Department of Ophthalmology
Schepens Eye Research Institute
Harvard Medical School, Boston, Massachusetts

BASIC RESEARCH PROJECT

Metabolic modulation of complement in the retinal pigment epithelium

Research Interests

Dr. Wu recently learned that the eye uses glucose (a common sugar) to fuel its activities in a peculiar way. The retina, the light-detecting part of the eye, uses most of the glucose in a process called glycolysis – creating a leftover sugar known as lactate that is shuttled back as fuel for its neighboring tissue, called the retinal pigment epithelium (RPE). Since the retina is the source of the RPE’s lactate, it follows that if the retina becomes sick, the RPE could also become sick. We have evidence that in a common blinding disease known as Age-related Macular Degeneration (AMD), the photoreceptors may become sick. As they make less lactate to share with the neighboring RPE, the RPE may also become sick. One of the ways the RPE can become sick in AMD is through dysregulation of something called the complement system. The complement system is part of the body’s defense against outside invaders (like bacteria), but sometimes instead of destroying bacteria, it also damages the surrounding tissue. In fact, some people who have variations in their complement genes get AMD more frequently than the average population. Dr. Wu finds that complement in the RPE may be regulated by lactate metabolism in the eye, and he wants to explore this further and see if those with complement genes putting them at high risk for AMD are more vulnerable to disturbances in lactate metabolism.

Plans for 2024

Purpose of Project: To understand how the retinal pigment epithelium (RPE), the cell type in the eye that is central to the pathology of age-related macular degeneration (AMD), becomes more vulnerable to damage as the metabolism of the eye changes with age.

Subsequent to the discovery of a role of lactate in maintaining a high level of oxygen consumption rates, Dr. Wu’s laboratory team will assess the mechanisms by which it does so. Some patients have differences in genes coding for proteins called complement. The lab had previously found that lactate changes complement levels. Now, they will see whether changes in complement levels, or iPSC-RPE from patients who have changes in complement genes that make them at higher risk for AMD, have changes in mitochondrial
oxygen consumption rates.

Specific Aims:
1. To identify the mechanism(s) by which lactate enhances mitochondrial function.

2. To determine whether complement levels inside the cells and changes in
complement genes may affect mitochondrial metabolism, making the RPE more
likely to become sick. Taken together, these aims may help us find new ways to protect mitochondria (and thus reduce the rate of progression of AMD).

Progress in 2023

During 2023, Dr. Wu’s lab was able to initiate the study of a specialized model of RPE – the iPSC-RPE (induced pluripotent stem cell) in the laboratory. This is an important model that has the advantages of being able to be grown from a patient, thus incorporating their own intrinsic background genetic risks that can be studied. the team learned that a normal metabolite that declines in aging – lactate – may play a central role in helping to maintaining/enhancing the function of mitochondria of the RPE. The Mitochondria are the cellular “energy factories,” of the RPE, and deterioration of these factories is a known occurrence as one’s AMD worsens. Dr. Wu found a particular assay in which he could measure the ability of lactate to enhance mitochondria, called the oxygen consumption rate assay. This is important because better mitochondria function leads to a healthier cell.