MFN2 interacts with nuage-associated proteins and is essential for male germ cell development by controlling mRNA fate during spermatogenesis

Wang, Xiaoli; Wen, Yujiao; Zhang, Jin; Swanson, Grace; Guo, Shuangshuang; Cao, Congcong; Krawetz, Stephen A.; Zhang, Zhibing; Yuan, Shuiqiao

doi:10.1242/dev.196295

Cited by 14 publications

(19 citation statements)

References 75 publications

(108 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When spermatocytes are deficient in MFN2, then they cannot continue to the pachytene stage and this leads to apoptosis, which ultimately results in the death of both the spermatocytes and spermatogonia in the seminiferous tubule, hence the empty appearance of this region in our histology sections. A similar phenotype has previously been reported in other studies ( Varuzhanyan et al, 2019 ; Chen et al, 2020 ; Wang et al, 2021 ), but to our knowledge, our data are the first to show details of disrupted meiosis in MFN2 deficient spermatocytes.…”

Section: Discussionsupporting

confidence: 92%

“…Moreover, RAB7 was shown to regulate the phosphorylation of DRP1 and thus control mitochondrial dynamics during oocytogenesis ( Pan et al, 2020 ). In addition to DRP1, several studies demonstrated that the conditional knock-out of mitofusin 1 or 2 (MFN1 or MFN2) leads to male or female infertility in mice models ( Varuzhanyan et al, 2019 ; Zhang et al, 2019 ; Chen et al, 2020 ; Wang et al, 2021 ). However, the underlying molecular mechanism responsible for this phenotype remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

MFN2 Deficiency Impairs Mitochondrial Functions and PPAR Pathway During Spermatogenesis and Meiosis in Mice

Wang

Xiao

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Mitochondria are highly dynamic organelles and their activity is known to be regulated by changes in morphology via fusion and fission events. However, the role of mitochondrial dynamics on cellular differentiation remains largely unknown. Here, we explored the molecular mechanism of mitochondrial fusion during spermatogenesis by generating an Mfn2 (mitofusin 2) conditional knock-out (cKO) mouse model. We found that depletion of MFN2 in male germ cells led to disrupted spermatogenesis and meiosis during which the majority of Mfn2 cKO spermatocytes did not develop to the pachytene stage. We showed that in these Mfn2 cKO spermatocytes, oxidative phosphorylation in the mitochondria was affected. In addition, RNA-Seq analysis showed that there was a significantly altered transcriptome profile in the Mfn2 deficient pachytene (or pachytene-like) spermatocytes, with a total of 262 genes up-regulated and 728 genes down-regulated, compared with wild-type (control) mice. Pathway enrichment analysis indicated that the peroxisome proliferator-activated receptor (PPAR) pathway was altered, and subsequent more detailed analysis showed that the expression of PPAR α and PPAR γ was up-regulated and down-regulated, respectively, in the MFN2 deficient pachytene (or pachytene-like) spermatocytes. We also demonstrated that there were more lipid droplets in the Mfn2 cKO cells than in the control cells. In conclusion, our study demonstrates a novel finding that MFN2 deficiency negatively affects mitochondrial functions and alters PPAR pathway together with lipid metabolism during spermatogenesis and meiosis.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

MFN2 Deficiency Impairs Mitochondrial Functions and PPAR Pathway During Spermatogenesis and Meiosis in Mice

Wang

Xiao

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…In undifferentiated spermatogonia, mitochondria are generally small and fragmented. As spermatogonia differentiate into spermatocytes and initiate meiosis, their mitochondria undergo mitofusin-mediated fusion to fuel meiosis ( Chen et al, 2020 ; Varuzhanyan et al, 2019 ; Wang et al, 2021 ; Zhang et al, 2016 ). In post-meiotic spermatids, acute mitochondrial fragmentation mediated by mitochondrial fission factor (MFF) generates small mitochondrial spheres, which enables their organization into a spiral array within the midpiece ( Varuzhanyan et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation

et al. 2021

View full text Add to dashboard Cite

Male germline development involves choreographed changes to mitochondrial number, morphology, and organization. Mitochondrial reorganization during spermatogenesis was recently shown to require mitochondrial fusion and fission. Mitophagy, the autophagic degradation of mitochondria, is another mechanism for controlling mitochondrial number and physiology, but its role during spermatogenesis is largely unknown. During post-meiotic spermatid development, restructuring of the mitochondrial network results in packing of mitochondria into a tight array in the sperm midpiece to fuel motility. Here, we show that disruption of mouse Fis1 in the male germline results in early spermatid arrest that is associated with increased mitochondrial content. Mutant spermatids coalesce into multinucleated giant cells (GCs) that accumulate mitochondria of aberrant ultrastructure and numerous mitophagic and autophagic intermediates, suggesting a defect in mitophagy. We conclude that Fis1 regulates mitochondrial morphology and turnover to promote spermatid maturation.

show abstract

“…The other portion of the daughter cells differentiate to form Type A spermatogonia and Type B spermatogonia [ 96 ], thus allowing meiosis. To investigate the effects of Mfns in the self-renewal and differentiation of SSCs, many studies have knocked out Mfns or inhibited the expression of Mfns [ 24 , 97 ]. Interestingly, the depletion of Mfn1 and Mfn2 does not influence the self-renewal of SSCs; instead, this inhibits the differentiation of SSCs (Fig.…”

Section: Mfns In the Development Of Germ Cells And Embryosmentioning

confidence: 99%

Mitofusins: from mitochondria to fertility

Zhao

Heng

Wang

et al. 2022

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Germ cell formation and embryonic development require ATP synthesized by mitochondria. The dynamic system of the mitochondria, and in particular, the fusion of mitochondria, are essential for the generation of energy. Mitofusin1 and mitofusin2, the homologues of Fuzzy onions in yeast and Drosophila, are critical regulators of mitochondrial fusion in mammalian cells. Since their discovery mitofusins (Mfns) have been the source of significant interest as key influencers of mitochondrial dynamics, including membrane fusion, mitochondrial distribution, and the interaction with other organelles. Emerging evidence has revealed significant insight into the role of Mfns in germ cell formation and embryonic development, as well as the high incidence of reproductive diseases such as asthenospermia, polycystic ovary syndrome, and gestational diabetes mellitus. Here, we describe the key mechanisms of Mfns in mitochondrial dynamics, focusing particularly on the role of Mfns in the regulation of mammalian fertility, including spermatogenesis, oocyte maturation, and embryonic development. We also highlight the role of Mfns in certain diseases associated with the reproductive system and their potential as therapeutic targets.

show abstract

MFN2 interacts with nuage-associated proteins and is essential for male germ cell development by controlling mRNA fate during spermatogenesis

Cited by 14 publications

References 75 publications

MFN2 Deficiency Impairs Mitochondrial Functions and PPAR Pathway During Spermatogenesis and Meiosis in Mice

MFN2 Deficiency Impairs Mitochondrial Functions and PPAR Pathway During Spermatogenesis and Meiosis in Mice

Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation

Mitofusins: from mitochondria to fertility

Contact Info

Product

Resources

About