title: Energizing Genetics and Epi-genetics: Role in the Regulation of Mitochondrial Function.
abstract: Energy metabolism and mitochondrial function hold a core position in cellular homeostasis. Oxidative metabolism is regulated at multiple levels, ranging from gene transcription to allosteric modulation. To accomplish the fine tuning of these multiple regulatory circuits, the nuclear and mitochondrial compartments are tightly and reciprocally controlled. The fact that nuclear encoded factors, PPARγ coactivator 1α and mitochondrial transcription factor A, play pivotal roles in the regulation of oxidative metabolism and mitochondrial biogenesis is paradigmatic of this crosstalk. Here we provide an updated survey of the genetic and epigenetic mechanisms involved in the control of energy metabolism and mitochondrial function. Chromatin dynamics highly depends on post-translational modifications occurring at specific amino acids in histone proteins and other factors associated to nuclear DNA. In addition to the well characterized enzymes responsible for histone methylation/demethylation and acetylation/deacetylation, other factors have gone on the "metabolic stage". This is the case of the new class of α-ketoglutarate-regulated demethylases (Jumonji C domain containing demethylases) and of the NAD+-dependent deacetylases, also known as sirtuins. Moreover, unexpected features of the machineries involved in mitochondrial DNA (mtDNA) replication and transcription, mitochondrial RNA processing and maturation have recently emerged. Mutations or defects of any component of these machineries profoundly affect mitochondrial activity and oxidative metabolism. Finally, recent evidences support the importance of mtDNA packaging in replication and transcription. These observations, along with the discovery that non-classical CpG islands present in mtDNA undergo methylation, indicate that epigenetics also plays a role in the regulation of the mitochondrial genome function.
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.
authors: Matteo
authors: M
authors: Audano
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.
authors: Alessandra
authors: A
authors: Ferrari
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.
authors: Erika
authors: E
authors: Fiorino
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.
authors: Martin
authors: M
authors: Kuenzl
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.
authors: Donatella
authors: D
authors: Caruso
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.
authors: Nico
authors: N
authors: Mitro
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.
authors: Maurizio
authors: M
authors: Crestani
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.
authors: Emma
authors: E
authors: De Fabiani
keywords: Chromatin; DNA modification; Energy metabolism; Histone modification; Mitochondrial biogenesis; Transcription.
references: Proc Natl Acad Sci U S A. 2012 Sep 18;109 (38):15330-5
references: 22949648
references: Biochem J. 2012 Apr 15;443(2):573-84
references: 22280412
references: Mol Biol Cell. 2003 Sep;14(9):3848-56
references: 12972568
references: Cell Metab. 2013 Sep 3;18(3):341-54
references: 24011070
references: J Biol Chem. 2007 Mar 2;282(9):6823-32
references: 17197703
references: PLoS One. 2012;7(11):e47986
references: 23144842
references: Cell. 1996 Dec 27;87(7):1261-70
references: 8980232
references: J Biol Chem. 2013 Oct 25;288(43):31386-99
references: 24036117
references: Diabetes Res Clin Pract. 2001 Dec;54 Suppl 2:S3-9
references: 11733104
references: J Biol Chem. 2011 Sep 23;286(38):33301-9
references: 21808063
references: Diabetologia. 2010 Jun;53(6):1164-73
references: 20238096
references: Biochem J. 2012 May 1;443(3):655-61
references: 22309213
