Lee 2017 MiP2017
Metabolic syndrome (MetS) was created cluster state of risk factors for atherosclerosis, abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides and low HDL levels. Resistance to insulin action is basic common biochemical abnormality of components comprising MetS. While MetS or its component diseases are regarded as complex ‘genetic’ diseases, few (nuclear) genes causing MetS were found, while common mitochondrial DNA (mtDNA) polymorphisms were associated with type 2 diabetes and MetS.
Functional differences between mtDNA polymorphisms are well established by generation of conplastic animals, which have same nuclear genome but different mitochondrial genomes. Animals selected for low aerobic capacity scored high on cardiovascular risk factors that constitute the metabolic syndrome, suggesting mitochondrial function is closely associated with it. However reports examining the functional difference of mitochondrial genome at the cellular level are scarce. We made trans-mitochondrial cytoplasmic hybrid cells (cybrids) with common Asian mtDNA haplogroups A, B, D, and F from young healthy volunteers and analyzed their bioenergetics function and growth behaviors in vitro and in vivo. The mitochondrial oxygen consumption rates of cybrids were associated with quantitative parameters of components of metabolic syndrome such as body mass index, waist circumference, serum triglyceride levels and high-density lipoprotein cholesterol levels of donors. In addition, the cybrids showed different growth patterns both in vitro and in vivo, rate of which was statistically different. Especially, the cybrids harboring mtDNA haplogroup D had a significantly slower growth rate. These findings suggest that mitochondrial genome could be important determinant of common complex diseases.
During the last decade, endocrine disrupting chemicals emerged as important factor for MetS as well as type 2 diabetes. With a novel cell based assays we found serum levels of mitochondria inhibitor activity and arylhydrocarbon receptor transactivation activity, which correlated each other, are elevated in MetS and predict future development of type 2 diabetes. These findings suggest the exposure to dioxin-like chemicals could impair mitochondrial function and induce insulin resistance, thus MetS.
In summary, these evidences support a concept that MetS is dys-mitochondrial syndrome caused by environmental polluting chemicals and mtDNA is it’s susceptibility genome.
Labels: MiParea: mtDNA;mt-genetics
- Lee HK(1), Cho YM(2), Park KS(2), Pak YK(3), Tanaka M(4)
- Dept Int Med, Univ Eulji
- Seoul Nat Univ
- Dept Physiol, Kyung Hee Univ, Korea
- Dept Clin Lab, Tokyo Metro Geront Hosp, Japan. - [email protected]
- Wisløff U, Najjar SM, Ellingsen O, Haram PM, Swoap S, Al-Share Q, Fernström M, Rezaei K, Lee SJ, Koch LG, Britton SL (2005) Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science. 307:418-20.
- Latorre-Pellicer A, Moreno-Loshuertos R, Lechuga-Vieco AV, Sánchez-Cabo F, Torroja C, Acín-Pérez R, Calvo E, Aix E, González-Guerra A, Logan A, Bernad-Miana ML, Romanos E, Cruz R, Cogliati S, Sobrino B, Carracedo Á, Pérez-Martos A, Fernández-Silva P, Ruíz-Cabello J, Murphy MP, Flores I, Vázquez J, Enríquez JA (2016) Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature. 535:561–65.
- Fuku N, Park KS, Yamada Y, Nishigaki Y, Cho YM, Matsuo H, Segawa T, Watanabe S, Kato K, Yokoi K, Nozawa Y, Lee HK, Tanaka M (2007) Mitochondrial haplogroup N9a confers resistance against type 2 diabetes in Asians. Am J Hum Genet 80:407-15.
- Hwang S, Kwak SH, Bhak J, Kang HS, Lee YR, Koo BK, Park KS, Lee HK, Cho YM (2011) Gene expression pattern in transmitochondrial cytoplasmic hybrid cells harboring type 2 diabetes-associated mitochondrial DNA haplogroups. PLoS One 6:e22116.
- Wallace DC (2015) Mitochondrial DNA variation in human radiation and disease. Cell 163:33-8.
- Taylor KW, Novak RF, Anderson HA, Birnbaum LS, Blystone C, Devito M, Jacobs D, Köhrle J, Lee DH, Rylander L, Rignell-Hydbom A, Tornero-Velez R, Turyk ME, Boyles AL, Thayer KA, Lind L (2013) Evaluation of the association between persistent organic pollutants (POPs) and diabetes in epidemiological studies: a national toxicology program workshop review. Environ Health Perspect. 121:774-83.
- Park WH, Jun DW, Kim JT, Jeong JH, Park H, Chang YS, Park KS, Lee HK, Pak YK (2013) Novel cell-based assay reveals associations of circulating serum AhR-ligands with metabolic syndrome and mitochondrial dysfunction. Biofactors. 39:494-504.