Abstract
In the year 2000, the discovery of OPA1 mutations as causative for dominant optic atrophy (DOA) was pivotal to rapidly expand the field of mitochondrial dynamics and describe the complex machinery governing this pathway, with a multitude of other genes and encoded proteins involved in neurodegenerative disorders of the optic nerve. OPA1 turned out to be a much more complex protein than initially envisaged, connecting multiple pathways beyond its strict role in mitochondrial fusion, such as sensing of OXPHOS needs and mitochondrial DNA maintenance. As a consequence, an increasing need to investigate OPA1 functions at multiple levels has imposed the development of multiple tools and models that are here reviewed. Translational mitochondrial medicine, with the ultimate objective of translating basic science necessary to understand pathogenic mechanisms into therapeutic strategies, requires disease modeling at multiple levels: from the simplest, like in yeast, to cell models, including the increasing use of reprogrammed stem cells (iPSCs) from patients, to animal models. In the present review, we thoroughly examine and provide the state of the art of all these approaches.
Highlights
In the year 2000, the human OPA1 gene came to attention, as heterozygous mutations were associated with dominant optic atrophy (DOA) [1, 2], a blinding disorder originally described by the Danish ophthalmologist Paul Kjer in 1959, which usually leads to optic atrophy in the first decade of life [3]
This gene encodes a protein for which the role as one of the mitochondrial factors involved in the machinery regulating mitochondrial dynamics, promoting fusion of the inner membrane of mitochondria and being key to mitochondrial DNA maintenance, was clear by analogy with the orthologous genes MGM1/MSP1 in yeast [4,5,6]
Both the cell lines showed a reduction in oxygen consumption rate (OCR), complex I levels, and activity, whereas only neurons derived from the patient with Parkinsonism presented mitochondrial fragmentation and an increase of the OPA1 short forms
Summary
In the year 2000, the human OPA1 gene came to attention, as heterozygous mutations were associated with dominant optic atrophy (DOA) [1, 2], a blinding disorder originally described by the Danish ophthalmologist Paul Kjer in 1959, which usually leads to optic atrophy in the first decade of life [3] This gene encodes a protein for which the role as one of the mitochondrial factors involved in the machinery regulating mitochondrial dynamics, promoting fusion of the inner membrane of mitochondria and being key to mitochondrial DNA (mtDNA) maintenance, was clear by analogy with the orthologous genes MGM1/MSP1 in yeast [4,5,6]. We review the currently available tools for the study of this protein, looking at the future of this rapidly evolving field
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