Embryonic Surface Ectoderm-specific Mitofusin 2 Conditional Knockout Induces Congenital Cataracts in Mice

Abstract

Inherited mitochondrial mutations can result in mitochondrial dysfunction or stochastic oxidative damage. Cumulative mitochondrial damage is an important factor in age-related disorders, such as cataracts and macular degeneration. Mfn2 mediates the fusion of mitochondria and contribute to the dynamic balance between fusion and fission that determines mitochondria morphology. We report here that conditional loss of Mfn2 function in the head surface ectoderm leads to a range of congenital eye defects, including small, opacified lens and small eyeball in the most severe phenotypes. The Le-Cre transgenic mouse line and Mfn2 flox mouse line were used in this study to generate Mfn2 conditional knockout mice. Our study revealed Mfn2 gene function in lens development and addressed the relationship between the mitochondria and lens transparency. Conditional loss of Mfn2 affected lens epithelium cell proliferation, apoptosis and ultrastructure of mitochondria. We conclude that proper development of the lens and lens transparency depend on normal Mfn2 gene function.

<i>MFN2</i>-related Charcot-Marie-Tooth Disease with Atypical Ocular Manifestations

“…Therefore, there might be some unknown genetic etiology underlying the ocular manifestations in our family that could not be identified on whole-exome sequencing. Nevertheless, the clinical features we describe herein might corroborate with the findings of Zhao et al in their animal study ( 15 ). More clinical cases need to be identified to confirm the atypical ocular findings in MFN2 -related CMT.…”

“…The other family members without this mutation in MFN2 showed no ocular symptoms. Interestingly, Zhao et al ( 15 ) demonstrated in mice that a MFN2 gene conditional knockout could lead to congenital cataracts due to mitochondrial dysfunction in lens cells. It is interesting to note that the human and mouse MFN2 proteins exhibit over 95% sequence identity and the residue found mutated in our family is conserved in mouse MFN2 .…”

Zika Virus Neuropathogenesis: The Different Brain Cells, Host Factors and Mechanisms Involved

“…MFN2 is highly expressed in the brain ( 47 ) and it has been shown to be essential in embryonic development ( 48 ), neuronal maturation and synapse formation ( 138 ). Its deficiency has been shown to cause an increase in the levels of ROS and mitochondrial dysfunction and has resulted in a range of congenital eye defects ( 139 ), disruption of placental development and is associated with spontaneous abortion ( 140 ). A study demonstrated that Mdivi-1, a small molecule that inhibits mitochondrial fission blocked mitochondrial fragmentation and reduced ZIKV induced cell death ( 49 ).…”

Mitofusin 2 Dysfunction and Disease in Mice and Men

“…By comparison, our phenomenological understanding of mitofusin pathophysiology is quite detailed, having been informed by gene knockout experiments ( Chen et al, 2003 , 2007 , 2010 , 2011 , 2014 ; Lee et al, 2012 ; Sebastian et al, 2012 , 2016 ; Kasahara et al, 2013 ; Song et al, 2014 , 2015 , 2017 ; Mourier et al, 2015 ; Boutant et al, 2017 ; Ramirez et al, 2017 ; Zhao et al, 2018 ; Bell et al, 2019 ; Han et al, 2020 ) and gain- or loss-of-function manipulation with MFN-specific mini-peptides and small molecules ( Franco et al, 2016 ; Rocha et al, 2018 ). Collectively, this body of work supports three general conclusions: 1.…”