The Present and Future of Mitochondrial-Based Therapeutics for Eye Disease

Ji, Marco H.; Kreymerman, Alexander; Belle, Kinsley; Ghiam, Benjamin Kambiz; Muscat, Stephanie; Mahajan, Vinit B.; Enns, Gregory M.; Mercola, Mark; Wood, Edward H.

doi:10.1167/tvst.10.8.4

Cited by 9 publications

(3 citation statements)

References 163 publications

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“…Several common ocular diseases, such as glaucoma and diabetic retinopathy are characterized by mitochondrial dysfunction in the neural retina and retinal pigment epithelium (RPE). For such diseases, recent studies have focused on improving mitochondrial functions to restore vision, with therapeutic approaches directed to ameliorate mitochondrial membrane potential and stability, ROS production, mitochondrial fusion and fission, mitochondrial biogenesis, mitophagy, apoptosis, and mitochondrial DNA (mtDNA) transcription ( 70 ). Retinoblastoma is not classified as a mitochondrial disease; however, evidence suggests that mitochondria are affected in this disease ( Figure 2 ).…”

Section: Mitochondrial Morphology and Metabolism In Retinoblastomamentioning

confidence: 99%

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

Romani

Zauli²,

Zauli³

et al. 2022

Front. Oncol.

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MDM2 is the principal inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The half-life of p53 is very short in normal cells and tissues, and an uncontrolled increase in p53 levels has potential harmful effects. It has been shown that p53 is frequently mutated in most cancers; however, p53 mutations are rare in retinoblastoma. Therefore, therapeutic strategies aimed at increasing the expression levels of wild-type p53 are attractive. In this minireview, we discuss the potential use of nutlin-3, the prototype small molecule inhibitor that disrupts the MDM2-p53 interaction, for the treatment of retinoblastoma. Although p53 has pleiotropic biological effects, the functions of p53 depend on its sub-cellular localization. In the nucleus, p53 induces the transcription of a vast array of genes, while in mitochondria, p53 regulates mitochondrial metabolism. This review also discusses the relative contribution of p53-mediated gene transcription and mitochondrial perturbation for retinoblastoma treatment.

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Section: Mitochondrial Morphology and Metabolism In Retinoblastomamentioning

confidence: 99%

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

Romani

Zauli²,

Zauli³

et al. 2022

Front. Oncol.

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“…For instance, intervening on the chronic intake of active molecules such as caffeine has been recently reported to exert protective effects on RGCs through anti-inflammatory action (3). In addition, impairment of mitochondrial function by mechanical stress and decreased blood perfusion due to IOP increase is likely to affect RGC survival thus eliciting a great interest on strategies that intervene on mitochondrial dysfunction in order to delay or even halt RGC loss (4)(5)(6). Some dietary supplements targeting mitochondrial dysfunction have been demonstrated to lower the risk of developing glaucoma and potentially slow disease progression.…”

Section: Introductionmentioning

confidence: 99%

Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma

Melecchi,

Amato,

Dal Monte

et al. 2023

Front. Med.

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IntroductionMuch interest has been addressed to antioxidant dietary supplements that are known to lower the risk of developing glaucoma or delay its progression. Among them, niacin and citicoline protect retinal ganglion cells (RGCs) from degeneration by targeting mitochondria, though at different levels. A well-established mouse model of RGC degeneration induced by experimental intraocular pressure (IOP) elevation was used to investigate whether a novel combination of niacin/citicoline has better efficacy over each single component in preserving RGC health in response to IOP increase.MethodsOcular hypertension was induced by an intracameral injection of methylcellulose that clogs the trabecular meshwork. Electroretinography and immunohistochemistry were used to evaluate RGC function and density. Oxidative, inflammatory and apoptotic markers were evaluated by Western blot analysis.ResultsThe present results support an optimal efficacy of niacin with citicoline at their best dosage in preventing RGC loss. In fact, about 50% of RGCs were spared from death leading to improved electroretinographic responses to flash and pattern stimulation. Upregulated levels of oxidative stress and inflammatory markers were also consistently reduced by almost 50% after niacin with citicoline thus providing a significant strength to the validity of their combination.ConclusionNiacin combined with citicoline is highly effective in restoring RGC physiology but its therapeutic potential needs to be further explored. In fact, the translation of the present compound to humans is limited by several factors including the mouse modeling, the higher doses of the supplements that are necessary to demonstrate their efficacy over a short follow up period and the scarce knowledge of their transport to the bloodstream and to the eventual target tissues in the eye.

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“…Based on the central role of mitochondria in AMD, strategies targeting mitochondrial homeostasis have great potential [79]. Interestingly, subcutaneous treatment with Elamipretide (Stealth Biotherapeutics, Needham, MA, USA), a tetrapeptide SS-31 drug which targets mitochondrial cardiolipin, is currently under development for dry AMD, reversed RPE morphological changes, sub-RPE deposits, and visual dysfunction.…”

Section: Mitochondria-based Therapiesmentioning

confidence: 99%

Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration

Lenin,

Koh,

Zhang

et al. 2023

IJMS

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Retinal pigment epithelial (RPE) cell dysfunction is a key driving force of AMD. RPE cells form a metabolic interface between photoreceptors and choriocapillaris, performing essential functions for retinal homeostasis. Through their multiple functions, RPE cells are constantly exposed to oxidative stress, which leads to the accumulation of damaged proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. As miniature chemical engines of the cell, self-replicating mitochondria are heavily implicated in the aging process through a variety of mechanisms. In the eye, mitochondrial dysfunction is strongly associated with several diseases, including age-related macular degeneration (AMD), which is a leading cause of irreversible vision loss in millions of people globally. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species (ROS) generation, and increased numbers of mitochondrial DNA mutations. Mitochondrial bioenergetics and autophagy decline during aging because of insufficient free radical scavenger systems, the impairment of DNA repair mechanisms, and reductions in mitochondrial turnover. Recent research has uncovered a much more complex role of mitochondrial function and cytosolic protein translation and proteostasis in AMD pathogenesis. The coupling of autophagy and mitochondrial apoptosis modulates the proteostasis and aging processes. This review aims to summarise and provide a perspective on (i) the current evidence of autophagy, proteostasis, and mitochondrial dysfunction in dry AMD; (ii) current in vitro and in vivo disease models relevant to assessing mitochondrial dysfunction in AMD, and their utility in drug screening; and (iii) ongoing clinical trials targeting mitochondrial dysfunction for AMD therapeutics.

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The Present and Future of Mitochondrial-Based Therapeutics for Eye Disease

Cited by 9 publications

References 163 publications

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma

Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration

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