Mitochondrial Teamwork Within Cells Found to Regulate Calcium Flux

Penn State researchers were the first to find the mitochondrial mechanism controlling the levels of calcium inside cells. Disruption of mitochondrial calcium regulation can result in an uncontrollable rise of the molecule inside cells, contributing to a host of neurodegenerative, metabolic, and cardiovascular diseases.

The study was performed in the lab of Kevin Foskett at Perelman School of Medicine at the University of Pennsylvania. The findings are reported in the February issue of the journal Cell Reports in the article, “EMRE Is a Matrix Ca²⁺ Sensor that Governs Gatekeeping of the Mitochondrial Ca²⁺ Uniporter.“

Calcium is a crucial cellular signaling molecule, but excess levels following a signaling event need to be cleared for proper cell functioning. This essential compound is needed for cellular energy production, but very high levels are toxic and lead to cell death. The clearance of calcium from the cell is a task for a mitochondrial protein — the mitochondrial calcium uniporter (MCU).

“Understanding the molecular mechanisms by which mitochondrial calcium levels are regulated may have important implications for designing therapeutic targets for a variety of diseases, including diabetes, stroke, cancer, and age-related neurological diseases that have been related to mitochondrial dysfunction. Mitochondria are composed of two membranes. The outer membrane covers this cell component like a skin, and the inner membrane folds over many times, creating layers to increase surface area for the chemical reactions that produce the body’s energy molecules. Disorders of mitochondria can disrupt energy production, essentially like an electrical brown out or black out,” Dr. Foskett said in a press release.

When investigating calcium ion current flow through the MCU, researchers noticed that the levels of calcium inside the mitochondria matrix strongly regulated the activity of MCU. Calcium concentrations act as a brake on MCU, but during cell signaling higher levels of calcium release this brake.

In a previous study, the research group showed that the mitochondrial protein MICU1 is required to set the proper level of calcium uptake under normal conditions. The current study showed that MICU1 is not localized in the matrix, as previously believed, but in the inter-membrane space.

The researchers noticed that EMRE — an MCU-associated membrane — contained an acidic amino acid sequence similar to what is found in calcium-sensing regions of other ion channels. When the team neutralized these regions, calcium regulation became completely disrupted, and calcium levels within mitochondria rose uncontrollably.

Further investigation revealed that calcium regulation of MCU via EMRE required an array of players to function properly — MICU1 and MICU2 on one side of the inner membrane, and calcium on the other side of the inner membrane. EMRE couples these molecules, which act as calcium sensors on both sides of the inner membrane, to regulate MCU activity and thus the rate of mitochondrial calcium flux.

The findings offer a deeper understanding of cellular calcium flux, and may lead the way to new targets in this newly discovered mechanism affecting various diseases.