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Mitochondrial epigenetic modifications and nuclear-mitochondrial communication: A new dimension towards understanding and attenuating the pathogenesis in women with PCOS

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Abstract

Mitochondrial DNA (mtDNA) epigenetic modifications have recently gained attention in a plethora of complex diseases, including polycystic ovary syndrome (PCOS), a common cause of infertility in women of reproductive age. Herein we discussed mtDNA epigenetic modifications and their impact on nuclear-mitochondrial interactions in general and the latest advances indicating the role of mtDNA methylation in the pathophysiology of PCOS. We highlighted epigenetic changes in nuclear-related mitochondrial genes, including nuclear transcription factors that regulate mitochondrial function and may be involved in the development of PCOS or its related traits. Additionally, therapies targeting mitochondrial epigenetics, including time-restricted eating (TRE), which has been shown to have beneficial effects by improving mitochondrial function and may be mediated by epigenetic modifications, have also been discussed. As PCOS has become a major metabolic disorder and a risk factor for obesity, cardiometabolic disorders, and diabetes, lifestyle/behavior intervention using TRE that reinforces feeding-fasting rhythms without reducing caloric intake may be a promising therapeutic strategy for attenuating the pathogenesis. Furthermore, future perspectives in the area of mitochondrial epigenetics are described.

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Abbreviations

5-hmC:

5 Hydroxymethylcytosine

5-mC:

5-methylcytosine

5-MTHF:

5-methyl tetrahydrofolate

αKG:

Alpha-ketoglutarate

AMP:

Adenosine Monophosphate

AMPK:

AMP-activated protein kinase

ATP:

Adenosine Triphosphate

BHMT:

Betaine homocysteine methyltransferase

D-loop:

Displacement loop

DNMT:

DNA methyltransferase

DNMT1:

DNA methyltransferase 1

DNMT3:

DNA methyltransferase 3

D NMT3A:

DNA methyltransferase 3 alpha

DNMT3B:

DNA methyltransferase 3 Beta

DNMT3L:

DNA methyltransferase 3 Like

ETC:

Electron transport chain

GNMT:

Glycine N-methyltransferase

Hcy:

Homocysteine

IVF:

In-vitro fertilization

MBE:

Mitochondrial bifunctional enzyme

Met:

Methionine

miRNA:

micro-RNAs

MS:

Methionine synthase

mtDNA:

Mitochondrial DNA

mTERFs:

Mitochondrial transcription termination factors

MTHF:

Methyl tetrahydrofolate

MTS:

Mitochondrial targeting sequence

nDNA:

Nuclear DNA

ncRNA:

non-coding RNAs

NRF-1:

Nuclear respiratory factor 1

NRF-2:

Nuclear respiratory factor 2

OXPHOS:

Oxidative Phosphorylation

PCOS:

Polycystic ovary syndrome

PGC-1α:

Peroxisome proliferator-activated receptor-gamma coactivator

PGT-A:

Preimplantation genetic testing for aneuploidies

POLRMT:

Mitochondrial RNA polymerase

PPAR:

Peroxisome proliferator-activated receptors

PPARG:

Peroxisome Proliferator-Activated Receptor Gamma

PPARGC1A:

Peroxisome Proliferator-activated Receptor Gamma Coactivator-1 Alpha

PPARGC1B:

Peroxisome Proliferator-activated Receptor Gamma Coactivator-1 Beta

PPARD:

Peroxisome Proliferator-Activated Receptor Delta

ROS:

Reactive Oxygen Species

rRNA:

Ribosomal ribonucleic acid

SAM:

S-adenosylmethionine

SAMC:

SAM carrier

SIRTs:

Sirtuins

TCA:

Tricarboxylic acid cycle

TET:

Ten-eleven translocation

TFAM:

Mitochondrial transcription Factor A

TFB2M:

Mitochondrial transcription Factor B2

THF:

Tetrahydrofolate

TRE:

Time-restricted eating

tRNA:

Transfer ribonucleic acid

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Acknowledgements

The authors acknowledge the necessary support provided by the Indian Council of Medical Research-National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH) (Rev/1297/08-2022).

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Authors and Affiliations

  1. Department of Molecular Endocrinology, Indian Council of Medical Research-National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), J.M. Street, Parel, Mumbai, 400012, India

    Pallavi Shukla

  2. Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, United States

    Girish C. Melkani

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  1. Pallavi Shukla
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Correspondence to Pallavi Shukla.

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Shukla, P., Melkani, G.C. Mitochondrial epigenetic modifications and nuclear-mitochondrial communication: A new dimension towards understanding and attenuating the pathogenesis in women with PCOS. Rev Endocr Metab Disord 24, 317–326 (2023). https://doi.org/10.1007/s11154-023-09789-2

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