Oxidative stress and ATPase6 mutation is associated with primary ovarian insufficiency

被引:71
作者
Venkatesh, S. [1 ]
Kumar, M. [1 ]
Sharma, A. [1 ]
Kriplani, A. [2 ]
Ammini, A. C. [3 ]
Talwar, P. [4 ]
Agarwal, A. [5 ]
Dada, Rima [1 ]
机构
[1] All India Inst Med Sci, Dept Anat, Lab Mol Reprod & Genet, New Delhi 110029, India
[2] All India Inst Med Sci, Dept Obstet & Gynaecol, New Delhi 110029, India
[3] All India Inst Med Sci, Dept Endocrinol, New Delhi 110029, India
[4] Army Res & Referral Hosp, ART Ctr, New Delhi, India
[5] Cleveland Clin, Ctr Reprod Med, Glickman Urol & Kidney Inst, Obstet & Gynecol & Womens Hlth Inst, Cleveland, OH 44106 USA
关键词
Premature ovarian failure (POF); Reactive oxygen species (ROS); mtDNA mutation; Oxidative stress; ATPase6; Primary ovarian insufficiency (POI); MITOCHONDRIAL-DNA; SUPEROXIDE-DISMUTASE; QUALITY; SEMEN;
D O I
10.1007/s00404-010-1444-y
中图分类号
R71 [妇产科学];
学科分类号
100211 ;
摘要
Primary ovarian insufficiency (POI) is a heterogeneous, multifactorial disorder. Though genetic anomalies, infections, autoimmune disorder and hormonal imbalance are few of the causes of POI, in the majority of patients (50-60%) no etiology has been identified. Mitochondrial bioenergetics and biogenesis play an important role in oocyte and embryo development, whereas mtDNA integrity and content are essential for the normal development of oocytes. ATPase6 helps to maintain the mt genome integrity, and mutations in ATPase6 are associated with overproduction of reactive oxygen species (ROS) in a variety of diseases; however, its role in POI has not been evaluated. Therefore, we planned to evaluate the potential role of ATPase6 gene mutations and associated oxidative stress in idiopathic cases of POI. This pilot study included: 20 cases of POI with FSH level of > 40 mIU/ml; 4 cases of occult ovarian insufficiency (occult OI) with irregular menses and mean FSH levels of 16.4 mIU/ml; and 20 age-matched healthy female controls (FSH 2-5 mIU/ml). ROS levels in blood plasma were measured by luminol-dependent chemiluminescence assay and the ROS values were expressed as relative light unit per minute (RLU/min). mtDNA ATPase6 gene was amplified and sequenced from the blood lymphocyte DNA. Of all, 50% patients showed nucleotide changes in the ATPase6 gene, as compared to 10% in controls, and the majority of these mutations were non-synonymous. ATPase6 mt.8684 C > T and mt.9094 C > T were found to be significantly (P < 0.005) higher in cases as compared to controls. ROS levels were found to be significantly (P < 0.005) higher in POI and occult OI patients compared to controls and nucleotide changes were found to positively correlate with ROS levels. Moreover, ROS production was found to positively correlate (r = 0.7038, P < 0.001) with FSH levels of the patients (POI and OI) compared to controls. This pilot study clearly demonstrates for the first time ATPase6 gene nucleotide alterations and elevated ROS levels in idiopathic cases of POI. Therefore, it may be possible that OS associated with ATPase6 gene mutation may be causal in idiopathic cases of premature OI. However, larger studies with inclusion of more cases of both POI and occult OI are required to strongly establish the correlation between oxidative stress and mitochondrial nucleotide alterations in the pathogenesis of POI. Such cases with OS-induced POI may benefit immensely by early diagnosis and prompt antioxidant administration.
引用
收藏
页码:313 / 318
页数:6
相关论文
共 24 条
[1]   Oxidative stress and its implications in female infertility - a clinician's perspective [J].
Agarwal, A ;
Gupta, S ;
Sharma, R .
REPRODUCTIVE BIOMEDICINE ONLINE, 2005, 11 (05) :641-650
[2]   Biochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993 [J].
Baracca, Alessandra ;
Sgarbi, Gianluca ;
Mattiazzi, Marina ;
Casalena, Gabriella ;
Pagnotta, Eleonora ;
Valentino, Maria L. ;
Moggio, Maurizio ;
Lenaz, Giorgio ;
Carelli, Valerio ;
Solaini, Giancarlo .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 2007, 1767 (07) :913-919
[3]   Oxidative stress and the ovary [J].
Behrman, HR ;
Kodaman, PH ;
Preston, SL ;
Gao, SP .
JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION, 2001, 8 (01) :S40-S42
[4]   The antioxidant role of coenzyme Q [J].
Bentinger, Magnus ;
Brismar, Kerstin ;
Dallner, Gustav .
MITOCHONDRION, 2007, 7 :S41-S50
[5]   The use of mitochondrial nutrients to improve the outcome of infertility treatment in older patients [J].
Bentov, Yaakov ;
Esfandiari, Navid ;
Burstein, Eliezer ;
Casper, Robert F. .
FERTILITY AND STERILITY, 2010, 93 (01) :272-275
[6]  
DADA R, 1997, CYTOGENET CELL GENET, V177, P78
[7]   Genetically modified mouse models for premature ovarian failure (POF) [J].
Jagarlamudi, Krishna ;
Reddy, Pradeep ;
Adhikari, Deepak ;
Liu, Kui .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2010, 315 (1-2) :1-10
[8]  
KIM JH, 2004, KOREAN J OBSTET GYNE, V47, P16
[9]  
Kumar R, 2009, INDIAN J BIOCHEM BIO, V46, P172
[10]   Levels of lipid perioxides and superoxide dismutase in peritoneal fluid of patients with endometriosis [J].
Liu, Yi ;
Luo, Lilan ;
Zhao, Haibo .
CURRENT MEDICAL SCIENCE, 2001, 21 (02) :166-167