Retinal damage promotes mitochondrial transfer in the visual system of a mouse model of Leber hereditary optic neuropathy
Lenadogene nolparvovec is a gene therapy which has been developed to treat Leber hereditary optic neuropathy (LHON) caused by a point mutation in the mitochondrial NADH dehydrogenase 4 (ND4) gene. Clinical trials have demonstrated a significant improvement of visual acuity up to 5 years after treatment by lenadogene nolparvovec but, surprisingly, unilateral treatment resulted in bilateral improvement of vision. This contralateral effect – similarly observed with other gene therapy products in…
A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria
Eukaryotic cell function and survival rely on the use of a mitochondrial H^(+) electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H^(+). Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na^(+) gradient equates with the H^(+) gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This…
Diagnostic dilemma: Leber’s hereditary optic neuropathy in a 70-year-Old woman
CONCLUSIONS AND IMPORTANCE: LHON is typically not part of the initial differential diagnosis of an optic neuropathy in patients outside the typical demographic. As genetic testing has become more widely available, clinicians should consider including LHON in their differential diagnosis of any optic neuropathy, especially if other, more common causes have been ruled out.
Ocular genetics in the Japanese population
In today’s globalized society, ophthalmologists can examine people of different ethnicities regardless of where they live. The frequency of disease-causing genes varies according to a patient’s ethnic background. We explain genetic findings for Japanese patients with inherited eye diseases. Ocular genetics has made great advances over the past 30 years. For example, detecting mutations at nucleotide position 11778 in mitochondrial DNA was useful in the genetic diagnosis of Leber’s hereditary…
Mitochondrial tRNAGlu 14693A>G Mutation, an “Enhancer” to the Phenotypic Expression of Leber’s Hereditary Optic Neuropathy
Leber’s hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNA^(Glu) 14693A>G and ND6 14484T>C mutations in three Chinese families affected by LHON is investigated. The m.14693A>G mutation nearly abolishes…
Leber hereditary optic neuropathy in Slovenia: quality of life and costs from patient perspective
CONCLUSION: The findings highlight the significant economic and social burden of LHON on patients and their families. Ensuring prompt, accurate diagnosis, access to treatment, financial support, and psychological counselling and services are critical to helping individuals cope with and mitigate the profound challenges of vision loss and living with LHON.
Defective post-transcriptional modification of tRNA disrupts mitochondrial homeostasis in Leber’s hereditary optic neuropathy
Leber’s Hereditary Optic Neuropathy (LHON) is a rare, maternally inherited eye disease, predominantly due to the degeneration of retinal ganglion cells (RGCs). It is associated with a mitochondrial DNA (mtDNA) point mutation. Our previous study identified that the m.15927G>A homoplasmic mutation damaged the highly conserved basepairing (28C-42G) in anticodon stem of tRNA^(Thr), caused deficient t⁶A modification and significantly decreased efficiency in aminoacylation and steady-state levels of…
Metabolic Deficits in the Retina of a Familial Dysautonomia Mouse Model
Neurodegenerative retinal diseases such as glaucoma, diabetic retinopathy, Leber’s hereditary optic neuropathy (LHON), and dominant optic atrophy (DOA) are marked by progressive death of retinal ganglion cells (RGC). This decline is promoted by structural and functional mitochondrial deficits, including electron transport chain (ETC) impairments, increased oxidative stress, and reduced energy (ATP) production. These cellular mechanisms associated with progressive optic nerve atrophy have been…
Clinical follow-up investigation on thickness changes in the peripapillary retinal nerve fibre layer of patients with Leber hereditary optic neuropathy
CONCLUSION: The pattern of RNFL involvement could be helpful in the differential diagnosis of LHON and other optic neuropathies. LHON patients with better vision are more likely to experience some degree of spontaneous visual acuity recovery after the subacute phase.
Dysregulation of mitochondria, apoptosis and mitophagy in Leber’s hereditary optic neuropathy with MT-ND1 3635G>A mutation
Leber’s hereditary optic neuropathy (LHON) is a maternal inherited disorder, primarily due to mitochondrial DNA (mtDNA) mutations. This investigation aimed to assess the pathogenicity of m.3635G>A alteration known to confer susceptibility to LHON. The disruption of electrostatic interactions among S110 of the MT-ND1 and the side chain of E4, along with the carbonyl backbone of M1 in the NDUFA1, was observed in complex I of cybrids with m.3635G>A. This disturbance affected the complex I assembly…