Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation

Ryu, Seung-Wook; Jeong, Hyeon Joo; Choi, Myunghwan; Karbowski, Mariusz; Choi, Chulhee

doi:10.1007/s00018-010-0365-z

Cited by 60 publications

(76 citation statements)

References 24 publications

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“…Moreover, nigericin-induced mitochondrial damage, ROS production and inflammasome activation were normal when Drp1 was silenced, which indicates the existence of other pathways that regulate mitochondrial fission and mitochondrial damage during activation of the NLRP3 inflammasome induced by classic agonists. Indeed, DRP1-independent mitochondrial fission has been described 38,42 .…”

Section: Discussionmentioning

confidence: 98%

RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway

et al. 2014

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The NLRP3 inflammasome functions as a crucial component of the innate immune system in recognizing viral infection, but the mechanism by which viruses activate this inflammasome remains unclear. Here we found that inhibition of the serine-threonine kinases RIP1 (RIPK1) or RIP3 (RIPK3) suppressed RNA virus-induced activation of the NLRP3 inflammasome. Infection with an RNA virus initiated assembly of the RIP1-RIP3 complex, which promoted activation of the GTPase DRP1 and its translocation to mitochondria to drive mitochondrial damage and activation of the NLRP3 inflammasome. Notably, the RIP1-RIP3 complex drove the NLRP3 inflammasome independently of MLKL, an essential downstream effector of RIP1-RIP3-dependent necrosis. Together our results reveal a specific role for the RIP1-RIP3-DRP1 pathway in RNA virus-induced activation of the NLRP3 inflammasome and establish a direct link between inflammation and cell-death signaling pathways.

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Section: Discussionmentioning

confidence: 98%

RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway

et al. 2014

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“…The presence of a putative N-terminal MTS indicates its import into mitochondria (146). However the studies concerning OPA3 localization in the IMM or OMM are controversial (146,155,156). The N-and C-terminal regions are reported to be exposed to the IMS and cytoplasm, respectively.…”

Section: Bagli Et Al: Mitochondrial Dynamics and Optic Neuropathy (Rementioning

confidence: 99%

“…OPA3 seems to play a regulatory role in mitochondrial dynamics and more specifically in fission, since overexpression of OPA3 significantly induced mitochondrial fragmentation. It is also referred to as sensitizing cells to apoptosis (156).…”

Section: Afg3l2 Heterozygous Missense Mutations In the Afg3l2mentioning

confidence: 99%

“…Overexpression of a familial OPA3 mutant (G93S) induced mitochondrial fragmentation and spontaneous apoptosis, suggesting that OPA3 mutations may cause optic atrophy via a gain-of-function mechanism (156). Furthermore, a novel insertion, c.10_11insCGCCCG/p.V3_G4insAP, which is located in the mitochondrial presequence, results in decreased steady-state levels of the mutant protein compared with the native one and leads to DOA and hearing loss (153).…”

Section: Afg3l2 Heterozygous Missense Mutations In the Afg3l2mentioning

confidence: 99%

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Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Bagli

Zikou

Agnantis

et al. 2017

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Abstract. Inherited optic neuropathies are a genetically diverse group of disorders mainly characterized by visual loss and optic atrophy. Since the first recognition of Leber's hereditary optic neuropathy, several genetic defects altering primary mitochondrial respiration have been proposed to contribute to the development of syndromic and nonsyndromic optic neuropathies. Moreover, the genomics and imaging revolution in the past decade has increased diagnostic efficiency and accuracy, allowing recognition of a link between mitochondrial dynamics machinery and a broad range of inherited neurodegenerative diseases involving the optic nerve. Mutations of novel genes modifying mainly the balance between mitochondrial fusion and fission have been shown to lead to overlapping clinical phenotypes ranging from isolated optic atrophy to severe, sometimes lethal multisystem disorders, and are reviewed herein. Given the particular vulnerability of retinal ganglion cells to mitochondrial dysfunction, the accessibility of the eye as a part of the central nervous system and improvements in technical imaging concerning assessment of the retinal nerve fiber layer, optic nerve evaluation becomes critical -even in asymptomatic patients -for correct diagnosis, understanding and early treatment of these complex and enigmatic clinical entities.Mitochondria represent a tubular and branched membrane system playing a fundamental role in several cellular processes required for the development and maintenance of an organism, such as metabolism, apoptosis, ion buffering and autophagy (1-3). They reveal a high degree of interconnectivity and plasticity, mainly dictated by metabolic status and developmental stage (4) and, therefore, a constant state of mitochondrial network flux is fundamental. This dynamic state is achieved through mitochondrial dynamics, a complex machinery of highly conserved mechanisms, including mitochondrial fusion, fission, transport, interorganellar communication and mitochondrial quality control (i.e. mitophagy), tuned to a variety of signals and stimuli (5-7), and well-orchestrated by specific intracellular proteins.The morphology and intracellular distribution of mitochondria vary significantly between tissues and cell types, being enriched in areas of increased metabolic demand, such as neurons, especially the presynaptic and postsynaptic terminals (8). Accordingly, it is not surprising that the pathogenic mechanism of various neurodegenerative diseases is established through an underlying deficiency of mitochondrial energy metabolism (9). However, in recent years it has been shown that impairment of mitochondrial dynamics also leads to synaptic dysfunction, dendritic and axonal degeneration and consequently to neurodegeneration (10,11). In this respect, restoration of mitochondrial function has become, for some time now, the priority target of novel neuroprotective strategies (12).Mitochondrial membrane dynamics, and more specifically fission and fusion, are indispensable for mitochondrial distribution and hom...

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“…Currently, the function of the OPA3 protein, which is 179 amino acids long, is unknown, as are the metabolic basis and pathophysiology of CS. However, according to a mouse model, the protein localizes to the mitochondrial inner membrane, and there is both direct and indirect evidence of involvement of mitochondrial dysfunction in this disorder [12,13].…”

Section: Introductionmentioning

confidence: 98%

Costeff syndrome: clinical features and natural history

et al. 2014

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Costeff syndrome (CS) is a rare autosomal-recessive neurological disorder, which is known almost exclusively in patients of Iraqi Jewish descent, manifesting in childhood with optic atrophy, ataxia, chorea and spastic paraparesis. Our aim was to study the clinical spectrum of CS and natural history using a cross-sectional study design. Consecutive patients with CS were recruited to the study. Patients were diagnosed based on clinical features, along with elevated urinary levels of methylglutaconic and methylglutaric acid, and by identification of the disease-causing mutation in the OPA3 gene in most. All patients were examined by a neurologist and signs and symptoms were rated. 28 patients with CS (16 males, 21 families, age at last observation 28.6 ± 16.1 years, range 0.5-68 years) were included. First signs of neurological deficit appeared in infancy or early childhood, with delayed motor milestones, choreiform movements, ataxia and visual disturbances. Ataxia and chorea were the dominant motor features in childhood, but varied in severity among patients and did not seem to worsen with age. Pyramidal dysfunction appeared later and progressed with age (r = 0.71, p < 0.001) leading to spastic paraparesis and marked gait impairment. The course of neurological deterioration was slow and the majority of patients could still walk beyond the fifth decade. While visual acuity seemed to deteriorate, it did not correlate with age. CS is a rare neurogenetic disorder that causes serious disability and worsens with age. Spasticity significantly increases over the years and is the most crucial determinant of neurological dysfunction.

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Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation

Cited by 60 publications

References 24 publications

RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway

RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Costeff syndrome: clinical features and natural history

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