Mitochondrial Calcium uniporters are essential for meiotic progression in mouse oocytes by controlling Ca²⁺ entry

Abstract

Objectives The alteration of bioenergetics by oocytes in response to the demands of various biological processes plays a critical role in maintaining normal cellular physiology. However, little is known about the association between energy sensing and energy production with energy‐dependent cellular processes like meiosis. Materials and methods We demonstrated that cell cycle‐dependent mitochondrial Ca2+ connects energy sensing to mitochondrial activity in meiosis progression within mouse oocytes. Further, we established a model in mouse oocytes using siRNA knockdowns that target mitochondrial calcium uniporters (MCUs) in order to inhibit mitochondrial Ca2+ concentrations. Results Decreased numbers of oocytes successfully progressed to the germinal vesicle stage and extruded the first polar body during in vitro culture after inhibition, while spindle checkpoint‐dependent meiosis was also delayed. Mitochondrial Ca2+ levels changed, and this was followed by altered mitochondrial masses and ATP levels within oocytes during the entirety of meiosis progression. Abnormal mitochondrial Ca2+ concentrations in oocytes then hindered meiotic progress and activated AMP‐activated protein kinase (AMPK) signalling that is associated with gene expression. Conclusions These data provide new insight into the protective role that MCU‐dependent mitochondrial Ca2+ signalling plays in meiotic progress, in addition to demonstrating a new mechanism of mitochondrial energy regulation by AMPK signalling that influences meiotic maturation.

Mitochondrial Calcium Disorder Affects Early Embryonic Development in Mice through Regulating the ERK/MAPK Pathway

“…Obese, diabetic, and aging women having lower rate of oocyte activation, altered preimplantation embryo development, and even lower pregnancy rates have been highlighted [26][27][28][29], and these disorders have been related to the mitochondrial dysfunction in oocytes [5], because the ATP production and oxidative phosphorylation are essential for reproductive cellular processes including meiotic maturation and postimplantation development [30]. Our previous stud- We further found that the spindle/chromosome structure was damaged in drug-treated MII oocytes (Figures 2(a)-2(d)), indicating that oocytes are in poor quality, also supporting our previous studies that the depletion of MCU markedly disrupts spindle formation during oocyte meiosis [10]. The generation of ATP is one of the basic functions of mitochondria, and its cytoplasmic level reflects the quality of matured oocytes [31,32].…”

“…Oxidative Medicine and Cellular Longevity or mitochondrial Na + -Ca 2+ exchangers in germinal vesicle (GV) oocytes to realize [Ca 2+ ] mt overload and knocking down mitochondrial calcium uniporter (MCU) to realize [Ca 2+ ] mt defection), our previous studies found that both overload and defection of [Ca 2+ ] mt would delay oocyte meiotic maturation. Damaged mitochondrial function and delayed meiotic resumption were also observed in these models [5,10]. These results altogether highlight the role of [Ca 2+ ] mt in oocyte meiosis; in particular, a proper level of [Ca 2+ ] mt in oocytes at the GV stage can be a biomarker to assess oocyte quality [11], despite that its contribution to oocyte maturation is still unclear.…”

“…] mt Disorder Model by the MCU Activator and Inhibitor. Despite that previous research has shown that [Ca 2+ ] mt disorder led to delayed meiotic maturation and mitochondrial dysfunction in GV oocytes [5,10], the regulatory role of [Ca 2+ ] mt homeostasis in matured oocytes is still unclear. As shown in Figures 1(a) and 1(b), [Ca 2+ ] mt levels in MII oocytes markedly increased after spermine treatment, while Ru360-treated MII oocytes showed the opposite (25:33 ± 1:43 for control, 44:32 ± 1:84 for spermine treatment, and 10:33 ± 0:98 for Ru360 treatment; Figures 1(a) and 1(b)).…”

Effects of MICU1-Mediated Mitochondrial Calcium Uptake on Energy Metabolism and Quality of Vitrified-Thawed Mouse Metaphase II Oocytes

“…This will directly increase the concentration of mitochondrial calcium ion [ 25 ]. If mitochondrial calcium overload occurs, it will cause mitochondrial oxidative stress and dysfunction, which is not conducive to the subsequent development of oocytes [ 26 ].…”

Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions

“…During meiosis, mitochondrial dysfunction significantly affects spindle assembly and ratio of kinetochore-microtubule connection ( 127 , 128 ), and maternal age-related meiotic errors can be attenuated by reducing mitochondrial function ( 128 ). In the process of meiosis of mice oocyte, mitochondrial calcium uniporter protein (MCU) mediates the rapid entry of Ca2+ into mitochondria and provides high energy in an instant ( 129 ). The specific deletion of MCU leads to a low concentration of Ca2+ in mitochondria, low ATP levels, abnormal spindle assembly, and altered meiosis progression ( 129 ).…”