A peep into mitochondrial disorder:multifaceted from mitochondrial DNAmutations to nuclear gene modulation

Abstract

Mitochondrial genome is responsible for multiple human diseases in a maternal inherited pattern, yet phenotypes of patients in a same pedigree frequently vary largely. Genes involving in epigenetic modification, RNA processing, and other biological pathways, rather than “threshold effect” and environmental factors, provide more specific explanation to the aberrant phenotype. Thus, the double hit theory, mutations both in mitochondrial DNA and modifying genes aggravating the symptom, throws new light on mitochondrial dysfunction processes. In addition, mitochondrial retrograde signaling pathway that leads to reconfiguration of cell metabolism to adapt defects in mitochondria may as well play an active role. Here we review selected examples of modifier genes and mitochondrial retrograde signaling in mitochondrial disorders, which refine our understanding and will guide the rational design of clinical therapies.

Key words： mitochondrial disorder; mitochondrial DNA mutation; nuclear modifier gene; mitochondrial retrograde signaling

References

1 Abbott JA, Francklyn CS, Robey-Bond SM (2014) Transfer RNA and human disease. Front Genet 5:158

2 Arnould T, Vankoningsloo S, Renard P, Houbion A, Ninane N,Demazy C (2002) CREB activation induced by mitochondrial dysfunction is a new signaling pathway that impairs cell proliferation. EMBO J 21:53–63

3 Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23–49

4 Biswas G, Guha M, Avadhani NG (2005) Mitochondria-to-nucleus stress signaling in mammalian cells: nature of nuclear gene targets, transcription regulation, and induced resistance to apoptosis. Gene 354:132–139

5 Butow RA, Avadhani NG (2004) Mitochondrial signaling: the retrograde response. Mol Cell 14:1–15

6 Bykhovskaya Y, Mengesha E, Wang D, Yang H, Estivill X, Shohat M (2004) Human mitochondrial transcription factor B1 as a modifier gene for hearing loss associated with the mitochondrial A1555G mutation. Mol Genet Metab 82:27–32

7 Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125:1241–1252

8 DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668

9 Diodato D, Melchionda L, Haack TB, Dallabona C, Baruffini E, Donnini C (2014) VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies. Hum Mutat 35:983–989

10 Enriquez JA, Chomyn A, Attardi G (1995) MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNA(Lys) and premature translation termination. Nat Genet 10:47–55

11 Giordano C, Iommarini L, Giordano L, Maresca A, Pisano A, Valentino ML (2014) Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy. Brain 137:335–353

12 Gomes AP, Price NL, Ling AJY, Moslehi JJ, Montgomery MK, Rajman L (2013) Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155:1624–1638

13 Goto Y, Nonaka I, Horai S (1990) A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348:651–653

14 Guan M-X, Fischel-Ghodsian N, Attardi G (1996) Biochemical evidence for nuclear gene involvement in phenotype of nonsyndromic deafness associated with mitochondrial 12S rRNA mutation. Hum Mol Genet 5:963–971

15 Guan MX, Fischel-Ghodsian N, Attardi G (2001) Nuclear background determines biochemical phenotype in the deafnessassociated mitochondrial 12S rRNA mutation. Hum Mol Genet 10:573–580

16 Guan MX, Yan Q, Li X, Bykhovskaya Y, Gallo-Teran J, Hajek P (2006) Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am J Hum Genet 79:291–302

17 Guha M, Avadhani NG (2013) Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics. Mitochondrion 13:577–591

18 Gusella JF, MacDonald ME, Lee J-M (2014) Genetic modifiers of Huntington’s disease. Mov Disord 29:1359–1365

19 Harding AE, Sweeney MG, Govan GG, Riordan-Eva P (1995) Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation. Am J Hum Genet 57:77–86

20 Holt IJ, Harding AE, Morgan-Hughes JA (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331:717–719

21 Koopman WJ, Willems PH, Smeitink JA (2012) Monogenic mitochondrial disorders. N Engl J Med 366:1132–1141

22 Li X, Guan M-X (2003) Identification and characterization of mouse GTPBP3 gene encoding a mitochondrial GTP-binding protein involved in tRNA modification. Biochem Biophys Res Commun 312:747–754

23 Li X, Li R, Lin X, Guan MX (2002) Isolation and characterization of the putative nuclear modifier gene MTO1 involved in the pathogenesis of deafness-associated mitochondrial 12 S rRNA A1555G mutation. J Biol Chem 277:27256–27264

24 Luhmann UF, Carvalho LS, Holthaus SM, Cowing JA, Greenaway S, Chu CJ (2015) The severity of retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors. Hum Mol Genet 24:128–141

25 McMillan HJ, Humphreys P, Smith A, Schwartzentruber J, Chakraborty P, Bulman DE, . (2014) Congenital visual impairment and progressive microcephaly due to lysyl-transfer ribonucleic acid (rna) synthetase (kars) mutations: the expanding phenotype of aminoacyl-transfer RNA synthetase mutations in human disease. J Child Neurol.

