title: Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease.
abstract: Mitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP. Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia The Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Abena
authors.initials: A
authors.lastname: Nsiah-Sefaa
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia The Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia matthew.mckenzie@hudson.org.au.
authors.forename: Matthew
authors.initials: M
authors.lastname: McKenzie
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation
chemical_list: D005227:Fatty Acids
keywords: disease; mitochondria; protein complex assembly; protein interactions; supercomplex
references.citation: Cell. 2008 Jul 11;134(1):112-23
references.pmid: 18614015
references.citation: J Neurol Neurosurg Psychiatry. 1980 Aug;43(8):679-82
references.pmid: 7431028
references.citation: Biochem Biophys Res Commun. 1993 Mar 31;191(3):1369-72
references.pmid: 8466512
references.citation: Plant Physiol. 2004 Apr;134(4):1450-9
references.pmid: 15064371
references.citation: Pediatr Res. 1977 Oct;11(10 Pt 2):1088-93
references.pmid: 904972
references.citation: J Inherit Metab Dis. 2004;27(5):679-84
references.pmid: 15669684
references.citation: Brain. 2014 Nov;137(Pt 11):2903-8
references.pmid: 25125611
references.citation: J Med Genet. 2004 Feb;41(2):120-4
references.pmid: 14757859
references.citation: Am J Hum Genet. 2008 Jan;82(1):32-8
references.pmid: 18179882
references.citation: Biochem J. 1978 Sep 15;174(3):783-90
references.pmid: 215122
references.citation: J Inherit Metab Dis. 2012 Mar;35(2):211-25
references.pmid: 21874297
references.citation: J Med Genet. 2002 Mar;39(3):162-9
references.pmid: 11897814
references.citation: J Inherit Metab Dis. 2011 Apr;34(2):283-92
references.pmid: 20440652
references.citation: PLoS One. 2012;7(11):e48628
references.pmid: 23152787
references.citation: J Inherit Metab Dis. 2004;27(2):294-6
references.pmid: 15243991
references.citation: J Biol Chem. 1995 Dec 29;270(52):30881-92
references.pmid: 8537342
references.citation: Am J Hum Genet. 1999 Feb;64(2):479-94
references.pmid: 9973285
references.citation: Neurogenetics. 2013 May;14(2):153-60
references.pmid: 23532514
references.citation: Lancet. 1991 Feb 2;337(8736):298-9
references.pmid: 1671131
references.citation: Hum Mol Genet. 2010 Jan 15;19(2):374-86
references.pmid: 19875463
references.citation: IUBMB Life. 2010 Jul;62(7):497-502
references.pmid: 20552642
references.citation: N Engl J Med. 2003 Jun 5;348(23):2304-12
references.pmid: 12788994
references.citation: Annu Rev Physiol. 2016;78:23-44
references.pmid: 26474213
references.citation: Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):18934-9
references.pmid: 24191001
references.citation: Neurology. 1990 Aug;40(8):1302-3
references.pmid: 2166249
references.citation: Biochim Biophys Acta. 1976 Dec 2;455(2):466-84
references.pmid: 999923
references.citation: Am J Hum Genet. 2009 Jun;84(6):718-27
references.pmid: 19463981
references.citation: Nutrition. 1997 Nov-Dec;13(11-12):978-85
references.pmid: 9433715
references.citation: J Med Genet. 2011 Mar;48(3):177-82
references.pmid: 21147908
references.citation: J Inherit Metab Dis. 1996;19(2):157-60
references.pmid: 8739954
references.citation: Br J Pharmacol. 2014 Apr;171(8):1818-36
references.pmid: 24102298
references.citation: EMBO J. 2000 Apr 17;19(8):1777-83
references.pmid: 10775262
references.citation: Biofactors. 2005;25(1-4):5-20
references.pmid: 16873926
references.citation: Eur J Pediatr. 2000 Dec;159(12):908-11
references.pmid: 11131350
references.citation: J Biol Chem. 1998 Feb 27;273(9):4872-7
references.pmid: 9478928
references.citation: Hum Mol Genet. 2013 Dec 20;22(25):5249-61
references.pmid: 23933733
references.citation: Biochim Biophys Acta. 2014 Apr;1840(4):1355-9
references.pmid: 24462578
references.citation: Am J Med Genet A. 2010 Jun;152A(6):1531-5
references.pmid: 20503330
references.citation: Lancet Oncol. 2010 Apr;11(4):366-72
references.pmid: 20071235
references.citation: Orphanet J Rare Dis. 2015;10:79
references.pmid: 26081110
references.citation: Nat Genet. 2010 Oct;42(10):851-8
references.pmid: 20818383
references.citation: N Engl J Med. 1999 Jun 3;340(22):1723-31