references: J Biol Chem. 2013 May 31;288(22):15510-9
references: 23599432
references: EMBO J. 1995 Aug 1;14(15):3741-51
references: 7641693
references: Mol Cell. 2006 Dec 28;24(6):813-25
references: 17189185
references: Cell. 2010 Dec 23;143(7):1084-96
references: 21183072
references: J Biol Chem. 2008 Jul 18;283(29):20015-26
references: 18482975
references: Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1325-30
references: 17227870
references: Curr Opin Cell Biol. 2014 Aug;29:46-52
references: 24747170
references: Cell Death Differ. 2008 Apr;15(4):660-6
references: 18219320
references: Nat Rev Genet. 2010 Feb;11(2):109-23
references: 20084085
references: Nature. 2005 Mar 3;434(7029):113-8
references: 15744310
references: EMBO J. 2007 Nov 28;26(23 ):4831-40
references: 17972916
references: Cell. 2014 Jul 31;158(3):607-19
references: 25083871
references: Nature. 2006 Feb 16;439(7078):811-6
references: 16362057
references: Annu Rev Genet. 2011;45:299-329
references: 21910628
references: PLoS One. 2011;6(5):e20220
references: 21637849
references: Nucleic Acids Res. 2002 Dec 1;30(23):5036-55
references: 12466527
references: J Biol Chem. 2008 Oct 3;283(40):27064-73
references: 18678873
references: Genes Cells. 2009 Aug;14(8):991-1001
references: 19624751
references: FEBS Lett. 1993 Feb 15;317(3):175-80
references: 8425601
references: PLoS Genet. 2014 Feb 06;10(2):e1004110
references: 24516400
references: Cell Metab. 2014 Mar 4;19(3):357-72
references: 24561263
references: Biochem J. 2003 Mar 15;370(Pt 3):737-49
references: 12429021
references: Aging Clin Exp Res. 2012 Feb;24(1):21-7
references: 21499024
references: Mol Cell. 2013 Jan 10;49(1):121-32
references: 23201127
references: Science. 2013 Aug 9;341(6146):1237905
references: 23828890
references: Cell Metab. 2010 Sep 8;12 (3):224-36
references: 20816089
references: Physiol Rev. 2008 Apr;88(2):611-38
references: 18391175
references: Bioessays. 2007 Feb;29(2):145-54
references: 17226802
references: Biochim Biophys Acta. 2009 Jan;1789(1):45-57
references: 18603028
references: Nucleic Acids Res. 2014 Jan;42(2):952-67
references: 24163258
references: Cell. 2006 May 5;125(3):497-508
references: 16678094
references: Cell. 2002 Feb 22;108(4):489-500
references: 11909520
references: J Mol Biol. 2004 Apr 16;338(1):17-31
references: 15050820
references: Cell Rep. 2014 May 8;7(3):918-31
references: 24746820
references: PLoS One. 2010 Apr 26;5(4):e10345
references: 20436681
references: DNA Res. 2013 Dec;20(6):537-47
references: 23804556
references: J Biol Chem. 2005 May 20;280(20):19587-93
references: 15767263
references: Diabetes. 2014 May;63(5):1605-11
references: 24430439
references: J Biol Chem. 2007 Oct 12;282(41):30014-21
references: 17702743
references: Nature. 1990 Dec 13;348(6302):651-3
references: 2102678
references: Cell. 2012 Aug 3;150(3):620-32
references: 22863012
references: Nat Commun. 2013;4:2262
references: 23912449
references: Nature. 1997 Sep 25;389(6649):349-52
references: 9311776
references: Mol Cell Biol. 2004 Nov;24(22):9823-34
references: 15509786
references: J Biol Chem. 2001 Jun 29;276(26):23357-61
references: 11283020
references: Cold Spring Harb Symp Quant Biol. 2011;76:175-82
references: 22096028
references: Genes Dev. 2013 Dec 15;27(24):2615-27
references: 24352419
references: Nature. 2010 Mar 4;464(7285):121-5
references: 20203611
references: Neuron. 2013 Mar 6;77(5):886-98
references: 23473319
references: Hum Mol Genet. 2014 May 15;23(10):2580-92
references: 24399447
references: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3630-5
references: 21321201
references: Am J Hum Genet. 2012 Nov 2;91(5):919-27
references: 23084290
references: PLoS One. 2009 Jun 05;4(6):e5809
references: 19503838
references: Science. 2007 Oct 19;318(5849):444-7
