Generation and Bioenergetic Profiles of Cybrids with East Asian MtDNA Haplogroups

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2017 Nov 3

PMID 29093766

Citations 6

Authors

Huaibin Zhou

Ke Nie

Ruyi Qiu

Jingting Xiong

Xiaoli Shao

Bingqian Wang

Lijun Shen

Jianxin Lyu

Hezhi Fang

Affiliations

Soon will be listed here.

Abstract

Human mitochondrial DNA (mtDNA) variants and haplogroups may contribute to susceptibility to various diseases and pathological conditions, but the underlying mechanisms are not well understood. To address this issue, we established a cytoplasmic hybrid (cybrid) system to investigate the role of mtDNA haplogroups in human disease; specifically, we examined the effects of East Asian mtDNA genetic backgrounds on oxidative phosphorylation (OxPhos). We found that mtDNA single nucleotide polymorphisms such as m.489T>C, m.10398A>G, m.10400C>T, m.C16223T, and m.T16362C affected mitochondrial function at the level of mtDNA, mtRNA, or the OxPhos complex. Macrohaplogroup M exhibited higher respiratory activity than haplogroup N owing to its higher mtDNA content, mtRNA transcript levels, and complex III abundance. Additionally, haplogroup M had higher reactive oxygen species levels and NAD/NADH ratios than haplogroup N, suggesting difference in mitonuclear interactions. Notably, subhaplogroups G2, B4, and F1 appeared to contribute significantly to the differences between haplogroups M and N. Thus, our cybrid-based system can provide insight into the mechanistic basis for the role of mtDNA haplogroups in human diseases and the effect of mtDNA variants on mitochondrial OxPhos function. In addition, studies of mitonuclear interaction using this system can reveal predisposition to certain diseases conferred by variations in mtDNA.

Citing Articles

The Role of Mitonuclear Incompatibility in Bipolar Disorder Susceptibility and Resilience Against Environmental Stressors.

Gonzalez S Front Genet. 2021; 12:636294.

PMID: 33815470 PMC: 8010675. DOI: 10.3389/fgene.2021.636294.

Delineation of Mitochondrial DNA Variants From Exome Sequencing Data and Association of Haplogroups With Obesity in Kuwait.

Dashti M, Alsaleh H, Eaaswarkhanth M, John S, Nizam R, Melhem M Front Genet. 2021; 12:626260.

PMID: 33659027 PMC: 7920096. DOI: 10.3389/fgene.2021.626260.

A Mitochondrial DNA Variant Elevates the Risk of Gallstone Disease by Altering Mitochondrial Function.

Sun D, Niu Z, Zheng H, Wu F, Jiang L, Han T Cell Mol Gastroenterol Hepatol. 2020; 11(4):1211-1226.e15.

PMID: 33279689 PMC: 8053626. DOI: 10.1016/j.jcmgh.2020.11.015.

Associations of mitochondrial DNA 3777-4679 region mutations with maternally inherited essential hypertensive subjects in China.

Zhu Y, You J, Xu C, Gu X BMC Med Genet. 2020; 21(1):105.

PMID: 32414374 PMC: 7229621. DOI: 10.1186/s12881-020-01045-7.

Mitochondrial DNA Haplogroup N9a Negatively Correlates with Incidence of Hepatocellular Carcinoma in Northern China.

Hua S, Li M, Zhao Q, Wang J, Zhou Y, Liu J Mol Ther Nucleic Acids. 2019; 18:332-340.

PMID: 31629170 PMC: 6807372. DOI: 10.1016/j.omtn.2019.09.001.

References

Chae S, Ahn B, Byun K, Cho Y, Yu M, Lee B . A systems approach for decoding mitochondrial retrograde signaling pathways. Sci Signal. 2013; 6(264):rs4. DOI: 10.1126/scisignal.2003266. View

Tiao M, Liou C, Huang L, Wang P, Lin T, Chen J . Associations of mitochondrial haplogroups b4 and e with biliary atresia and differential susceptibility to hydrophobic bile Acid. PLoS Genet. 2013; 9(8):e1003696. PMC: 3744426. DOI: 10.1371/journal.pgen.1003696. View

Liou C, Chen J, Tiao M, Weng S, Huang T, Chuang J . Mitochondrial DNA coding and control region variants as genetic risk factors for type 2 diabetes. Diabetes. 2012; 61(10):2642-51. PMC: 3447893. DOI: 10.2337/db11-1369. View

Hyvarinen A, Kumanto M, Marjavaara S, Jacobs H . Effects on mitochondrial transcription of manipulating mTERF protein levels in cultured human HEK293 cells. BMC Mol Biol. 2010; 11:72. PMC: 2955023. DOI: 10.1186/1471-2199-11-72. View

