Dominant Optic Atrophy (DOA): Modeling the Kaleidoscopic Roles of OPA1 in Mitochondrial Homeostasis

Dotto, Valentina Del; Carelli, Valerio

doi:10.3389/fneur.2021.681326

Cited by 22 publications

(6 citation statements)

References 160 publications

(236 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Variants in OPA1 , a gene encoding the mitochondrial dynamin-like GTPase (OPA1) protein, are mainly responsible for the disease 35 . This protein, anchored to the mitochondrial inner membrane facing the inter-membrane space, plays a critical role in mitochondria, as a link between the mitochondrial structure and bioenergetic functions, regulating mitochondrial fusion 36 . This fusion process of mitochondrial membranes is promoted by the binding of OPA1 and the mitochondria-bound Mitofusin 2 protein (MFN2), a key tethering protein of the MAMs (for review 37 ).…”

Section: Discussionmentioning

confidence: 99%

The Wolfram-like variant WFS1^E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice

Patergnani,

Bataillard,

Danese

et al. 2023

Preprint

View full text Add to dashboard Cite

Dominant variants inWFS1, a gene coding for the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein Wolframin, have been associated with Wolfram-like syndrome (WLS).In vitroandin vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced autophagy and mitophagy. However, in WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that, in human fibroblasts and murine neuronal cultures, WLS protein WFS1E864Kleads to decreases in mitochondria bioenergetics and Ca2+uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in theWfs1E864Kmouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM’s integrity and functionality. It may open new treatment perspectives, until now non-existent, for patients with WLS.

show abstract

Section: Discussionmentioning

confidence: 99%

The Wolfram-like variant WFS1^E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice

Patergnani,

Bataillard,

Danese

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…For example, mutations in Optineurin ( OPTN ) affect mitophagy and these have been linked to incidence of glaucoma [ 130 ]. Mutations in the OPA1 gene affect mitochondrial fusion and leads to dominant optic neuropathy, the most common inherited optic neuropathy [ 131 ]. Mitochondrial DNA (mtDNA) can also harbor mutations that lead to disease, including Leber’s Hereditary Optic Neuropathy (LHON), which can occur due to a mutation in any of several mtDNA genes [ 132 , 133 ].…”

Section: Main Textmentioning

confidence: 99%

Solving neurodegeneration: common mechanisms and strategies for new treatments

Wareham

Liddelow²,

Temple

et al. 2022

Mol Neurodegeneration

154

View full text Add to dashboard Cite

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled “Solving Neurodegeneration”. This “think-tank” style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the world’s leading cause of irreversible blindness and the common interest of the three hosting foundations. Glaucoma, which causes vision loss through degeneration of the optic nerve, likely shares early cellular and molecular events with other neurodegenerative diseases of the central nervous system. Here we discuss major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions. We summarize important discussion points with emphasis on the research areas that are most innovative and promising in the treatment of neurodegeneration yet require further development. The research that is highlighted provides unique opportunities for collaboration that will lead to efforts in preventing neurodegeneration and ultimately vision loss.

show abstract

“…OPA1 codes for an inner mitochondrial membrane fusion protein which has been shown to be critical in mitochondrial network formation, bioenergetics, mitophagy and mtDNA stability [55][56][57]. OPA1 is ubiquitously expressed, but it is found at higher levels in metabolically active tissues such as neural tissue and cardiomyocytes.…”

Section: Dominant Optic Atrophy (Doa)mentioning

confidence: 99%

Mitochondria and the eye—manifestations of mitochondrial diseases and their management

Chen

Harvey

Gilhooley

et al. 2023

Eye

View full text Add to dashboard Cite

Historically, distinct mitochondrial syndromes were recognised clinically by their ocular features. Due to their predilection for metabolically active tissue, mitochondrial diseases frequently involve the eye, resulting in a range of ophthalmic manifestations including progressive external ophthalmoplegia, retinopathy and optic neuropathy, as well as deficiencies of the retrochiasmal visual pathway. With the wider availability of genetic testing in clinical practice, it is now recognised that genotype-phenotype correlations in mitochondrial diseases can be imprecise: many classic syndromes can be associated with multiple genes and genetic variants, and the same genetic variant can have multiple clinical presentations, including subclinical ophthalmic manifestations in individuals who are otherwise asymptomatic. Previously considered rare diseases with no effective treatments, considerable progress has been made in our understanding of mitochondrial diseases with new therapies emerging, in particular, gene therapy for inherited optic neuropathies.

show abstract

Dominant Optic Atrophy (DOA): Modeling the Kaleidoscopic Roles of OPA1 in Mitochondrial Homeostasis

Cited by 22 publications

References 160 publications

The Wolfram-like variant WFS1^E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice

The Wolfram-like variant WFS1^E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice

Solving neurodegeneration: common mechanisms and strategies for new treatments

Mitochondria and the eye—manifestations of mitochondrial diseases and their management

Contact Info

Product

Resources

About

Dominant Optic Atrophy (DOA): Modeling the Kaleidoscopic Roles of OPA1 in Mitochondrial Homeostasis

Cited by 22 publications

References 160 publications

The Wolfram-like variant WFS1E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice

The Wolfram-like variant WFS1E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice

Solving neurodegeneration: common mechanisms and strategies for new treatments

Mitochondria and the eye—manifestations of mitochondrial diseases and their management

Contact Info

Product

Resources

About

The Wolfram-like variant WFS1^E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice

The Wolfram-like variant WFS1^E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice