Respiratory Complex I Dysfunction Due to Mitochondrial DNA Mutations Shifts the Voltage Threshold for Opening of the Permeability Transition Pore toward Resting Levels

Porcelli, Anna Maria; Angelin, Alessia; Ghelli, Anna; Mariani, Elisa; Martinuzzi, Andrea; Carelli, Valerio; Petronilli, Valeria; Bernardi, Paolo; Rugolo, Michela

doi:10.1074/jbc.m807321200

Cited by 93 publications

(50 citation statements)

References 74 publications

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“…However, the mutation does cause an increase in ROS production and oxidative damage. If the biochemical alterations associated with the ND6 G14600A/G13997A (P25L) human and mouse mutations are characteristic of the LHON ND6 G14459A (A72V), ND4 G11778A (R340H), ND1 G3460A (A52T), and ND6 T14484C (M64V) mutations, our synaptosome results suggest that the pathophysiology of LHON is less about ATP deficiency and more about chronic oxidative damage, consistent with the sensitization of mtPTP in LHON mtDNA cybrids (41,42).…”

Section: Discussionmentioning

confidence: 58%

Mouse mtDNA mutant model of Leber hereditary optic neuropathy

Lin

Sharpley

Fan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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An animal model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human optic atrophy mtDNA ND6 P25L mutation into the mouse. Mice with this mutation exhibited reduction in retinal function by elecroretinogram (ERG), age-related decline in central smaller caliber optic nerve fibers with sparing of larger peripheral fibers, neuronal accumulation of abnormal mitochondria, axonal swelling, and demyelination. Mitochondrial analysis revealed partial complex I and respiration defects and increased reactive oxygen species (ROS) production, whereas synaptosome analysis revealed decreased complex I activity and increased ROS but no diminution of ATP production. Thus, LHON pathophysiology may result from oxidative stress.eber hereditary optic neuropathy (LHON), the first inherited mitochondrial (mt)DNA disease reported (1), is thought to be one of the most prevalent diseases caused by mtDNA missense mutations, having an estimated frequency of 15 in 100,000 (2). Most European LHON mutations occur in the mtDNA oxidative phosphorylation (OXPHOS) complex I (NADH:ubiquinone oxidoreductase or NADH dehydrogenase) genes, the three most common being the ND4 gene mutation at nucleotide G11778A causing an arginine 340 to histidine (R340H) substitution (1), the ND1 G3460A (A52T) mutation (3), and the ND6 T14484C (M64V) mutation (4). Milder LHON mutations are generally homoplasmic (pure mutant). In contrast, more severe mtDNA complex I ND gene mutations can cause basal ganglia degeneration presenting as dystonia or Leigh syndrome when homoplasmic but optic atrophy when heteroplasmic (mixed mutant and normal mtDNAs). Two examples of such mutations are ND6 G14459A (A72V) (5) and ND6 G14600A (P25L) (6).LHON generally presents in the second or third decade of life as acute or subacute onset of central vision loss, first in one eye and then in the other. The percentage of optic atrophy in patients varies markedly among pedigrees. Male patients are two to five times more likely to develop blindness than female patients (2), and maternal relatives who have not progressed to subacute optic atrophy can still show signs of visual impairment (7,8).In LHON, optic atrophy is associated with preferential loss of the central small-caliber optic nerve fibers of the papillomacular bundle, resulting in central scotoma but with sparing of the largercaliber peripheral fibers and retention of peripheral vision. The loss of the optic nerve fibers is attributed to the death of retinal ganglion cells (RGC) as a result of the high energy demand placed on the unmyelinated portion of the optic nerve fibers anterior to the lamina cribosa, an area associated with high mitochondrial density (2).Complex I is the largest and most intricate of the mitochondrial OXPHOS complexes. It is comprised of 45 subunits, 7 (ND1, -2, -3, -4, -4L, -5, and -6) of which are coded by the mtDNA (9). Complex I transfers electrons from NADH to ubiquinone, and the energy released from this redox reaction is coupled to pumping protons across the mitochondrial in...

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Section: Discussionmentioning

confidence: 58%

Mouse mtDNA mutant model of Leber hereditary optic neuropathy

Lin

Sharpley

Fan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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206

190

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“…Mitochondrial membrane potential (Δψ m ) was measured based on the accumulation of tetramethylrhodamine methyl ester (TMRM; Life Technologies) as previously reported 34. Cells were incubated in bicarbonate‐free and phenol red–free Hank balanced salt solution supplemented with 10mM N‐2‐hydroxyethylpiperazine‐N′‐2‐ethanesulfonic acid and loaded with 20nM TMRM for 30 minutes.…”

Section: Methodsmentioning

confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

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ObjectiveMounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.MethodsPatients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.ResultsAffected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase‐negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.InterpretationThe association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21–38

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“…7, B and C), a concentration capable of selectively inhibiting ATP synthase in cells (44). According to a recent report (45), when ATP hydrolysis significantly contributes to the maintenance of ⌬ m , the addition of oligomycin results in a ⌬ m collapse even in the presence of IF 1 . The observed higher ⌬ m shown by IF 1 -silenced cells compared with controls appears somehow intriguing because in normoxia IF 1 should not affect F 1 F 0 -ATPase unless uncoupled conditions are considered (32,46), therefore the enhanced ⌬ m seen in IF 1 -silenced cells deserves a different explanation.…”

Section: Discussionmentioning

confidence: 99%