Fang H, Liu X, Shen L, Li F, Liu Y, Chi H . Role of mtDNA haplogroups in the prevalence of knee osteoarthritis in a southern Chinese population. Int J Mol Sci. 2014; 15(2):2646-59. PMC: 3958873. DOI: 10.3390/ijms15022646. View

Moreno-Loshuertos R, Acin-Perez R, Fernandez-Silva P, Movilla N, Perez-Martos A, Rodriguez de Cordoba S . Differences in reactive oxygen species production explain the phenotypes associated with common mouse mitochondrial DNA variants. Nat Genet. 2006; 38(11):1261-8. DOI: 10.1038/ng1897. View

Aravamudan B, Kiel A, Freeman M, Delmotte P, Thompson M, Vassallo R . Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2014; 306(9):L840-54. PMC: 4116419. DOI: 10.1152/ajplung.00155.2013. View

Zhang X, Zuo X, Yang B, Li Z, Xue Y, Zhou Y . MicroRNA directly enhances mitochondrial translation during muscle differentiation. Cell. 2014; 158(3):607-19. PMC: 4119298. DOI: 10.1016/j.cell.2014.05.047. View

Hudson G, Gomez-Duran A, Wilson I, Chinnery P . Recent mitochondrial DNA mutations increase the risk of developing common late-onset human diseases. PLoS Genet. 2014; 10(5):e1004369. PMC: 4031051. DOI: 10.1371/journal.pgen.1004369. View

10.

Suissa S, Wang Z, Poole J, Wittkopp S, Feder J, Shutt T . Ancient mtDNA genetic variants modulate mtDNA transcription and replication. PLoS Genet. 2009; 5(5):e1000474. PMC: 2673036. DOI: 10.1371/journal.pgen.1000474. View

11.

Yu X, Koczan D, Sulonen A, Akkad D, Kroner A, Comabella M . mtDNA nt13708A variant increases the risk of multiple sclerosis. PLoS One. 2008; 3(2):e1530. PMC: 2217590. DOI: 10.1371/journal.pone.0001530. View

12.

Tanaka M, Cabrera V, Gonzalez A, Larruga J, Takeyasu T, Fuku N . Mitochondrial genome variation in eastern Asia and the peopling of Japan. Genome Res. 2004; 14(10A):1832-50. PMC: 524407. DOI: 10.1101/gr.2286304. View

13.

Kong Q, Yao Y, Sun C, Bandelt H, Zhu C, Zhang Y . Phylogeny of east Asian mitochondrial DNA lineages inferred from complete sequences. Am J Hum Genet. 2003; 73(3):671-6. PMC: 1180693. DOI: 10.1086/377718. View

14.

Sharma L, Fang H, Liu J, Vartak R, Deng J, Bai Y . Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation. Hum Mol Genet. 2011; 20(23):4605-16. PMC: 3209831. DOI: 10.1093/hmg/ddr395. View

15.

Fang H, Zhang F, Li F, Shi H, Ma L, Du M . Mitochondrial DNA haplogroups modify the risk of osteoarthritis by altering mitochondrial function and intracellular mitochondrial signals. Biochim Biophys Acta. 2015; 1862(4):829-836. DOI: 10.1016/j.bbadis.2015.12.017. View

16.

Weng S, Kuo H, Chuang J, Lin T, Huang H, Lin H . Study of insulin resistance in cybrid cells harboring diabetes-susceptible and diabetes-protective mitochondrial haplogroups. Mitochondrion. 2013; 13(6):888-97. DOI: 10.1016/j.mito.2013.08.001. View

17.

Ren W, Li X, Zhang H, Deng F, Liao W, Pang Y . Mitochondrial DNA haplogroups in a Chinese Uygur population and their potential association with longevity. Clin Exp Pharmacol Physiol. 2008; 35(12):1477-81. DOI: 10.1111/j.1440-1681.2008.05028.x. View

18.

Korkiamaki P, Kervinen M, Karjalainen K, Majamaa K, Uusimaa J, Remes A . Prevalence of the primary LHON mutations in Northern Finland associated with bilateral optic atrophy and tobacco-alcohol amblyopia. Acta Ophthalmol. 2012; 91(7):630-4. DOI: 10.1111/j.1755-3768.2012.02506.x. View

19.

Lu H, Koshkin V, Allister E, Gyulkhandanyan A, Wheeler M . Molecular and metabolic evidence for mitochondrial defects associated with beta-cell dysfunction in a mouse model of type 2 diabetes. Diabetes. 2009; 59(2):448-59. PMC: 2809957. DOI: 10.2337/db09-0129. View

20.

Niu Q, Zhang W, Wang H, Guan X, Lu J, Li W . Effects of mitochondrial haplogroup N9a on type 2 diabetes mellitus and its associated complications. Exp Ther Med. 2015; 10(5):1918-1924. PMC: 4665168. DOI: 10.3892/etm.2015.2751. View