Mitochondrial Oxidative Phosphorylation Compensation May Preserve Vision in Patients with OPA1-Linked Autosomal Dominant Optic Atrophy

Abstract

Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies.

Testosterone Deprivation Aggravates Left-Ventricular Dysfunction in Male Obese Insulin-Resistant Rats via Impairing Cardiac Mitochondrial Function and Dynamics Proteins

“…Therefore, a reduction in OPA1 directly affects mitochondrial respiration via a reduction in the oxidative phosphorylation process [36]. In the obese insulin-resistant rats with testosterone deprivation, OPA1 protein levels were reduced along with a reduction in mitochondrial respiratory complexes I and III.…”

Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity

“…The clinical manifestation of OPA1 mutations is often highly variable between siblings. 48 Experimental knockdown of OPA1 performed by different tools and laboratories resulted in highly variable phenotypes (see above). Ca 2 þ handling is not an exception from this.…”

“…54 Based on our data, mitochondrial Ca 2 þ load is likely to be reduced in OPA1-deficient RGCs, and therefore the aggravation of DCD that was observed is possibly due to the decreased respiratory capacity. Along this line, DOA patients with higher respiratory complex activities have been reported to maintain visual acuity for a longer period of time, 48 again suggesting that the bioenergetic compromise may be at the root of RGC damage. Because RGC mitochondria do not show any abnormalities in protein expression, the focus should turn to RGC idiosyncrasies in terms of mitochondrial energy metabolism and environmental stress factors.…”

Neurodegenerative Eye Disorders

“…42,43 It has been reported that poor visual acuity in ADOA patients is associated with mutations in the OPA1 gene, which result in defective OXPHOS capacity of the mitochondria. 44 Mutations in OPA1 lead to disruption of mtDNA structure, replication, and transcription, ultimately affecting OXPHOS capacity.…”