Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy

Giordano, Carla; Iommarini, Luisa; Giordano, Luca; Maresca, Alessandra; Pisano, Annalinda; Valentino, Maria Lucia; Caporali, Leonardo; Liguori, Rocco; Deceglie, Stefania; Roberti, Marina; Fanelli, Francesca; Fracasso, Flavio; Ross‐Cisneros, Fred N.; D’Adamo, Pio; Hudson, Gavin; Pyle, Angela; Yu‐Wai‐Man, Patrick; Chinnery, Patrick F.; Zeviani, Massimo; Salomão, Solange Rios; Berezovsky, Adriana; Belfort, Rubens; Ventura, Dora Fix; Moraes, Maria Nathália; Filho, Milton Moraes; Barboni, Piero; Sadun, Federico; Negri, Anna Maria De; Sadun, Alfredo A.; Tancredi, Andrea; Mancini, Massimiliano; d’Amati, Giulia; Polosa, Paola Loguercio; Cantatore, Palmiro; Carelli, Valerio

doi:10.1093/brain/awt343

Cited by 240 publications

(249 citation statements)

References 59 publications

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“…A more favourable final visual outcome was observed for all three genotypes in our childhood-onset LHON cohort compared with previously published figures (m.3460G>A: 14% vs 55%–96%; m.11778G>A: 45% vs 73%–98%; and m.14484T>C mutation: 6% vs 30%–50% of eyes achieving a BCVA <0.1) 1 6 8 20 21. Mitochondrial turnover is implicated in the pathogenesis of LHON, both mitochondrial biogenesis and mitophagy being increased in fibroblasts of patients with LHON 23 24. The known age-related decline in mitophagy, and hence presumably mitochondrial biogenesis, may underlie this difference from adult disease 25…”

Section: Discussionsupporting

confidence: 68%

Childhood-onset Leber hereditary optic neuropathy

et al. 2017

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Section: Discussionsupporting

confidence: 68%

Childhood-onset Leber hereditary optic neuropathy

et al. 2017

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“…There is increasing evidence in in vitro studies and animal models that increased mitochondrial biogenesis might be beneficial in many mitochondrial diseases. Interestingly, a recent observation suggested that increased mitochondrial content influences incomplete penetrance in LHON patients and that mitochondrial biogenesis could be used as a therapeutic strategy in this group of patients (44). The biological pathway that controls mitochondrial biogenesis is complex and relies mostly on the PPAR γ coactivator 1α (PGC1α).…”

Section: Emerging Therapiesmentioning

confidence: 99%

Emerging therapies for mitochondrial diseases

Hirano

Emmanuele

Quinzii

2018

Essays in Biochemistry

119

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For the vast majority of patients with mitochondrial diseases, only supportive and symptomatic therapies are available. However, in the last decade, due to extraordinary advances in defining the causes and pathomechanisms of these diverse disorders, new therapies are being developed in the laboratory and are entering human clinical trials. In this review, we highlight the current use of dietary supplement and exercise therapies as well as emerging therapies that may be broadly applicable across multiple mitochondrial diseases or tailored for specific disorders. Examples of non-tailored therapeutic targets include: activation of mitochondrial biogenesis, regulation of mitophagy and mitochondrial dynamics, bypass of biochemical defects, mitochondrial replacement therapy, and hypoxia. In contrast, tailored therapies are: scavenging of toxic compounds, deoxynucleoside and deoxynucleotide treatments, cell replacement therapies, gene therapy, shifting mitochondrial DNA mutation heteroplasmy, and stabilization of mutant mitochondrial transfer RNAs.

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“…The idea that mitochondrial biogenesis is critical to determine the phenotypic outcome of disease has been boosted by the recent observation that increased mitochondrial content protects non-manifesting carriers of the LHON mutations. This can partly explain the incomplete penetrance of the disease and opens the possibility to stimulate mitochondrial biogenesis as a therapeutic strategy for LHON [16].…”

Section: Increasing Mitochondrial Biogenesismentioning

confidence: 99%

Emerging concepts in the therapy of mitochondrial disease

Viscomi

Bottani

Zeviani

2015

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Mitochondrial disorders are an important group of genetic conditions characterized by impaired oxidative phosphorylation. Mitochondrial disorders come with an impressive variability of symptoms, organ involvement, and clinical course, which considerably impact the quality of life and quite often shorten the lifespan expectancy. Although the last 20 years have witnessed an exponential increase in understanding the genetic and biochemical mechanisms leading to disease, this has not resulted in the development of effective therapeutic approaches, amenable of improving clinical course and outcome of these conditions to any significant extent. Therapeutic options for mitochondrial diseases still remain focused on supportive interventions aimed at relieving complications. However, new therapeutic strategies have recently been emerging, some of which have shown potential efficacy at the pre-clinical level. This review will present the state of the art on experimental therapy for mitochondrial disorders.

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Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy

Cited by 240 publications

References 59 publications

Childhood-onset Leber hereditary optic neuropathy

Childhood-onset Leber hereditary optic neuropathy

Emerging therapies for mitochondrial diseases

Emerging concepts in the therapy of mitochondrial disease

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