SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation

Abstract

SIRT4 modulates energy homeostasis in multiple cell types and tissues. However, its role in meiotic oocytes remains unknown. Here, we report that mouse oocytes overexpressing SIRT4 are unable to completely progress through meiosis, showing the inadequate mitochondrial redistribution, lowered ATP content, elevated reactive oxygen species (ROS) level, with the severely disrupted spindle/chromosome organization. Moreover, we find that phosphorylation of Ser293‐PDHE1α mediates the effects of SIRT4 overexpression on metabolic activity and meiotic events in oocytes by performing functional rescue experiments. By chance, we discover the SIRT4 upregulation in oocytes from aged mice; and importantly, the maternal age‐associated deficient phenotypes in oocytes can be partly rescued through the knockdown of SIRT4. These findings reveal the critical role for SIRT4 in the control of energy metabolism and meiotic apparatus during oocyte maturation and indicate that SIRT4 is an essential factor determining oocyte quality.

Visualization of Sirtuin 4 Distribution between Mitochondria and the Nucleus, Based on Bimolecular Fluorescence Self-Complementation

“…This observation is well in line with several reports [6,59,60] demonstrating the localization and function of Sirt4 within mitochondria. Nevertheless, there is also evidence for the abundance of Sirt4 within the nucleus [2]. Hence, it appears relevant to investigate the possible distribution of Sirt4 between these two organelles.…”

“…The sirtuin (Sirt) isoforms Sirt3, Sirt4, and Sirt5 harbor an N-terminal mitochondrial targeting sequence (MTS), responsible for the localization of these enzymes in the lumen of mitochondria [1]. Several studies, however, have reported that these Sirts can also occur outside of mitochondria [2][3][4], while the molecular mechanisms responsible for the subcellular distribution of Sirts are largely unclear. Sirt4 is an adenosine diphosphate (ADP)-ribosyltransferase enzyme located in the mitochondrial matrix [1,5] that regulates the metabolic activities of the organelle [6][7][8][9], but might also influence a toxic effect of this particular fusion construct.…”

Subcellular Localization and Mitotic Interactome Analyses Identify SIRT4 as a Centrosomally Localized and Microtubule Associated Protein

“…Moreover, SIRT4 was recently identified at the meiotic spindle apparatus during oocyte maturation. Oocytes from aged mice display higher SIRT4 levels leading to increased meiotic defects [ 39 ], which can be ameliorated by SIRT4 depletion. Consistent with its accumulation in aged oocytes, expression of SIRT4 is upregulated during replicative and stress-induced senescence, the latter triggered by different DNA-damaging stressors [ 37 ] as well as in vivo by UV radiation in photo-aged human skin [ 40 ].…”

Roles of Mitochondrial Sirtuins in Mitochondrial Function, Redox Homeostasis, Insulin Resistance and Type 2 Diabetes

“…However, several studies demonstrated a negative regulatory role of SIRT4 in mitochondrial function and redox homeostasis. It was reported that overexpression of SIRT4 resulted in increase of ROS levels and mitochondrial dysfunction and impaired meiosis and maturation process of mouse oocytes [62]. Moreover, the expression level of SIRT4 is increased in aged oocytes.…”

“…Moreover, the expression level of SIRT4 is increased in aged oocytes. Deleting SIRT4 in oocytes could partially restore the age-associated defective phenotypes from maternal contribution [62]. Luo et al highlighted the role of SIRT4 in the pathophysiology of cardiac hypertrophy [63].…”