TMEM126A is a mitochondrial located mRNA (MLR) protein of the mitochondrial inner membrane

Background

Hereditary optic neuropathies (HONs) are a heterogeneous group of disorders that affect retinal ganglion cells (RGCs) and axons that form the optic nerve. Leber's Hereditary Optic Neuropathy and the autosomal dominant optic atrophy related to OPA1 mutations are the most common forms. Nonsyndromic autosomal recessive optic neuropathies are rare and their existence has been long debated. We recently identified the first gene responsible for these conditions, TMEM126A. This gene is highly expressed in retinal cellular compartments enriched in mitochondria and supposed to encode a mitochondrial transmembrane protein of unknown function.

Methods

A specific polyclonal antibody targeting the TMEM126A protein has been generated. Quantitative fluorescent in situ hybridization, cellular fractionation, mitochondrial membrane association study, mitochondrial sub compartmentalization analysis by both proteolysis assays and transmission electron microscopy, and expression analysis of truncated TMEM126A constructs by immunofluorescence confocal microscopy were carried out.

Results

TMEM126A mRNAs are strongly enriched in the vicinity of mitochondria and encode an inner mitochondrial membrane associated cristae protein. Moreover, the second transmembrane domain of TMEM126A is required for its mitochondrial localization.

Conclusions

TMEM126A is a mitochondrial located mRNA (MLR) that may be translated in the mitochondrial surface and the protein is subsequently imported to the inner membrane. These data constitute the first step toward a better understanding of the mechanism of action of TMEM126A in RGCs and support the importance of mitochondrial dysfunction in the pathogenesis of HON.

General significance

Local translation of nuclearly encoded mitochondrial mRNAs might be a mechanism for rapid onsite supply of mitochondrial membrane proteins.     

Spatial and temporal expressions of prune reveal a role in Müller gliogenesis during Xenopus retinal development

The development of stratified retinal cell architecture is highly conserved in all vertebrates, implying that a common fundamental molecular mechanism is involved in the generation of the organized retina. However, the detailed molecular mechanisms of retinal development are not fully understood. Here we have identified the Xenopus ortholog of prune and show that it is expressed in both differentiating and differentiated retinal domains during development. Interestingly, these spatial and temporal expression patterns coincide with the expression of prune binding partners, the NM23 family members. Overexpression of prune in retinal precursor cells significantly increases the ratio of Müller glial cells as observed by modulation of NM23 activity (Mochizuki et al., 2009). However, a mutated form of prune that has replacement of four aspartate (D) residues (D'Angelo et al., 2004), essential for phosphodiesterase activity, does not exhibit gliogenic activity. Our observations suggest that Xenopus prune may regulate Müller gliogenesis through phosphodiesterase-mediated regulation of NM23 family members.     

Hypoxia induces beta-amyloid in association with death of RGC-5 cells in culture

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24S-hydroxycholesterol and cholesterol-24S-hydroxylase (CYP46A1) in the retina: from cholesterol homeostasis to pathophysiology of glaucoma

Free cholesterol is the predominant form of cholesterol in the neural retina. The vertebrate neural retina exhibits its own capacity to synthesize cholesterol and meets its demand also by taking it from the circulation. Defects in cholesterol synthesis and trafficking in the neural retina has detrimental consequences on its structure and function, highlighting the crucial importance of maintaining cholesterol homeostasis in the retina. Our purpose was to give a review on the functioning of the retina, the role of cholesterol and cholesterol metabolism therein, with special emphasis on cholesterol-24S-hydroxylase (CYP46A1). Similar to the brain, the retina expresses cholesterol-24S-hydroxylase (CYP46A1) and is enriched in its metabolic product, 24S-hydroxycholesterol. We recently published that one single nucleotide polymorphism in CYP46A1 gene, designated as rs754203, was a risk factor for glaucoma. Glaucoma is the second leading cause of blindness worldwide, affecting more than 60 million people. Glaucoma is characterized by the loss of retinal ganglion cells, which show high CYP46A1 expression. These data suggest the potential involvement of CYP46A1 and 24S-hydroxycholesterol in the pathophysiology of glaucoma.     

Matrix metalloproteinase 2 and membrane type 1 matrix metalloproteinase co‐regulate axonal outgrowth of mouse retinal ganglion cells

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Chronic and acute models of retinal neurodegeneration TrkA activity are neuroprotective whereas p75NTR activity is neurotoxic through a paracrine mechanism

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p27Kip1 participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

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