26 Meseguer S, Martinez-Zamora A, Garcia-Arumi E, Andreu AL, Armengod ME (2015) The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome. Hum Mol Genet 24:167–184

27 Nakajima J, Eminoglu TF, Vatansever G, Nakashima M, Tsurusaki Y, Saitsu H (2014) A novel homozygous YARS2 mutation causes severe myopathy, lactic acidosis, and sideroblastic anemia 2. J Hum Genet 59:229–232

28 Newmeyer DD, Ferguson-Miller S (2003) Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112:481–490

29 Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148:1145–1159

30 Owusu-Ansah E, Song W, Perrimon N (2013) Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155:699–712

31 Parikh VS, Morgan MM, Scott R, Clements LS, Butow RA (1987) The mitochondrial genotype can influence nuclear gene expression in yeast. Science 235:576–580

32 Parson W, Bandelt HJ (2007) Extended guidelines for mtDNA typing of population data in forensic science. Forensic Sci Int Genet 1:13–19

33 Pellegrino MW, Nargund AM, Haynes CM (2013) Signaling the mitochondrial unfolded protein response. Biochim et Biophys Acta 1833:410–416

34 Perli E, Giordano C, Pisano A, Montanari A, Campese AF, Reyes A (2014) The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells. EMBO Mol Med 6:169–182

35 Picard M, Zhang J, Hancock S, Derbeneva O, Golhar R, Golik P (2014) Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming. Proc Natl Acad Sci USA 111:E4033–E4042

36 Prezant TR, Agapian JV, Bohlman MC, Bu X, Oztas S, Qiu WQ (1993) Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet 4:289–294

37 Raimundo N (2014) Mitochondrial pathology: stress signals from the energy factory. Trends Mol Med 20:282–292

38 Raimundo N, Song L, Shutt TE, McKay SE, Cotney J, Guan MX (2012) Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness. Cell 148:716–726

39 Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE (1995) The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 118(Pt 2):319–337

40 Ross JM, Stewart JB, Hagstrom E, Brene S, Mourier A, Coppotelli G (2013) Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501:412–415

41 Ross JM, Coppotelli G, Hoffer BJ, Olson L (2014) Maternally transmitted mitochondrial DNA mutations can reduce lifespan. Sci Rep4:6569

42 Rubinsztein DC, Marino G, Kroemer G (2011) Autophagy and aging. Cell 146:682–695

43 Ryan MT, Hoogenraad NJ (2007) Mitochondrial-nuclear communications. Annu Rev Biochem 76:701–722

44 Samuels DC, Schon EA, Chinnery PF (2004) Two direct repeats cause most human mtDNA deletions. Trends Genet 20:393–398

45 Suzuki T, Nagao A (2011) Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases. Annu Rev Genet 45:299–329

46 Taylor RW, Turnbull DM (2005) Mitochondrial DNA mutations in human disease. Nat Rev Genet 6:389–402

47 van den Ouweland JMW, Lemkes HHPJ, Ruitenbeek W, Sandkuijl LA, de Vijlder MF, Struyvenberg PAA (1992) Mutation in mitochondrial tRNALeu(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet 1:368–371

48 Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407

49 Wallace DC (2012) Mitochondria and cancer. Nature reviews. Cancer 12:685–698

50 Wallace DC, Chalkia D (2013) Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb Perspect Biol 5:a021220

51 Yasukawa T, Suzuki T, Ishii N, Ueda T, Ohta S, Watanabe K (2000a) Defect in modification at the anticodon wobble nucleotide of mitochondrial tRNA(Lys) with the MERRF encephalomyopathy pathogenic mutation. FEBS Lett 467:175–178

52 Yasukawa T, Suzuki T, Ueda T, Ohta S, Watanabe K (2000b) Modification defect at anticodon wobble nucleotide of mitochondrial tRNAs(Leu)(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. J Biol Chem 275:4251–4257

53 Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59

54 Zhao H, Li R, Wang Q, Yan Q, Deng JH, Han D (2004) Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family. Am J Hum Genet 74:139–152