Top

Journal of Translational Medicine

Published in:

Open Access 01-12-2019 | Obesity | Research

Mitochondrial DNA methylation and copy number predict body composition in a young female population

Authors: Laura Bordoni, Vanessa Smerilli, Cinzia Nasuti, Rosita Gabbianelli

Published in: Journal of Translational Medicine | Issue 1/2019

Abstract

Background

Since both genomic and environmental factors are involved in obesity etiology, several studies about the influence of adiposity on both nuclear DNA and mitochondrial DNA methylation patterns have been carried out. Nevertheless, few evidences exploring the usage of buccal swab samples to study mitochondrial DNA epigenetics can be found in literature.

Methods

In this study, mitochondrial DNA from buccal swabs collected from a young Caucasian population (n = 69) have been used to examine potential correlation between mitochondrial DNA copy number and methylation with body composition (BMI, WHtR and bioimpedance measurements).

Results

A negative correlation between mitochondrial DNA copy number and BMI was measured in females (p = 0.028), but not in males. The mean percentage of D-loop methylation is significantly higher in overweight than in lean female subjects (p = 0.003), and a specific CpG located in the D-loop shows per se an association with impaired body composition (p = 0.004). Body composition impairment is predicted by a combined variable including mtDNA copy number and the D-loop methylation (AUC = 0.785; p = 0.009).

Conclusions

This study corroborates the hypothesis that mitochondrial DNA carries relevant information about body composition. However, wider investigations able to validate the usage of mtDNA methylation from buccal swabs as a biomarker are warranted.

Wormser D, Kaptoge S, Di Angelantonio E, Wood AM, Pennells L, Thompson A, et al. Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. Lancet (London, England). 2011;377:1085–95.CrossRef

Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet (London, England). 2008;371:569–78.CrossRef

Cunningham SA, Kramer MR, Narayan KMV. Incidence of childhood obesity in the United States. N Engl J Med. 2014;370:403–11.PubMedPubMedCentralCrossRef

Rivera JA, de Cossio TG, Pedraza LS, Aburto TC, Sanchez TG, Martorell R. Childhood and adolescent overweight and obesity in Latin America: a systematic review. Lancet Diabetes Endocrinol. 2014;2:321–32.PubMedCrossRef

Lakshman R, Elks CE, Ong KK. Childhood obesity. Circulation. 2012;126:1770–9.PubMedPubMedCentralCrossRef

Mazidi M, Banach M, Kengne AP. Prevalence of childhood and adolescent overweight and obesity in Asian countries: a systematic review and meta-analysis. Arch Med Sci. 2018;14:1185–203.PubMedPubMedCentralCrossRef

Mistry SK, Puthussery S. Risk factors of overweight and obesity in childhood and adolescence in South Asian countries: a systematic review of the evidence. Public Health. 2015;129:200–9.PubMedCrossRef

Rzehak P, Covic M, Saffery R, Reischl E, Wahl S, Grote V, et al. DNA-methylation and body composition in preschool children: epigenome-wide-analysis in the European Childhood Obesity Project (CHOP)-Study. Sci Rep. 2017;7:14349.PubMedPubMedCentralCrossRef

Bordoni L, Gabbianelli R. Primers on nutrigenetics and nutri(epi)genomics: origins and development of precision nutrition. Biochimie. 2019;160:156–71.PubMedCrossRef

10.

He F, Berg A, Imamura Kawasawa Y, Bixler EO, Fernandez-Mendoza J, Whitsel EA, et al. Association between DNA methylation in obesity-related genes and body mass index percentile in adolescents. Sci Rep. 2019;9:2079.PubMedPubMedCentralCrossRef

11.

Goyal D, Limesand SW, Goyal R. Epigenetic responses and the developmental origins of health and disease. J Endocrinol. 2019;242:T105–19.PubMedCrossRef

12.

Martin EM, Fry RC. Environmental influences on the epigenome: exposure-associated DNA methylation in human populations. Annu Rev Public Health. 2018;39:309–33. https://doi.org/10.1146/annurev-publhealth-040617-014629.CrossRefPubMed

13.

Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature. 2016;541:81. https://doi.org/10.1038/nature20784.CrossRefPubMedPubMedCentral

14.

Crujeiras AB, Diaz-Lagares A. Chapter 16—DNA methylation in obesity and associated diseases. Boston: Academic Press; 2016. p. 313–29.

15.

Sayols-Baixeras S, Subirana I, Fernández-Sanlés A, Sentí M, Lluís-Ganella C, Marrugat J, et al. DNA methylation and obesity traits: an epigenome-wide association study. The REGICOR study. Epigenetics. 2017;12:909–16.PubMedPubMedCentralCrossRef

16.

Arner P, Sinha I, Thorell A, Ryden M, Dahlman-Wright K, Dahlman I. The epigenetic signature of subcutaneous fat cells is linked to altered expression of genes implicated in lipid metabolism in obese women. Clin Epigenetics. 2015;7:93.PubMedPubMedCentralCrossRef

17.

Eipel M, Mayer F, Arent T, Ferreira MRP, Birkhofer C, Gerstenmaier U, et al. Epigenetic age predictions based on buccal swabs are more precise in combination with cell type-specific DNA methylation signatures. Aging (Albany NY). 2016;8:1034–48.PubMedPubMedCentralCrossRef

18.

Nishitani S, Parets SE, Haas BW, Smith AK. DNA methylation analysis from saliva samples for epidemiological studies. Epigenetics. 2018;13:352–62.PubMedPubMedCentralCrossRef

19.

Castegna A, Iacobazzi V, Infantino V. The mitochondrial side of epigenetics. Physiol Genomics. 2015;47:299–307.PubMedCrossRef

20.

Iacobazzi V, Castegna A, Infantino V, Andria G. Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool. Mol Genet Metab. 2013;110:25–34.PubMedCrossRef

21.

Sharma N, Pasala MS, Prakash A. Mitochondrial DNA: epigenetics and environment. Environ Mol Mutagen. 2019;60(8):668–82.PubMedCrossRefPubMedCentral

22.

Coppedè F, Stoccoro A. Mitoepigenetics and Neurodegenerative Diseases. Front Endocrinol (Lausanne). 2019;10:86.PubMedPubMedCentralCrossRef

23.

Ashar FN, Zhang Y, Longchamps RJ, Lane J, Moes A, Grove ML, et al. Association of mitochondrial DNA copy number with cardiovascular disease. JAMA Cardiol. 2017;2:1247–55.PubMedPubMedCentralCrossRef

24.

Hosgood HD 3rd, Liu C-S, Rothman N, Weinstein SJ, Bonner MR, Shen M, et al. Mitochondrial DNA copy number and lung cancer risk in a prospective cohort study. Carcinogenesis. 2010;31:847–9.PubMedPubMedCentralCrossRef

25.

Zheng LD, Linarelli LE, Liu L, Wall SS, Greenawald MH, Seidel RW, et al. Insulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humans. Clin Epigenetics. 2015;7:60.PubMedPubMedCentralCrossRef

26.

Al-Kafaji G, Aljadaan A, Kamal A, Bakhiet M. Peripheral blood mitochondrial DNA copy number as a novel potential biomarker for diabetic nephropathy in type 2 diabetes patients. Exp Ther Med. 2018;16:1483–92.PubMedPubMedCentral

27.

Skuratovskaia DA, Sofronova JK, Zatolokin PA, Popadin KY, Vasilenko MA, Litvinova LS, et al. Additional evidence of the link between mtDNA copy number and the body mass index. Mitochondrial DNA A. 2018;29:1240–4.CrossRef

28.

Lee J-W, Park KD, Im J-A, Kim MY, Lee D-C. Mitochondrial DNA copy number in peripheral blood is associated with cognitive function in apparently healthy elderly women. Clin Chim Acta. 2010;411:592–6.PubMedCrossRef

29.

