19553694