Mitochondrial Dysfunction in Primary Ovarian Insufficiency

Author:

Tiosano Dov12,Mears Jason A34,Buchner David A567ORCID

Affiliation:

1. Division of Pediatric Endocrinology, Ruth Rappaport Children’s Hospital, Rambam Medical Center, Haifa, Israel

2. Rappaport Family Faculty of Medicine, Technion—Israel Institute of Technology, Haifa, Israel

3. Center for Mitochondrial Diseases, Case Western Reserve University, Cleveland, Ohio

4. Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio

5. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio

6. Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio

7. Research Institute for Children’s Health, Case Western Reserve University, Cleveland, Ohio

Abstract

Abstract Primary ovarian insufficiency (POI) is defined by the loss or dysfunction of ovarian follicles associated with amenorrhea before the age of 40. Symptoms include hot flashes, sleep disturbances, and depression, as well as reduced fertility and increased long-term risk of cardiovascular disease. POI occurs in ∼1% to 2% of women, although the etiology of most cases remains unexplained. Approximately 10% to 20% of POI cases are due to mutations in a single gene or a chromosomal abnormality, which has provided considerable molecular insight into the biological underpinnings of POI. Many of the genes for which mutations have been associated with POI, either isolated or syndromic cases, function within mitochondria, including MRPS22, POLG, TWNK, LARS2, HARS2, AARS2, CLPP, and LRPPRC. Collectively, these genes play roles in mitochondrial DNA replication, gene expression, and protein synthesis and degradation. Although mutations in these genes clearly implicate mitochondrial dysfunction in rare cases of POI, data are scant as to whether these genes in particular, and mitochondrial dysfunction in general, contribute to most POI cases that lack a known etiology. Further studies are needed to better elucidate the contribution of mitochondria to POI and determine whether there is a common molecular defect in mitochondrial function that distinguishes mitochondria-related genes that when mutated cause POI vs those that do not. Nonetheless, the clear implication of mitochondrial dysfunction in POI suggests that manipulation of mitochondrial function represents an important therapeutic target for the treatment or prevention of POI.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

The Endocrine Society

Subject

Endocrinology

Reference146 articles.

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