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A 100-year-old mystery of what activates magnesium ions in the cell, solved

Magnesium is the most abundant divalent cation in metazoans and an essential cofactor for ATP, nucleic acids, and countless metabolic enzymes. But, what activates Magnesium in cells remains obscure.

A study by the University of Texas Health Science Center at San Antonio (UT Health San Antonio) has solved this century old mystery.

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.

This discovery is expected to be a springboard for the future development of novel drugs to treat cardiovascular disease, metabolic disorders such as diabetes, and other diseases.

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

Scientists also discovered a protein called Mrs2 that transports the released magnesium ions into mitochondria.

Study coauthor W. Brian Reeves, MD, chairman of the Department of Medicine at UT Health San Antonio, said, “We believe this loop is essential for health. 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.”

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.”

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 various diseases, including migraines, cardiovascular diseases, diabetes, and preeclampsia. But to take the next step forward, we needed to understand Magnesium’s dynamics in our bodies. With this finding, we believe we have laid out one of the pillars of support that the scientific world needed.”

Journal Reference:
  1. Lactate Elicits ER-Mitochondrial Mg2+ Dynamics to Integrate Cellular Metabolism, Cell (2020). DOI: 10.1016/j.cell.2020.08.049

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