Administration of Bicarbonate Protects Mitochondria, Rescues Retinal Ganglion Cells, and Ameliorates Visual Dysfunction Caused by Oxidative Stress

Abstract

Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway is involved in mitochondrial protection, promoting RGC survival. Soluble adenylyl cyclase (sAC) is a key regulator of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway, which is known to protect mitochondria and promote RGC survival. However, the precise molecular mechanisms connecting the sAC-mediated signaling pathway with mitochondrial protection in RGCs against oxidative stress are not well characterized. Here, we demonstrate that sAC plays a critical role in protecting RGC mitochondria from oxidative stress. Using mouse models of oxidative stress induced by ischemic injury and paraquat administration, we found that administration of bicarbonate, as an activator of sAC, protected RGCs, blocked AMP-activated protein kinase activation, inhibited glial activation, and improved visual function. Moreover, we found that this is the result of preserving mitochondrial dynamics (fusion and fission), promoting mitochondrial bioenergetics and biogenesis, and preventing metabolic stress and apoptotic cell death. Notably, the administration of bicarbonate ameliorated mitochondrial dysfunction in RGCs by enhancing mitochondrial biogenesis, preserving mitochondrial structure, and increasing ATP production in oxidatively stressed RGCs. These findings suggest that activating sAC enhances the mitochondrial structure and function in RGCs to counter oxidative stress, consequently promoting RGC protection. We propose that modulation of the sAC-mediated signaling pathway has therapeutic potential acting on RGC mitochondria for treating glaucoma and other retinal diseases.

LazyNet: Interpretable ODE Modeling of Sparse CRISPR Single-Cell Screens Reveals New Biological Insights

“…Immune–redox cross-talk involving TLR4–STAT3 that amplifies mitochondrial ROS is also recovered [ 51 ]. In parallel, ADCY10-driven mitochondrial cAMP has been shown to protect neurons under oxidative stress, matching the directionality of edges observed here [ 52 ]. These concordances indicate that LazyNet recovers known biology across mitochondrial, immune, and metabolic axes.…”

LazyNet: Interpretable ODE Modeling of Sparse CRISPR Single-Cell Screens Reveals New Biological Insights

“…Immune–redox cross-talk involving TLR4–STAT3 that amplifies mitochondrial ROS is also recovered [ 51 ]. In parallel, ADCY10-driven mitochondrial cAMP has been shown to protect neurons under oxidative stress, matching the directionality of edges observed here [ 52 ]. These concordances indicate that LazyNet recovers known biology across mitochondrial, immune, and metabolic axes.…”

SPG302 protects retinal ganglion cells and preserves visual function by preserving synaptic activity in a mouse model of glaucoma

“…SPG302 treatment in mice exhibiting microbead-induced elevations in IOP was efficacious in preserving RGCs, their axons, and visual function in the context of glaucomatous neurodegeneration. Notably, this protective effect was associated with the preservation of synapses as evidenced by normalization of the expression levels of pre- and post-synaptic proteins, including synaptophysin, Bassoon, and PSD95, as well as TUJ1, which spans the soma, dendrites, and axons ( Bastola et al, 2024 ; Zhang et al, 2010 ).…”

Challenging glaucoma with emerging therapies: an overview of advancements against the silent thief of sight

“…When the cellular antioxidant system fails to neutralize excess ROS, oxidative stress ensues, leading to RGCs degeneration and optic nerve damage ( 124 ). Elevated IOP has been shown to exacerbate oxidative stress by reducing the activity of key antioxidant enzymes, such as glutathione peroxidases, which are essential for combating oxidative damage ( 125 , 126 ). Additionally, mitochondrial defects contribute to increased ROS levels and decreased ATP production, which is vital for maintaining cellular homeostasis, particularly in energy demanding cells like RGCs ( 1 , 127 ).…”

LazyNet: Interpretable ODE Modeling of Sparse CRISPR Single-Cell Screens Reveals New Biological Insights

“…Immune–redox cross-talk involving TLR4–STAT3 that amplifies mitochondrial ROS is also recovered [ 51 ]. In parallel, ADCY10-driven mitochondrial cAMP has been shown to protect neurons under oxidative stress, matching the directionality of edges observed here [ 52 ]. These concordances indicate that LazyNet recovers known biology across mitochondrial, immune, and metabolic axes.…”

SPG302 protects retinal ganglion cells and preserves visual function by preserving synaptic activity in a mouse model of glaucoma

“…SPG302 treatment in mice exhibiting microbead-induced elevations in IOP was efficacious in preserving RGCs, their axons, and visual function in the context of glaucomatous neurodegeneration. Notably, this protective effect was associated with the preservation of synapses as evidenced by normalization of the expression levels of pre- and post-synaptic proteins, including synaptophysin, Bassoon, and PSD95, as well as TUJ1, which spans the soma, dendrites, and axons ( Bastola et al, 2024 ; Zhang et al, 2010 ).…”

Challenging glaucoma with emerging therapies: an overview of advancements against the silent thief of sight

“…When the cellular antioxidant system fails to neutralize excess ROS, oxidative stress ensues, leading to RGCs degeneration and optic nerve damage ( 124 ). Elevated IOP has been shown to exacerbate oxidative stress by reducing the activity of key antioxidant enzymes, such as glutathione peroxidases, which are essential for combating oxidative damage ( 125 , 126 ). Additionally, mitochondrial defects contribute to increased ROS levels and decreased ATP production, which is vital for maintaining cellular homeostasis, particularly in energy demanding cells like RGCs ( 1 , 127 ).…”

LazyNet: Interpretable ODE Modeling of Sparse CRISPR Single-Cell Screens Reveals New Biological Insights

“…Immune–redox cross-talk involving TLR4–STAT3 that amplifies mitochondrial ROS is also recovered [ 51 ]. In parallel, ADCY10-driven mitochondrial cAMP has been shown to protect neurons under oxidative stress, matching the directionality of edges observed here [ 52 ]. These concordances indicate that LazyNet recovers known biology across mitochondrial, immune, and metabolic axes.…”

SPG302 protects retinal ganglion cells and preserves visual function by preserving synaptic activity in a mouse model of glaucoma

“…SPG302 treatment in mice exhibiting microbead-induced elevations in IOP was efficacious in preserving RGCs, their axons, and visual function in the context of glaucomatous neurodegeneration. Notably, this protective effect was associated with the preservation of synapses as evidenced by normalization of the expression levels of pre- and post-synaptic proteins, including synaptophysin, Bassoon, and PSD95, as well as TUJ1, which spans the soma, dendrites, and axons ( Bastola et al, 2024 ; Zhang et al, 2010 ).…”

Challenging glaucoma with emerging therapies: an overview of advancements against the silent thief of sight

“…When the cellular antioxidant system fails to neutralize excess ROS, oxidative stress ensues, leading to RGCs degeneration and optic nerve damage ( 124 ). Elevated IOP has been shown to exacerbate oxidative stress by reducing the activity of key antioxidant enzymes, such as glutathione peroxidases, which are essential for combating oxidative damage ( 125 , 126 ). Additionally, mitochondrial defects contribute to increased ROS levels and decreased ATP production, which is vital for maintaining cellular homeostasis, particularly in energy demanding cells like RGCs ( 1 , 127 ).…”