references.pmid: 10352164
references.citation: Am J Hum Genet. 1990 Mar;46(3):428-33
references.pmid: 2137962
references.citation: Nat Genet. 1995 Oct;11(2):144-9
references.pmid: 7550341
references.citation: Biochem Mol Biol Int. 1996 Oct;40(3):487-95
references.pmid: 8908357
references.citation: J Med Genet. 2015 Oct;52(10):691-8
references.pmid: 26251176
references.citation: J Biol Chem. 1990 Nov 15;265(32):19434-40
references.pmid: 2147180
references.citation: Mol Cell Biol. 2006 Jul;26(13):4872-81
references.pmid: 16782876
references.citation: Mol Genet Metab. 2000 Sep-Oct;71(1-2):10-8
references.pmid: 11001791
references.citation: Hum Mol Genet. 2013 Aug 1;22(15):3138-51
references.pmid: 23575228
references.citation: Hum Mutat. 2015 Feb;36(2):232-9
references.pmid: 25393721
references.citation: Brain Dev. 2006 Oct;28(9):576-81
references.pmid: 16737791
references.citation: Biochim Biophys Acta. 2004 Jan 30;1608(1):1-9
references.pmid: 14741580
references.citation: Pediatr Res. 2001 Jan;49(1):18-23
references.pmid: 11134486
references.citation: Ann Neurol. 1995 Aug;38(2):163-9
references.pmid: 7654063
references.citation: Ann Clin Transl Neurol. 2015 May;2(5):492-509
references.pmid: 26000322
references.citation: Biochim Biophys Acta. 2004 Dec 6;1659(2-3):136-47
references.pmid: 15576045
references.citation: Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):633-40
references.pmid: 20116362
references.citation: Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):15735-40
references.pmid: 25331896
references.citation: Am J Hum Genet. 2008 Jun;82(6):1281-9
references.pmid: 18499082
references.citation: Biochem J. 2002 Jun 15;364(Pt 3):833-9
references.pmid: 12049648
references.citation: Genetics. 1992 Jan;130(1):163-73
references.pmid: 1732158
references.citation: Hum Genet. 2015 Sep;134(9):981-91
references.pmid: 26099313
references.citation: J Neurol Sci. 1983 Dec;62(1-3):327-55
references.pmid: 6142097
references.citation: Science. 2013 Jun 28;340(6140):1567-70
references.pmid: 23812712
references.citation: Physiol Rev. 1992 Oct;72(4):881-940
references.pmid: 1438581
references.citation: Eur J Hum Genet. 2002 Aug;10(8):457-61
references.pmid: 12111639
references.citation: Biochim Biophys Acta. 2009 Jan;1793(1):181-5
references.pmid: 18601960
references.citation: J Pediatr. 2000 Feb;136(2):251-4
references.pmid: 10657835
references.citation: Neurology. 1989 May;39(5):693-6
references.pmid: 2710360
references.citation: Pediatr Res. 1985 Jul;19(7):666-71
references.pmid: 4022672
references.citation: Acta Myol. 2014 Oct;33(2):86-93
references.pmid: 25709378
references.citation: J Biochem. 1997 Jul;122(1):1-16
references.pmid: 9276665
references.citation: Biochim Biophys Acta. 2004 Dec 6;1659(2-3):121-8
references.pmid: 15576043
references.citation: J Biol Chem. 1987 Nov 15;262(32):15386-91
references.pmid: 2824457
references.citation: Am J Hum Genet. 2001 Jun;68(6):1344-52
references.pmid: 11349233
references.citation: Ann Neurol. 2004 Jan;55(1):58-64
references.pmid: 14705112
references.citation: JAMA. 2005 Oct 26;294(16):2057-63
references.pmid: 16249420
references.citation: J Neurochem. 1990 Mar;54(3):823-7
references.pmid: 2154550
references.citation: Hum Mol Genet. 1998 Apr;7(4):619-27
references.pmid: 9499414
references.citation: N Engl J Med. 2007 Feb 22;356(8):809-19
references.pmid: 17314340
references.citation: Biochim Biophys Acta. 2012 Jun;1817(6):851-62
references.pmid: 21924235
references.citation: J Clin Invest. 2005 Oct;115(10):2784-92
references.pmid: 16200211
references.citation: Nat Rev Genet. 2005 May;6(5):389-402
references.pmid: 15861210
references.citation: Semin Pediatr Neurol. 2008 Sep;15(3):140-9
references.pmid: 18708005
references.citation: Cell. 2012 Mar 16;148(6):1145-59
references.pmid: 22424226
references.citation: Nat Genet. 2011 Mar;43(3):259-63
references.pmid: 21278747
references.citation: J Biol Chem. 1985 Feb 25;260(4):2458-67
references.pmid: 2982819
references.citation: Acta Neurol Scand. 1994 Oct;90(4):281-4
references.pmid: 7839816
references.citation: Neurology. 2013 Apr 23;80(17):1577-83
references.pmid: 23553477
references.citation: Cell Metab. 2010 Sep 8;12(3):283-94
references.pmid: 20816094
references.citation: Hum Mutat. 2003 Jun;21(6):598-607
