Small Molecules that Protect Mitochondrial Function from Metabolic Stress Decelerate Loss of Photoreceptor Cells in...

Area of Science:

• Biochemistry
• Neuroscience
• Pharmacology

Background:

• Retinal degeneration is linked to metabolic stress and impaired mitochondrial function.
• Metabolic stressors like calcium ionophores and oxidants reduce mitochondrial capacity.

Purpose of the Study:

• To screen a large library of drug-like molecules for compounds that protect mitochondrial function.
• To identify molecules that can prevent photoreceptor cell loss in models of retinal degeneration.

Main Methods:

• Screening of 50,000 molecules against calcium-induced mitochondrial dysfunction in cell lines.
• Testing protective hits against IBMX-induced mitochondrial dysfunction using respirometry.
• Evaluating efficacy in protecting rod photoreceptor cells in retinal explants from rd1 mice.

Main Results:

• Two molecules demonstrated protection against mitochondrial capacity loss.
• These molecules attenuated photoreceptor cell loss in the rd1 mouse model.
• The compounds also blocked mitochondrial fragmentation induced by stressors in 661W cells.

Conclusions:

• Identified molecules protect mitochondria and photoreceptor cells.
• These compounds represent promising leads for developing therapeutics for retinal dystrophies.
• Targeting mitochondrial dysfunction is a viable strategy for treating retinal degeneration.