Lee HK, Song JH, Shin CS, Park DJ, Park KS, Lee KU, et al. Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract. 1998;42:161–7.PubMedCrossRef

30.

Lee J-Y, Lee D-C, Im J-A, Lee J-W. Mitochondrial DNA copy number in peripheral blood is independently associated with visceral fat accumulation in healthy young adults. Int J Endocrinol. 2014;2014:586017.PubMedPubMedCentral

31.

Kristensen TN, Loeschcke V, Tan Q, Pertoldi C, Mengel-From J. Sex and age specific reduction in stress resistance and mitochondrial DNA copy number in Drosophila melanogaster. Sci Rep. 2019;9:12305. https://doi.org/10.1038/s41598-019-48752-7.CrossRefPubMedPubMedCentral

32.

Skuratovskaia D, Litvinova L, Vulf M, Zatolokin P, Popadin K, Mazunin I. From normal to obesity and back: the associations between mitochondrial DNA copy number, gender, and body mass index. Cells. 2019;8:430.PubMedCentralCrossRef

33.

Shoar Z, Goldenthal MJ, De Luca F, Suarez E. Mitochondrial DNA content and function, childhood obesity, and insulin resistance. Endocr Res. 2016;41:49–56.PubMedCrossRef

34.

Langie SAS, Moisse M, Declerck K, Koppen G, Godderis L, Vanden Berghe W, et al. Salivary DNA methylation profiling: aspects to consider for biomarker identification. Basic Clin Pharmacol Toxicol. 2017;121(Suppl):93–101.PubMedPubMedCentralCrossRef

35.

Thaler R, Karlic H, Rust P, Haslberger AG. Epigenetic regulation of human buccal mucosa mitochondrial superoxide dismutase gene expression by diet. Br J Nutr. 2009;101:743–9.PubMedCrossRef

36.

van Dongen J, Ehli EA, Jansen R, van Beijsterveldt CEM, Willemsen G, Hottenga JJ, et al. Genome-wide analysis of DNA methylation in buccal cells: a study of monozygotic twins and mQTLs. Epigenetics Chromatin. 2018;11:54.PubMedPubMedCentralCrossRef

37.

Bordoni L, Marchegiani F, Piangerelli M, Napolioni V, Gabbianelli R. Obesity-related genetic polymorphisms and adiposity indices in a young Italian population. IUBMB Life. 2017;69:98–105.PubMedCrossRef

38.

Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000;320:1240–3.PubMedPubMedCentralCrossRef

39.

Bordoni L, Napolioni V, Marchegiani F, Amadio E, Gabbianelli R. Angiotensin-converting enzyme ins/del polymorphism and body composition: the intermediary role of hydration status. Lifestyle Genomics. 2017;10(1–2):1–8.

40.

Oliveira CMC, Kubrusly M, Mota RS, Silva CAB, Choukroun G, Oliveira VN. The phase angle and mass body cell as markers of nutritional status in hemodialysis patients. J Ren Nutr. 2010;20:314–20.PubMedCrossRef

41.

Brantlov S, Jodal L, Andersen RF, Lange A, Rittig S, Ward LC. An evaluation of phase angle, bioelectrical impedance vector analysis and impedance ratio for the assessment of disease status in children with nephrotic syndrome. BMC Nephrol. 2019;20:331.PubMedPubMedCentralCrossRef

42.

Mattiello R, Amaral MA, Mundstock E, Ziegelmann PK. Reference values for the phase angle of the electrical bioimpedance: Systematic review and meta-analysis involving more than 250,000 subjects. Clin Nutr. 2019. https://doi.org/10.1016/j.clnu.2019.07.004.CrossRefPubMed

43.

Genton L, Norman K, Spoerri A, Pichard C, Karsegard VL, Herrmann FR, et al. Bioimpedance-derived phase angle and mortality among older people. Rejuvenation Res. 2017;20:118–24.PubMedCrossRef

44.

