Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium

Abstract

Retinal degenerative diseases are generally characterized by a permanent loss of light-sensitive retinal neurons known as photoreceptors, or their support cells, the retinal pigmented epithelium (RPE). Metabolic dysfunction has been implicated as a common mechanism of degeneration. In this study, we used the drug metformin in a gain-of-function approach to activate adenosine monophosphate-activated protein kinase (AMPK). We found that treatment protected photoreceptors and the RPE from acute injury and delayed inherited retinal degeneration. Protection was associated with decreased oxidative stress, decreased DNA damage, and increased mitochondrial energy production. To determine whether protection was a local or a systemic effect of metformin, we used AMPK retinal knockout mice and found that local expression of AMPK catalytic subunit α2 was required for metformin-induced protection. Our data demonstrate that increasing the activity of AMPK in retinal neurons or glia can delay or prevent degeneration of photoreceptors and the RPE from multiple types of cell-death triggers.

Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, provides photoreceptor neuroprotection

“…Studies have demonstrated that reprogramming photoreceptor metabolism may prove to be an inventive therapeutic strategy for photoreceptor neuroprotection in retinal degenerations. 4,11,49 This study coupled with our previous work that genetically increased the levels of activated PKM in photoreceptors gives credence to this therapeutic strategy. 15 However, further studies are needed to not only circumvent the solubility issues that limit the translation of ML-265 into the clinic but also to obtain mechanistic insight into the differential actions of PKM1 and PKM2 in photoreceptor metabolism, function, and viability.…”

Systemic Treatment with Nicotinamide Riboside is Protective in Three Mouse Models of Retinal Degeneration

“…Three mouse models of retinal degeneration were tested: an albino mouse model of light-induced retinal degeneration (LIRD) and two models of retinitis pigmentosa (RP), including a mouse line deficient in interphotoreceptor binding protein (IRBP) gene expression (IRBP KO), and a naturally-occuring cGMP phosphodiesterase 6b mutant mouse model of RP (the Pde6b rd10 mouse). Mice were intraperitoneally (IP) injected with PBS or NR at various times relative to damage or degeneration onset.…”

“…9 Because of this, photoreceptors are thought to be especially sensitive to dysregulation of bioenergetic metabolism. 10–12 Indeed, genetic mutations that degrade photoreceptor bioenergetic metabolism cause blindness, including mutations of Krebs cycle enzymes that cause forms of RP 13 and mutations in mitochondrial DNA (mtDNA) that cause Leber Hereditary Optic Neuropathy (LHON). 14 Also, as photoreceptor and RPE cells exist within a metabolic symbiosis, 15 functional compromise in one cell type may negatively affect function in the other.…”

“…14 Also, as photoreceptor and RPE cells exist within a metabolic symbiosis, 15 functional compromise in one cell type may negatively affect function in the other. 10 Thus, targeting metabolic pathways of photoreceptor or RPE cells may be therapeutic across a variety of retinal diseases.…”

AMP-activated-protein kinase (AMPK) is an essential sensor and metabolic regulator of retinal neurons and their integrated metabolism with RPE

“…AMPK is an evolutionarily conserved serine/threonine kinase that functions as a heterotrimeric protein comprised of a single catalytic α-subunit (encoded by either Prkaa1 or Prkaa2 in mice), a regulatory β-regulatory subunit (encoded by either Prkab1 or Prkab2 in mice), and the AMP-binding γ -subunit (encoded by Prkag1, Prkag2 , or Prkag3 in mice) 13 . Expression levels of each of the AMPK subunit isoforms has previously been characterized in both human and mouse retinas 9 . AMPK is activated by increased AMP:ATP ratios within cells, which only occurs with ATP depletion.…”