As a UT Health San Antonio Ph.D. candidate, under the mentorship of Dr. Madesh Muniswamy, I am studying mitochondrial biology and the many pathways involved in physiologic (healthy) and pathophysiologic (unhealthy) states.

Mitochondria are double-membraned organelles that have a vital role in controlling cellular function. Two main roles of mitochondria are to (1) regulate cellular metabolism, and (2) produce energy from sugar and fat (the reason why mitochondria are called the “powerhouse of the cell”).

By studying mitochondrial function, we can understand how cells process signals including bioenergetics, oxidative signaling and ion homeostasis. In other words, we study how certain nutrients available to the cell influence mitochondrial function.

We have previously characterized a transmembrane protein called mitochondrial calcium uniporter (MCU), which is a major route of calcium entry into the mitochondria. Appropriate calcium regulation and concentration is necessary to increase the cell’s energy supply and regulate functions, such as cell death. In a prior study, our lab found that by deleting the MCU gene in mouse liver, there was an inhibition of mitochondrial calcium uptake, delayed cytosolic calcium clearance, reduction in oxidative phosphorylation, and an increased in lipid accumulation.

In our recently published study, we investigated the influence of TCA (tricarboxylic acid)cycle substrates on MCU-mediated mitochondrial calcium uptake, bioenergetics and quality control. The TCA cycle is a series of chemical reactions used to release stored energy derived from carbohydrates, fats, and proteins, into usable energy (in the form of adenosine triphosphate (ATP)). Mitochondria rapidly adapt to energy supply and demand and alter their efficiency of energy generation.

The ability to sense and respond to stress conditions is a crucial cellular feature. Our lab has identified a mitochondrial protein that functions as a gatekeeper of MCU function, known as MICU1. When the availability of nutrients is limited, MICU1 will restrict MCU channel activity. This results in halting excess energy from being produced. Alternatively, in conditions where nutrients are available, MICU1 will increase MCU activity, and more energy will be produced.

We found that MICU1 senses metabolite stress and controls MCU channel activity. Our studies revealed that MICU1 regulates MCU-mediated calcium flux machinery and depends on substrate availability. This mechanism facilitates metabolic homeostasis which protects cells from bioenergetic crisis and mitochondrial calcium overload during periods of nutrient deprivation.

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