Mitochondrial Flavoprotein Fluorescence for Retinal Metabolic Imaging

Mitochondrial Flavoprotein Fluorescence for Retinal Metabolic Imaging

January 10, 2022

The mitochondrion is considered to be the powerhouse of eukaryotic cells. Oxidative phosphorylation produces energy, leading to adenosine triphosphate production.

In addition, mitochondria perform numerous other functions in cellular homeostases such as apoptosis regulation, steroid biosynthesis, and nucleotide metabolism.

For this reason, mitochondrial dysfunction can severely compromise cellular homeostasis and has been highlighted as a crucial mechanism in the pathophysiology of normal aging and pathologic processes including retinal diseases.

Mitochondrial dysfunction is recognized to play a crucial role in a wide range of diseases and organs, with the most affected organs being those that have a high metabolic rate such as brain and heart. 

For example, previous studies have shown evidence of mitochondrial involvement in the pathophysiology of neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, and in cardiac ischemia-reperfusion injury.

Retinal pathologies, including diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma, are leading causes of ocular morbidity worldwide. Early detection and treatment of these pathologies has the potential to result in more positive visual outcomes.

Currently, spectral domain optical coherence tomography (SD-OCT) is standard of care for imaging and diagnosis of retinal pathologies, visualizing structural change in disease state with high resolution and sensitivity.

However, SD-OCT is primarily structural; it cannot provide insight into retinal oxidative stress and damage nor metabolic function. As a highly metabolic tissue, the retina is susceptible to stressors that limit energy supply.

Inefficient mitochondria result in metabolic dysfunction, which has been implicated in the pathogenesis of DR, AMD, and glaucoma.

Oxidative stress is a primary driver of mitochondrial dysfunction over time, leading to impaired cellular respiration organelle death. Oxidized flavoproteins are mitochondrial proteins that reflect oxidative stress.

When in a prooxidative environment, these proteins display properties of autofluorescence. When excited by blue-spectrum light, they emit green-spectrum light, and this phenomenon is termed flavoprotein fluorescence (FPF).

Flavoprotein fluorescence can be harnessed with retinal metabolic imaging devices, to detect fluorescence of these proteins and, by extension, the first signs of retinal pathology before it manifests in gross anatomic change.

This, in turn, can lead to earlier treatment and positive visual outcomes. This review article will summarize FPF physiology and its application to retinal imaging by examining the role of mitochondrial dysfunction in retinal diseases, preclinical FPF studies, and recent clinical studies exploring FPF in patients with DR, AMD, and glaucoma.

MITOCHONDRIAL DYSFUNCTION AT THE CELLULAR LEVEL

Mitochondria play crucial roles in cellular function, including adenosine triphosphate (ATP) production, regulation of cellular metabolism, calcium signaling, inflammatory signaling, and control of apoptosis.

Dysfunctional mitochondria can therefore lead to decreased energy production, increased inflammation, and apoptosis.

Increased reactive oxidative species (ROS) combined with decreased host antioxidant defenses are known to generate a pro-oxidative state, which contributes to mitochondrial dysfunction through alteration of mtDNA, lipid oxidation, and protein oxidation.

Alterations in mtDNA can produce defective electron transport chain proteins and protein oxidation compounds this effect, causing inefficient cellular respiration and further favors ROS production.

Peroxidation of lipids can increase apoptosis and autophagy. Because of their crucial role in cellular energy production, highly metabolic tissues are susceptible to damage in the setting of mitochondrial dysfunction.

The retina is a primary example of this due to high mitochondrial density in retinal pigment epithelium and photoreceptor layers. Mitochondrial dysfunction in these retinal layers has been implicated in retinal pathogenesis of AMD, DR, and glaucoma.

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