Jayaprakash AD, Benson EK, Gone S, Liang R, Shim J, Lambertini L, et al. Stable heteroplasmy at the single-cell level is facilitated by intercellular exchange of mtDNA. Nucleic Acids Res. 2015;43:2177–87.PubMedPubMedCentralCrossRef

45.

Rooney JP, Ryde IT, Sanders LH, Howlett EH, Colton MD, Germ KE, et al. PCR based determination of mitochondrial DNA copy number in multiple species. Methods Mol Biol. 2015;1241:23–38.PubMedPubMedCentralCrossRef

46.

Tsuji J, Frith MC, Tomii K, Horton P. Mammalian NUMT insertion is non-random. Nucleic Acids Res. 2012;40:9073–88.PubMedPubMedCentralCrossRef

47.

Liu B, Du Q, Chen L, Fu G, Li S, Fu L, et al. CpG methylation patterns of human mitochondrial DNA. Sci Rep. 2016;6:23421.PubMedPubMedCentralCrossRef

48.

Bosy-Westphal A, Danielzik S, Dorhofer R-P, Later W, Wiese S, Muller MJ. Phase angle from bioelectrical impedance analysis: population reference values by age, sex, and body mass index. J Parenter Enteral Nutr. 2006;30:309–16.CrossRef

49.

Russell O, Turnbull D. Mitochondrial DNA disease-molecular insights and potential routes to a cure. Exp Cell Res. 2014;325:38–43.PubMedPubMedCentralCrossRef

50.

Yue P, Jing S, Liu L, Ma F, Zhang Y, Wang C, et al. Association between mitochondrial DNA copy number and cardiovascular disease: current evidence based on a systematic review and meta-analysis. PLoS ONE. 2018;13:e0206003.PubMedPubMedCentralCrossRef

51.

Yorns WRJ, Valencia I, Jayaraman A, Sheth S, Legido A, Goldenthal MJ. Buccal swab analysis of mitochondrial enzyme deficiency and DNA defects in a child with suspected myoclonic epilepsy and ragged red fibers (MERRF). J Child Neurol. 2012;27:398–401.PubMedCrossRef

52.

Skuratovskaia D, Zatolokin P, Vulf M, Mazunin I, Litvinova L. Interrelation of chemerin and TNF-α with mtDNA copy number in adipose tissues and blood cells in obese patients with and without type 2 diabetes. BMC Med Genomics. 2019;12:40. https://doi.org/10.1186/s12920-019-0485-8.CrossRefPubMedPubMedCentral

53.

Mengel-From J, Thinggaard M, Dalgård C, Kyvik KO, Christensen K, Christiansen L. Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly. Hum Genet. 2014;133:1149–59.PubMedPubMedCentralCrossRef

54.

Meng S, Wu S, Liang L, Liang G, Giovannucci E, De Vivo I, et al. Leukocyte mitochondrial DNA copy number, anthropometric indices, and weight change in US women. Oncotarget. 2016;7:60676–86.PubMedPubMedCentral

55.

Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA. 2005;102:5618–23.PubMedCrossRefPubMedCentral

56.

Liu C-S, Tsai C-S, Kuo C-L, Chen H-W, Lii C-K, Ma Y-S, et al. Oxidative stress-related alteration of the copy number of mitochondrial DNA in human leukocytes. Free Radic Res. 2003;37:1307–17.PubMedCrossRef

57.

Shin J, Kim KC, Lee DC, Lee HR, Shim JY. Association between salivary mitochondrial DNA copy number and chronic fatigue according to combined symptoms in Korean adults. Korean J Fam Med. 2017;38:206–12.PubMedPubMedCentralCrossRef

58.

Saenen ND, Provost EB, Cuypers A, Kicinski M, Pieters N, Plusquin M, et al. Child’s buccal cell mitochondrial DNA content modifies the association between heart rate variability and recent air pollution exposure at school. Environ Int. 2019;123:39–49.PubMedPubMedCentralCrossRef

59.