references: 17947579
references: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12017-22
references: 17609368
references: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12861-6
references: 17646659
references: Biochim Biophys Acta. 2012 Sep-Oct;1819(9-10):1035-54
references: 22172991
references: Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17687-92
references: 16301523
references: Endocr Rev. 2010 Jun;31(3):364-95
references: 20156986
references: Mol Cell Biol. 2006 Nov;26(22):8475-87
references: 16966381
references: Cell Metab. 2009 Apr;9(4):327-38
references: 19356714
references: Cell Metab. 2009 Sep;10 (3):189-98
references: 19723495
references: Cell Metab. 2013 Mar 5;17(3):386-98
references: 23473033
references: Nature. 2005 Sep 15;437(7057):436-9
references: 16079795
references: Cold Spring Harb Symp Quant Biol. 2000;65:297-302
references: 12760043
references: J Clin Endocrinol Metab. 2009 Mar;94(3):1017-25
references: 19088160
references: Cell Metab. 2012 Apr 4;15(4):505-17
references: 22482732
references: Cell. 2010 Aug 6;142(3):456-67
references: 20691904
references: IUBMB Life. 2014 Feb;66(2):89-99
references: 24488813
references: Nucleic Acids Res. 2012 Sep;40(16):8033-47
references: 22661577
references: Circulation. 2014 Aug 12;130(7):565-72
references: 24920721
references: Nature. 2007 Nov 29;450(7170):736-40
references: 18046414
references: Diabetes. 2013 Mar;62(3):732-42
references: 23069623
references: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18410-5
references: 20930118
references: Mitochondrion. 2004 Apr;3(5):251-9
references: 16120358
references: Exp Cell Res. 2001 Jan 15;262(2):75-83
references: 11139331
references: Epigenetics. 2012 Nov;7(11):1315-30
references: 23051921
references: Mol Cell. 2003 Jan;11(1):139-50
references: 12535528
references: Biochem Biophys Res Commun. 2013 Apr 19;433(4):368-73
references: 23261425
references: Gene. 2000 Mar 7;245(1):1-11
references: 10713439
references: Nature. 1961 Jul 8;191:144-8
references: 13771349
references: Cell. 2011 Nov 11;147(4):827-39
references: 22078881
references: Oncogene. 2010 Jul 29;29(30):4362-8
references: 20498629
references: Nat Rev Mol Cell Biol. 2007 Apr;8(4):284-95
references: 17380162
references: Recent Prog Horm Res. 2001;56:309-28
references: 11237219
references: Cell. 2008 Jan 25;132(2):171-6
references: 18243090
references: Genes Dev. 2006 May 15;20(10):1256-61
references: 16648462
references: Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14682-7
references: 23969834
references: Ageing Res Rev. 2014 Jul;16:45-65
references: 24910305
references: Curr Opin Plant Biol. 2007 Oct;10(5):528-33
references: 17692561
references: Nature. 2009 Jul 30;460(7255):587-91
references: 19641587
references: Cell. 2008 Oct 31;135(3):462-74
references: 18984158
references: Proc Natl Acad Sci U S A. 2011 May 31;108(22):9232-7
references: 21576456
references: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19229-34
references: 19047629
references: Trends Pharmacol Sci. 2010 May;31(5):212-20
references: 20226541
references: Nat Rev Mol Cell Biol. 2010 Dec;11(12):872-84
references: 21102612
references: IUBMB Life. 2005 Apr-May;57(4-5):277-81
references: 16036611
references: Biochem Biophys Res Commun. 2000 Jul 5;273(2):793-8
references: 10873683
references: J Biol Chem. 2014 Jun 13;289(24):16727-35
references: 24770417
references: FASEB J. 2011 Sep;25(9):3271-8
references: 21670064
references: Nat Rev Genet. 2009 Jan;10(1):32-42
references: 19065135
references: J Biol Chem. 2007 Dec 7;282(49):35425-9
references: 17897944
references: Diabetes. 2009 May;58(5):1229-36
references: 19208907
references: Mitochondrion. 2007 Feb-Apr;7(1-2):39-44
references: 17280879
references: Cell Metab. 2006 Jun;3(6):429-38
references: 16753578
references: Mol Cell Biol. 2007 Dec;27(24):8807-14
references: 17923681
references: Nucleic Acids Res. 2013 Jan;41(2):1223-40
references: 23221631
references: Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1873-8
references: 24449870
references: Cell Metab. 2014 Nov 4;20(5):856-69
references: 25200183
references: Cell Metab. 2014 Jun 3;19(6):941-51
references: 24794974
references: Cell. 2007 Feb 23;128(4):693-705
references: 17320507
references: Cell Rep. 2012 Aug 30;2(2):419-31
references: 22902405
references: Hum Mol Genet. 2012 May 1;21(9):2086-101
references: 22307237
references: Part Fibre Toxicol. 2013 May 08;10:18
references: 23656717
references: Nature. 2009 Apr 9;458(7239):757-61
references: 19194461
references: Leukemia. 2012 Oct;26(10):2216-23
references: 22469782
references: Mol Cell Biol. 2005 Apr;25(8):2873-84
references: 15798178
references: Neuron. 2013 Sep 18;79(6):1109-22
references: 24050401
references: J Am Chem Soc. 2013 Oct 2;135(39):14593-9
references: 23980549
references: Trends Endocrinol Metab. 2012 Sep;23(9):459-66
references: 22817841
references: PLoS One. 2013 Aug 07;8(8):e69089
references: 24282625
references: Am J Hum Genet. 2013 Aug 8;93(2):211-23
references: 23849775
references: Cell. 2004 Jan 23;116(2):281-97
references: 14744438
references: Science. 1999 Mar 5;283(5407):1488-93
references: 10066163
references: Hum Mol Genet. 2013 May 15;22(10):1983-93
references: 23393161
references: Lancet. 2014 Jun 7;383(9933):1990-8
references: 24630777
references: EMBO J. 2012 Jan 18;31(2):443-56
references: 22045337
references: EMBO Rep. 2014 Jun;15(6):678-85
references: 24781695
references: J Clin Invest. 2009 Sep;119(9):2758-71
references: 19652361
references: Aging Clin Exp Res. 2012 Oct;24(5):530-6
references: 22732472
references: Trends Cell Biol. 2013 Sep;23(9):457-63
references: 23721879
references: Prog Mol Biol Transl Sci. 2014;127:155-82
references: 25149217
references: Annu Rev Biochem. 2001;70:81-120
references: 11395403
references: Front Cell Neurosci. 2013 Dec 25;7:279
references: 24399935
references: Cell Rep. 2014 Jul 10;8(1):66-74
references: 24981867
references: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4070-5
references: 10737771
references: Cell. 2012 Mar 16;148(6):1145-59
references: 22424226
references: Cell. 2004 Dec 29;119(7):941-53
references: 15620353
references: J Med Genet. 2014 Mar;51(3):176-84
references: 24367055
references: Biochim Biophys Acta. 2012 Sep-Oct;1819(9-10):914-20
references: 22142616
references: Front Genet. 2014 Jun 03;5:158
references: 24917879
references: J Biol Chem. 2005 Feb 18;280(7):5909-16
references: 15590647
references: Cell Metab. 2012 Dec 5;16(6):765-76
references: 23168219
references: Hum Mol Genet. 2014 Dec 1;23(23):6345-55
references: 25008111
references: Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4840-5
references: 22411789
references: Otol Neurotol. 2014 Jul;35(6):1087-90
references: 24770403
references: Transcription. 2011 Mar;2(2):55-59
references: 21468229
references: Oncogene. 2007 Aug 13;26(37):5395-407
references: 17694081
references: Nat Med. 2004 Apr;10(4):355-61
references: 15057233
references: Nat Rev Mol Cell Biol. 2005 Apr;6(4):298-305
references: 15768047
references: Diabetes. 2009 Jul;58(7):1509-17
references: 19366864
references: Mol Cell Biol. 2012 Aug;32(16):3333-46
references: 22711985
references: Cell Metab. 2011 Jan 5;13(1):80-91
references: 21195351
references: Cell. 1999 Jul 9;98 (1):115-24
references: 10412986
references: Nat Struct Mol Biol. 2011 Oct 30;18(11):1290-6
references: 22037171
references: PLoS One. 2012;7(7):e41612
references: 22848545
references: Curr Top Microbiol Immunol. 2003;274:203-36
references: 12596909
references: Thromb J. 2012 Aug 14;10(1):13
