Mitofusins: from mitochondria to fertility

Zhao, Shanjiang; Heng, Nuo; Wang, Huan; Wang, Haoyu; Zhang, Haobo; Gong, Jianfei; Hu, Zhihui; Zhu, Huabin

doi:10.1007/s00018-022-04386-z

Cited by 24 publications

(14 citation statements)

References 166 publications

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“…At the GV stage, mitochondria in the oocyte gradually accumulate in the perinuclear space to provide energy for nuclear rupture and spindle traction. Subsequently, mitochondria gradually distribute evenly throughout oocytes to maintain the basal metabolism level [ 21 , 43 , 44 ]. However, in Dguok – / – oocytes, the movement and distribution of mitochondria were aberrant; mitochondria were irregularly clustered around the nucleus and in the cytoplasm both before and after germinal vesicle breakdown ( Figure 5 D,E).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial deoxyguanosine kinase is required for female fertility in mice

Gao,

Dong,

Yan

et al. 2024

ABBS

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Mitochondrial homeostasis plays a pivotal role in oocyte maturation and embryonic development. Deoxyguanosine kinase (DGUOK) is a nucleoside kinase that salvages purine nucleosides in mitochondria and is critical for mitochondrial DNA replication and homeostasis in non-proliferating cells. Dguok loss-of-function mutations and deletions lead to hepatocerebral mitochondrial DNA deletion syndrome. However, its potential role in reproduction remains largely unknown. In this study, we find that Dguok knockout results in female infertility. Mechanistically, DGUOK deficiency hinders ovarian development and oocyte maturation. Moreover, DGUOK deficiency in oocytes causes a significant reduction in mitochondrial DNA copy number and abnormal mitochondrial dynamics and impairs germinal vesicle breakdown. Only few DGUOK-deficient oocytes can extrude their first polar body during in vitro maturation, and these oocytes exhibit irregular chromosome arrangements and different spindle lengths. In addition, DGUOK deficiency elevates reactive oxygen species levels and accelerates oocyte apoptosis. Our findings reveal novel physiological roles for the mitochondrial nucleoside salvage pathway in oocyte maturation and implicate DGUOK as a potential marker for the diagnosis of female infertility.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial deoxyguanosine kinase is required for female fertility in mice

Gao,

Dong,

Yan

et al. 2024

ABBS

View full text Add to dashboard Cite

show abstract

“…At the GV stage, mitochondria in the oocyte gradually accumulate in the perinuclear space to provide energy for nuclear rupture and spindle traction. Subsequently, mitochondria gradually distribute evenly throughout the oocytes to maintain the basal metabolism level (21, 42, 43). However, in Dguok -/- oocytes, the movement and distribution of mitochondria are abnormal: mitochondria were irregularly clustered around the nucleus and in the cytoplasm, both before and after the germinal vesicle breakdown (Fig 5D-E).…”

Section: Resultsmentioning

confidence: 99%

The mitochondrial deoxyguanosine kinase is required for female fertility in mice

Gao,

Dong,

Yan

et al. 2023

Preprint

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Mitochondrial homeostasis plays a pivotal role in oocyte maturation and embryonic development. Deoxyguanosine kinase (DGUOK) is a nucleoside kinase that salvages purine nucleoside in the mitochondria and is critical for mitochondrial DNA replication and homeostasis in non-proliferating cells.Dguokloss-of-function mutations and deletions lead to hepatocerebral mitochondrial DNA deletion syndrome. However, its potential role in reproduction remains largely unknown. We found thatDguokknockout results in female infertility. Mechanistically, the deficiency of DGUOK hinders ovarian development and oocyte maturation. Moreover,Dguokdeficiency in oocytes caused a significant reduction in mitochondrial DNA and abnormal mitochondrial dynamics, and impaired germinal vesicle breakdown. Only few DGUOK-deficient oocytes were able to extrude the first polar body duringin vitromaturation, and these oocytes showed irregular chromosome arrangement and different spindle lengths. In addition,Dguokdeficiency elevated reactive oxygen species and accelerated apoptosis in oocytes. Our findings reveal novel physiological roles for the mitochondrial nucleoside salvage pathway in oocyte maturation and implicate that DGUOK is a potential marker for the diagnosis of female infertility.

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“…Surprisingly, even though BHBA damaged mitochondria, leading to dysfunction, we found that the ATP content was increased; this may be related to increased mitochondrial fusion. We acknowledge the view that activation of the apoptotic system can uncouple the mitochondrial electron transport chain and down-regulate the level of ATP production [ 68 ]. Yet, the observed increase in ATP may be related to the properties of BHBA as an energetic substance; however, this requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 3 regulation: a target to alleviate β-hydroxybutyric acid-induced mitochondrial dysfunction in bovine granulosa cells

Zhao

Gong

Wang

et al. 2023

J Animal Sci Biotechnol

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Background During the transition period, the insufficient dry matter intake and a sharply increased in energy consumption to produce large quantities of milk, high yielding cows would enter a negative energy balance (NEB) that causes an increase in ketone bodies (KBs) and decrease in reproduction efficiency. The excess concentrations of circulating KBs, represented by β-hydroxybutyric acid (BHBA), could lead to oxidative damage, which potentially cause injury to follicular granulosa cells (fGCs) and delayed follicular development. Sirtuin 3 (Sirt3) regulates mitochondria reactive oxygen species (mitoROS) homeostasis in a beneficial manner; however, the molecular mechanisms underlying its involvement in the BHBA-induced injury of fGCs is poorly understood. The aim of this study was to explore the protection effects and underlying mechanisms of Sirt3 against BHBA overload-induced damage of fGCs. Results Our findings demonstrated that 2.4 mmol/L of BHBA stress increased the levels of mitoROS in bovine fGCs. Further investigations identified the subsequent mitochondrial dysfunction, including an increased abnormal rate of mitochondrial architecture, mitochondrial permeability transition pore (MPTP) opening, reductions in mitochondrial membrane potential (MMP) and Ca2+ release; these dysfunctions then triggered the caspase cascade reaction of apoptosis in fGCs. Notably, the overexpression of Sirt3 prior to treatment enhanced mitochondrial autophagy by increasing the expression levels of Beclin-1, thus preventing BHBA-induced mitochondrial oxidative stress and mitochondrial dysfunction in fGCs. Furthermore, our data suggested that the AMPK-mTOR-Beclin-1 pathway may be involved in the protective mechanism of Sirt3 against cellular injury triggered by BHBA stimulation. Conclusions These findings indicate that Sirt3 protects fGCs from BHBA-triggered injury by enhancing autophagy, attenuating oxidative stress and mitochondrial damage. This study provides new strategies to mitigate the fGCs injury caused by excessive BHBA stress in dairy cows with ketosis.

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Mitofusins: from mitochondria to fertility

Cited by 24 publications

References 166 publications

Mitochondrial deoxyguanosine kinase is required for female fertility in mice

Mitochondrial deoxyguanosine kinase is required for female fertility in mice

The mitochondrial deoxyguanosine kinase is required for female fertility in mice

Sirtuin 3 regulation: a target to alleviate β-hydroxybutyric acid-induced mitochondrial dysfunction in bovine granulosa cells

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