Murphy SK, Huang Z, Hoyo C. Differentially methylated regions of imprinted genes in prenatal, perinatal and postnatal human tissues. PLoS ONE. 2012;7:e40924.PubMedPubMedCentralCrossRef

60.

Fradin D, Boëlle P-Y, Belot M-P, Lachaux F, Tost J, Besse C, et al. Genome-wide methylation analysis identifies specific epigenetic marks in severely obese children. Sci Rep. 2017;7:46311.PubMedPubMedCentralCrossRef

61.

Rounge TB, Page CM, Lepisto M, Ellonen P, Andreassen BK, Weiderpass E. Genome-wide DNA methylation in saliva and body size of adolescent girls. Epigenomics. 2016;8:1495–505.PubMedCrossRef

62.

Smith AK, Kilaru V, Klengel T, Mercer KB, Bradley B, Conneely KN, et al. DNA extracted from saliva for methylation studies of psychiatric traits: evidence tissue specificity and relatedness to brain. Am J Med Genet B Neuropsychiatr Genet. 2015;168B:36–44.PubMedCrossRef

63.

Talens RP, Boomsma DI, Tobi EW, Kremer D, Jukema JW, Willemsen G, et al. Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J Off Publ Fed Am Soc Exp Biol. 2010;24:3135–44.

64.

Alves Junior CA, Mocellin MC, Goncalves ECA, Silva DA, Trindade EB. Anthropometric indicators as body fat discriminators in children and adolescents: a systematic review and meta-analysis. Adv Nutr. 2017;8:718–27.PubMedPubMedCentralCrossRef

65.

Fujita Y, Kouda K, Nakamura H, Iki M. Cut-off values of body mass index, waist circumference, and waist-to-height ratio to identify excess abdominal fat: population-based screening of Japanese school children. J Epidemiol. 2011;21:191–6.PubMedPubMedCentralCrossRef

66.

de Castro JA, Lima TR, Silva DAS. Body composition estimation in children and adolescents by bioelectrical impedance analysis: a systematic review. J Bodyw Mov Ther. 2018;22:134–46.CrossRef

67.

Silleras B, Marcos S, Alonso-Izquierdo L, Camina-Martín MA, Miguelsanz JM, Río MP. Bioelectrical impedance vector analysis in obese and overweight children. PLoS ONE. 2019;14:e0211148. https://doi.org/10.1371/journal.pone.0211148.CrossRef

68.

Meleleo D, Bartolomeo N, Cassano L, Nitti A, Susca G, Mastrototaro G, et al. Evaluation of body composition with bioimpedence A comparison between athletic and non-athletic children. Eur J Sport Sci. 2017;17:710–9.PubMedCrossRef

69.

Zheng LD, Brooke J, Smith C, Almeida FA, Cheng Z. Mitochondrial epigenetic changes and progression from metabolically healthy obesity to metabolically unhealthy obesity: a cross-sectional study. Lancet Diabetes Endocrinol. 2016;4:S16. https://doi.org/10.1016/S2213-8587(16)30371-0.CrossRef

Title: Mitochondrial DNA methylation and copy number predict body composition in a young female population
Authors: Laura Bordoni
Vanessa Smerilli
Cinzia Nasuti
Rosita Gabbianelli
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Obesity
Obesity
Overweight
Epigenetics
Published in: Journal of Translational Medicine / Issue 1/2019
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-019-02150-9

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2019

Evaluation of endoscopic visible light spectroscopy: comparison with microvascular oxygen tension measurements in a porcine model

An innovative total temporomandibular joint prosthesis with customized design and 3D printing additive fabrication: a prospective clinical study

Annexin A8 can serve as potential prognostic biomarker and therapeutic target for ovarian cancer: based on the comprehensive analysis of Annexins

Diabetogenic effect of pravastatin is associated with insulin resistance and myotoxicity in hypercholesterolemic mice

Plasma concentration and expression of adipokines in epicardial and subcutaneous adipose tissue are associated with impaired left ventricular filling pattern

Cartilage progenitor cells combined with PHBV in cartilage tissue engineering

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage