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 2025

Dr. Wu plans to study whether the rules for lactate regulation of the mitochondria that his laboratory  learned in iPSC-RPE from patients without AMD are the same or different for those from patients with high or low risk variations in genes for AMD or with different types of AMD (for example wet vs dry).  Dr Wu also plans to study how missing lactate may interfere with the normal importing, metabolizing, and transporting lipids for the retina – a task that is usually an important role of the RPE.

Specific Aims:

Aim 1: To understand how lactate regulation of mitochondria changes in the RPE cells of patients with genes that put them at risk for AMD or those with different types of AMD

Aim 2: To understand how a loss of lactate can lead to changes in the RPE that reduce the import and metabolism of lipids important for building the retina.

Progress in 2024

Throughout 2024, Dr. Wu’s laboratory was able to continue its studies in the iPSC-RPE model (induced pluripotent stem cell derived RPE cell) – an important model that allows us to grow RPE cells from patients without damaging their eyes.  This allowed the team to study how a patient’s own genetic background may affect different cellular processes.  They learned that a normal metabolite that declines in aging – lactate – can cause specific changes to the structure and function of mitochondria of the RPE.  The mitochondria are the energy factories of the cell, and deterioration of these factories is known to occur as AMD worsens.  This past year, Dr Wu’s team learned that lactate regulation of mitochondria is more complex than previously imagined, as what lactate does can change depending on what other metabolites are present.  In trying to understand what metabolites are present and absent, the lab also learned that the retinas of mice that are missing lactate also end up having fewer lipids than normal, an important building block for retinal cells.

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.