references.pmid: 12754706
references.citation: Hum Mol Genet. 2014 Mar 1;23(5):1311-9
references.pmid: 24158852
references.citation: Ann Neurol. 2000 Sep;48(3):330-5
references.pmid: 10976639
references.citation: Science. 1973 Nov 20;182(4115):929-31
references.pmid: 4745596
references.citation: Am J Med Genet A. 2015 Jan;167A(1):211-4
references.pmid: 25338548
references.citation: Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6206-10
references.pmid: 8016139
references.citation: Nat Genet. 2001 Sep;29(1):57-60
references.pmid: 11528392
references.citation: Hum Mol Genet. 2015 Jun 1;24(11):3238-47
references.pmid: 25721401
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15196-200
references.pmid: 21876144
references.citation: Antioxid Redox Signal. 2013 Nov 1;19(13):1469-80
references.pmid: 23581604
references.citation: Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):664-70
references.pmid: 20036212
references.citation: J Mol Biol. 2011 Dec 2;414(3):413-26
references.pmid: 22019594
references.citation: Hum Genet. 2015 Aug;134(8):869-79
references.pmid: 26008905
references.citation: Neuromuscul Disord. 2002 Mar;12(3):235-46
references.pmid: 11801395
references.citation: Orphanet J Rare Dis. 2012;7:69
references.pmid: 22995659
references.citation: J Bioenerg Biomembr. 2013 Feb;45(1-2):47-57
references.pmid: 23065309
references.citation: Am J Hum Genet. 2008 Oct;83(4):468-78
references.pmid: 18940309
references.citation: Nat Rev Genet. 2001 May;2(5):342-52
references.pmid: 11331900
references.citation: Mol Cell. 2004 Mar 26;13(6):805-15
references.pmid: 15053874
references.citation: Am J Obstet Gynecol. 2002 Sep;187(3):715-20
references.pmid: 12237653
references.citation: Ann Neurol. 2012 Jun;71(6):850-4
references.pmid: 22718549
references.citation: Science. 2000 Feb 4;287(5454):848-51
references.pmid: 10657297
references.citation: Plant Physiol. 2003 Sep;133(1):274-86
references.pmid: 12970493
references.citation: J Pediatr. 1997 Jan;130(1):67-76
references.pmid: 9003853
references.citation: J Biol Chem. 2010 Sep 24;285(39):29834-41
references.pmid: 20663895
references.citation: Hum Mutat. 2001 Sep;18(3):169-89
references.pmid: 11524729
references.citation: Hum Mol Genet. 2010 Aug 1;19(15):3011-20
references.pmid: 20484225
references.citation: Neuromuscul Disord. 1996 Oct;6(5):327-37
references.pmid: 8938697
references.citation: J Appl Physiol (1985). 1987 Mar;62(3):999-1005
references.pmid: 3571098
references.citation: J Inherit Metab Dis. 2009 Aug;32(4):498-505
references.pmid: 19452263
references.citation: PLoS One. 2012;7(4):e35048
references.pmid: 22496890
references.citation: EMBO J. 2007 Jul 11;26(13):3227-37
references.pmid: 17557076
references.citation: Eur J Pediatr. 2000 Apr;159(4):243-6
references.pmid: 10789927
references.citation: J Inherit Metab Dis. 2003;26(7):659-70
references.pmid: 14707514
references.citation: J Biol Chem. 1974 Aug 10;249(15):4905-10
references.pmid: 4367811
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12356-8
references.pmid: 16105947
references.citation: Am J Hum Genet. 2014 Feb 6;94(2):209-22
references.pmid: 24462369
references.citation: Genet Med. 2006 Apr;8(4):205-12
references.pmid: 16617240
references.citation: Biochemistry. 1999 Jul 13;38(28):9031-8
references.pmid: 10413476
references.citation: Biochim Biophys Acta. 2009 Jan;1793(1):78-88
references.pmid: 18501715
references.citation: J Med Genet. 2012 Sep;49(9):578-90
references.pmid: 22972949
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8625-9
references.pmid: 9671728
references.citation: Nat Genet. 2009 Jun;41(6):654-6
references.pmid: 19465911
references.citation: IUBMB Life. 2001 Sep-Nov;52(3-5):135-41
references.pmid: 11798025
references.citation: J Mol Biol. 2006 Aug 18;361(3):462-9
references.pmid: 16857210
references.citation: J Neurosci. 2006 May 10;26(19):5256-64
references.pmid: 16687518
references.citation: J Biol Chem. 1984 Dec 25;259(24):15040-5
references.pmid: 6439716
references.citation: Hum Mol Genet. 1997 May;6(5):695-707
references.pmid: 9158144
references.citation: J Mol Biol. 1998 Apr 17;277(5):1033-46
references.pmid: 9571020
references.citation: J Am Soc Nephrol. 2003 Dec;14(12):2995-3007
references.pmid: 14638899