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MFN2 Plays a Distinct Role from MFN1 in Regulating Spermatogonial Differentiation.

ABSTRACT: Although mitochondrial morphology is well-known for its role in cellular homeostasis, there is surprisingly little knowledge on whether mitochondrial remodeling is required for postnatal germ cell development. In this study, we investigated the functions of MFN1 and MFN2, two GTPases in mitochondrial fusion, during early spermatogenesis. We observed increased MFN expressions along with increased mitochondrial and endoplasmic reticulum (ER) activities during spermatogonial differentiation. Deletion of either Mfn led to DNA oxidation and apoptosis specifically in differentiating spermatogonia and spermatocytes, which in turn caused male infertility. We further found MFN2 regulated spermatogenesis by modulating both mitochondrial and ER functions, a mechanism distinct from that of MFN1. Defects of germ cell development in MFN2 mutants were corrected by MFN2 at either mitochondria or ER but not by MFN1. Our study thus reveals an essential requirement of MFN-mediated mitochondrial and ER coordination in spermatogenesis, providing critical insights into mitochondrial determinants of male fertility.

SUBMITTER: Chen W

PROVIDER: S-EPMC7221103 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mitochondria alter their shape by undergoing cycles of fusion and fission. Changes in mitochondrial morphology impact on the cellular response to stress, and their interactions with other organelles such as the sarcoplasmic reticulum (SR). Inhibiting mitochondrial fission can protect the heart against acute ischemia/reperfusion (I/R) injury. However, the role of the mitochondrial fusion proteins, Mfn1 and Mfn2, in the response of the adult heart to acute I/R injury is not clear, and is investigated in this study. To determine the effect of combined Mfn1/Mfn2 ablation on the susceptibility to acute myocardial I/R injury, cardiac-specific ablation of both Mfn1 and Mfn2 (DKO) was initiated in mice aged 4-6 weeks, leading to knockout of both these proteins in 8-10-week-old animals. This resulted in fragmented mitochondria (electron microscopy), decreased mitochondrial respiratory function (respirometry), and impaired myocardial contractile function (echocardiography). In DKO mice subjected to in vivo regional myocardial ischemia (30 min) followed by 24 h reperfusion, myocardial infarct size (IS, expressed as a % of the area-at-risk) was reduced by 46% compared with wild-type (WT) hearts. In addition, mitochondria from DKO animals had decreased MPTP opening susceptibility (assessed by Ca(2+)-induced mitochondrial swelling), compared with WT hearts. Mfn2 is a key mediator of mitochondrial/SR tethering, and accordingly, the loss of Mfn2 in DKO hearts reduced the number of interactions measured between these organelles (quantified by proximal ligation assay), attenuated mitochondrial calcium overload (Rhod2 confocal microscopy), and decreased reactive oxygen species production (DCF confocal microscopy) in response to acute I/R injury. No differences in isolated mitochondrial ROS emissions (Amplex Red) were detected in response to Ca(2+) and Antimycin A, further implicating disruption of mitochondria/SR tethering as the protective mechanism. In summary, despite apparent mitochondrial dysfunction, hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction due to impaired mitochondria/SR tethering.

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MFN2 Plays a Distinct Role from MFN1 in Regulating Spermatogonial Differentiation.

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