MECR and MEPAN - A Role in Immune Function?

Basic science plays a crucial role in the development of treatments for rare genetic diseases like MEPAN Syndrome. While this work often focuses on understanding fundamental biological processes, the discoveries can have significant translational implications.

That idea came full circle this week when I listened to the thesis defense of KayLee Steiner, PhD, who studied in the Rathmell Lab at Vanderbilt University, where she researched the role of mitochondrial fatty acid synthesis (mtFAS) and the MECR gene in CD4+T cell metabolism and oxidative metabolism.

KayLee contacted me in April 2023 after coming across the MEPAN Foundation website and learning of our work in facilitating awareness and collaboration in mtFAS and MECR research, and I was happy to connect her with researchers studying the pathway.

Her research found that several genes in the mtFAS pathway – MECR, MCAT, and OXSM – were found to be differentially expressed in several different cell types, resulting in reduced CD4+ T cell function, reduced oxidative metabolism, and a compromised immune response.

This observed reduction in activated T cell fitness and impaired immune responses may contribute to infection susceptibility seen in mitochondrial disease patients, including those with MEPAN. Since immune cell activation, inflammation resolution, and oxidative metabolism are crucial for proper tissue repair, MECR deficiency may also hinder effective wound healing.

The findings provide insights relevant to understanding MEPAN pathology and may help explain some issues that we have experienced with Carson and Chase. KayLee also noted that:

• MECR is crucial for activated CD4+ T cells’ ability to proliferate, differentiate, and survive.

• In MECR-deficient mice, activated T cells showed reduced mitochondrial respiration, reduced TCA cycle intermediates, and an accumulation of intracellular iron. This aligns with known mitochondrial dysfunction in MEPAN.

• MECR-deficient T cells showed reduced ETC complex proteins (especially complexes I and II), impaired oxidative metabolism, and ATP deficiency, mirroring the mitochondrial dysfunction seen in people with MEPAN.

From Steiner, et al: comparison of labile and mitochondrial iron levels in CD4+T cells

Importantly, KayLee’s research also showed that Mecr knockout T cells accumulated iron and showed increased susceptibility to ferroptosis, a form of iron-dependent cell death; this aligns with the iron metabolism dysfunction seen in patient fibroblasts analyzed by Dutta et al in 2023. She was then able to rescue cell viability in MECR knockout cells in mice by treating them with UAMC-3203, an experimental compound that can inhibit ferroptosis (UAMC-3203 has also been shown to aid in functional recovery in rats with spinal cord injuries).

When basic researchers understand the downstream clinical implications of their work, they are more likely to engage with translational scientists, clinicians, and patient groups. This collaboration is essential for turning promising discoveries into viable treatments. We congratulate KayLee and thank her for considering MEPAN!

Dr. Steiner's paper will appear soon in the Journal of Immunology.