Groundbreaking study finds activator of magnesium dynamics in the body

Magnesium energetics
This illustration depicts the exercise-induced surge of the metabolite lactate (seen in red, black and white) from skeletal muscle (shown as a factory) into liver cells. The lactate surge elicits release of magnesium ions (seen as green balls) from cellular storehouses called the endoplasmic reticulum (depicted as a rock outcrop in the water). The magnesium ions release as waves that are funneled into energy centers called mitochondria (depicted as a boat) through a transporter called Mrs2 (depicted as fishermen). Cover image courtesy Sarah Bussey Artistry. Concept by Travis Madaris.

Discovery seen as avenue to develop novel therapies for many conditions.

Researchers from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) have solved the 100-year-old mystery of what activates magnesium ions in the cell. The discovery is expected to be a springboard for future development of novel drugs to treat cardiovascular disease, metabolic disorders such as diabetes, and other diseases.

Reporting Oct. 8 in Cell, scientists in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio said the magnesium activator is a metabolite called lactate, which is elevated in the blood during intense exercise and in many diseases, including heart disease, diabetes, sepsis and cancer.

“Lactate is a signal that – like a light switch – turns on magnesium ions,” said lead author Madesh Muniswamy, PhD, professor of cardiology in the Long School of Medicine. “On lactate’s signal, the ions rush out of cellular storehouses called the endoplasmic reticulum.”

The team made a second discovery: A protein called Mrs2 transports the released magnesium ions into cell powerhouses known as mitochondria. These power plants generate ATP, which is the energy currency fueling all the processes in the body.

“We believe this loop is essential for health,” said study coauthor W. Brian Reeves, MD, chairman of the Department of Medicine at UT Health San Antonio. “If there is a problem with magnesium routing, impairments ensue, such as the diminished mitochondrial function and poor energy production observed in Type 2 diabetes or severe infections.”

IP3, the activator for calcium ions, was discovered in 1984. Since that time, the calcium field has grown in monumental fashion, whereas magnesium continued to be a riddle, said coauthor Karthik Ramachandran, PhD, postdoctoral fellow in the Muniswamy laboratory.

Coauthor Travis Madaris, a graduate student on the research team, said, “As a student in the lab, this discovery is exciting because it lays out a pathway for multiple publications while I’m in this lab, and most importantly, it can lead to many future discoveries to improve human health.”

Madaris is supported by a predoctoral research training fellowship awarded by the National Institutes of Health.

Summing up the discovery, Dr. Muniswamy said: “Magnesium is essential for life. It’s in our blood. It’s been implicated in and used as a treatment for a variety of diseases, including migraines, cardiovascular diseases, diabetes and preeclampsia. But to take the next step forward, we needed to understand the dynamics of magnesium in our bodies. With this finding, we believe we have laid out one of the pillars of support that the scientific world needed.”

The National Institutes of Health (National Institute of General Medical Sciences and National Heart, Lung, and Blood Institute); the U.S. Department of Defense; and the San Antonio Partnership for Precision Therapeutics provided funding for this research.

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Lactate Elicits ER-Mitochondrial Mg2+ Dynamics to Integrate Cellular Metabolism

Cassidy C. Daw, Karthik Ramachandran, Benjamin T. Enslow, Soumya Maity, Brian Bursic, Matthew J. Novello, Cherubina S. Rubannelsonkumar, Ayah H. Mashal, Joel Ravichandran, Terry M. Bakewell, Weiwei Wang, Kang Li, Travis R. Madaris, Christopher E. Shannon, Luke Norton, Soundarya Kandala, Jeffrey Caplan, Subramanya Srikantan, Peter B. Stathopulos, W. Brian Reeves and Madesh Muniswamy

First published: Oct. 8, 2020, Cell

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The Long School of Medicine at The University of Texas Health Science Center at San Antonio is named for Texas philanthropists Joe R. and Teresa Lozano Long. The school is the largest educator of physicians in South Texas, many of whom remain in San Antonio and the region to practice medicine. The school teaches more than 900 students and trains 800 residents each year. As a beacon of multicultural sensitivity, the school annually exceeds the national medical school average of Hispanic students enrolled. The school’s clinical practice is the largest multidisciplinary medical group in South Texas with 850 physicians in more than 100 specialties. The school has a highly productive research enterprise where world leaders in Alzheimer’s disease, diabetes, cancer, aging, heart disease, kidney disease and many other fields are translating molecular discoveries into new therapies. The Long School of Medicine is home to a National Cancer Institute-designated cancer center known for prolific clinical trials and drug development programs, as well as a world-renowned center for aging and related diseases.

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