references: 22891684
references: Nature. 2013 Aug 22;500(7463):477-81
references: 23925113
references: Nat Rev Mol Cell Biol. 2010 Sep;11(9):607-20
references: 20683471
references: Mitochondrion. 2014 Sep;18:76-81
references: 25128872
references: Tumori. 2014 Jan-Feb;100(1):e4-7
references: 24675509
references: Cell Metab. 2010 Oct 6;12(4):321-7
references: 20889125
references: Trends Genet. 1998 May;14 (5):178-83
references: 9613201
references: Leukemia. 2012 Mar;26(3):404-13
references: 22182919
references: Mitochondrion. 2011 Mar;11(2):237-45
references: 21047563
references: Cell Metab. 2011 May 4;13(5):517-26
references: 21531334
references: Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):239-50
references: 22436747
references: Nat Genet. 2000 Nov;26(3):336-40
references: 11062475
references: Biochim Biophys Acta. 2012 Sep-Oct;1819(9-10):1080-7
references: 22172992
references: Cell. 2011 Nov 11;147(4):815-26
references: 22078880
references: Nature. 2004 Jun 17;429(6993):771-6
references: 15175761
references: Hum Mol Genet. 2014 Nov 1;23(21):5733-49
references: 24916378
references: Nat Rev Mol Cell Biol. 2012 Mar 07;13(4):225-38
references: 22395773
references: Cell Metab. 2014 Aug 5;20(2):226-40
references: 25088301
references: Cell Res. 2013 Jun;23(6):759-74
references: 23478297
references: Comp Biochem Physiol C Toxicol Pharmacol. 2003 Mar;134(3):281-9
references: 12643975
references: Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):16862-7
references: 24082118
references: Nat Genet. 1998 Mar;18(3):231-6
references: 9500544
references: EMBO J. 2007 Apr 4;26(7):1913-23
references: 17347648
references: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9047-52
references: 18579779
references: Cell Metab. 2014 Apr 1;19(4):618-29
references: 24703694
references: J Lipid Res. 2011 Sep;52(9):1693-701
references: 21743036
references: Mol Cell Biol. 2008 Dec;28(24):7451-64
references: 18838535
references: Cell. 2006 Dec 15;127(6):1109-22
references: 17112576
references: N Engl J Med. 2004 Nov 11;351(20):2080-6
references: 15537906
references: Mol Cell Biol. 2006 Nov;26(22):8488-97
references: 16966379
references: Front Oncol. 2013 Dec 02;3:292
references: 24350057
references: Annu Rev Biochem. 2008;77:289-312
references: 18518822
references: J Biol Chem. 2005 Apr 8;280(14 ):13560-7
references: 15653680
references: Development. 2014 Jan;141(2):269-80
references: 24335252
references: Int Immunopharmacol. 2014 Aug;21(2):439-46
references: 24946096
references: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14447-52
references: 18794531
references: Diabetes. 2014 May;63(5):1546-59
references: 24757201
references: Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17551-8
references: 16251272
references: J Exp Med. 2008 Sep 29;205(10 ):2409-17
references: 18809715
references: Trends Genet. 2012 Apr;28(4):164-74
references: 22386917
references: Am J Physiol Endocrinol Metab. 2004 Oct;287(4):E686-95
references: 15165993
references: J Biomed Biotechnol. 2010;2010:737385
references: 20396601
references: Sci Rep. 2014 Aug 15;4:6076
references: 25123547
references: Nucleic Acids Res. 2014 Apr;42(6):4100-12
references: 24413562
references: Cell Cycle. 2011 Sep 1;10(17):2904-16
references: 21857155
references: Biochem Soc Trans. 2010 Dec;38(6):1523-6
references: 21118119
references: Nature. 1981 Apr 9;290(5806):470-4
references: 7219536
references: Mol Genet Metab. 2013 Sep-Oct;110(1-2):25-34
references: 23920043
references: Biochim Biophys Acta. 2012 Sep-Oct;1819(9-10):921-9
references: 22465614
references: Biochemistry (Mosc). 2005 Feb;70(2):200-14
references: 15807660
references: Biochem Biophys Res Commun. 2013 Nov 29;441(4):743-50
references: 24211571
references: FASEB J. 2009 Oct;23(10):3347-60
references: 19497982