Abstract
The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more complex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns–Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mitochondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29.
Highlights
The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment
autosomal dominant optic atrophy (ADOA) has been known to be associated with sensorineural deafness as occasional cooccurring feature [134], but in 2008 an unexpected observation was reported, that missense heterozygous OPA1 mutations affecting the GTPase domain could lead to a multisystem disorder characterized by chronic progressive external ophthalmolplegia (CPEO), peripheral neuropathy, sensorineural deafness, cerebellar atrophy, white matter lesions and myopathy with RRF due to accumulation of mtDNA multiple deletions, providing a mechanistic link of OPA1 with mtDNA maintenance disorders [135,136]
As frequently occurs in mitochondrial medicine, the dichotomy between defects leading only to optic atrophy (LHON and dominant optic atrophy (DOA)) as opposed to those leading to retinal dystrophies affecting both photoreceptors and retinal pigmented epithelium (KSS and NARP) is a paradigm that has been blurred by the most recent findings
Summary
This review is focused on retinopathy caused by primary genetic mitochondrial disorders, mitochondrial dysfunction may be an important pathogenetic component of other retinopathies. Present in virtually all eukaryotes, mitochondria are doublemembraned organelles with a central role as the powerhouses of the cell [1] They are the major source of the high-energy phosphate molecule, adenosine triphosphate (ATP), synthesized by the mitochondrial respiratory chain (MRC) through the process of oxidative phosphorylation (OXPHOS) [2]. Genetic defects affecting mtDNA or OXPHOS-related nDNA genes can impair ATP synthesis, determine mitochondrial dysfunction, and cause human disease [9]. Tissue and organ functions where energy demand is high, such as neurons and muscle fibres, critically depend on adequate ATP supply This explains why primary mitochondrial disorders usually cause neurodegeneration and/or muscle weakness, in children and adults [11]. The number of individuals carrying a mtDNA mutation in a percentage below the clinical threshold is probably much higher, around 1 in 500 live births
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