Calcium and mitochondria

October 21, 2021

By Ruolin Fan, MPFI Postdoctoral Fellow

Calcium is an important mineral in human body. Most of us have been familiar with it since we were children. However, it has been a long time before I realized that, aside from being the major component of bones and teeth, calcium is also a critical signal that controls muscle contraction, heartbeat, and brain activities.

By directly interacting with various proteins, calcium effectively turns them “on” or “off”. In this way, the flow of calcium serves as signals that control multiple cellular processes. In the brain, a spike of calcium flux could be triggered by a beautiful scene, a crazy idea, or a warm hug from the lover; it could also represent just a subtle move, a random intention; or, if we further zoom in to the world of a single nerve cell (i.e. neuron), an action potential, which means that just less than a millisecond ago this neuron has decided to fire upon compiling information received from other neurons. Upon firing, calcium enters the neurons through activated channels on the cell membrane, which would induce a sequence of reactions, including energy production, the release of neurotransmitters, production of new proteins, etc.

Observing the calcium dynamics in living neurons under the microscope gives me a fascinating sense of calm and peace as if watching the cell breathing, or visualizing a harmonious rhythm. In this rhythm, the calcium concentration is delicately controlled in all cellular compartments, so that everything stays in tune. This might be the reason why the mechanisms for calcium regulation have always been a key subject in the research of neuronal functions.

The calcium concentration in the extracellular space is typically ~10,000-fold of that inside the cells. Given this fact, when the calcium channels are opened, calcium floods into the cell spontaneously, rapidly increasing its local concentration. If the incoming calcium exceeds the capacity of the cell, the cell will suffer from stress and even burst, similar to the floods in the rainy season. In this case, mitochondria can work as reservoirs where calcium could be stored temporarily, and further released when needed. For example, uptake and efflux of mitochondria calcium regulates the release of neurotransmitters stored in synaptic vesicles by controlling calcium concentration. Meanwhile, mitochondria sense calcium overload as one of the earliest warning signs for neuronal stress. This may trigger a series of processes that eventually lead to cell death, which has been linked with many neurodegenerative diseases, including Alzheimer’s Disease and Parkinson’s Disease.

On the other hand, the calcium entering mitochondria could be of further use. It serves as a signal that promotes energy production by reacting with several enzyme molecules in mitochondria. Since neuron activities consume large amounts of energy, this smart mechanism allows for timely reactions to local needs. Even more amazingly, mitochondria are dynamic reservoirs that can actively traffic and be selectively sequestered to specific positions. Even their size and shape could be changed through splitting (fission) and merging (fusion). All of these  processes are under the regulation of calcium

In a neuron, the place where the dynamic feature of mitochondria is best manifested is probably the synapse. Synapse is the connection between two neurons that works like plugs and sockets, where neuronal signals are transmitted. By microscopic imaging, scientists found that mitochondria on the two sides of a synapse have a distinct morphology and behave differently. On the presynaptic side, where neuronal signals are emitted, mitochondria are motile ovals with diameters generally around 1 µm. In contrast, postsynaptic mitochondria are static filaments with lengths of up to 10 µm. Are they reacting differentially with calcium in neuronal activities? Is their energy production regulated in different manners? Since different activities are taking place on the two sides of the synapse, it is assumed that the mitochondria are also respectively adapted to different energy expenditures. How exactly are they different is still an open question and an attractive topic of ongoing research.

If calcium is the rhythm of life, the mitochondrion is the most delicate part of the instrument. If calcium is the stream, the mitochondrion is the smartest reservoir. If calcium is the language of the cell, the mitochondrion is the wisest communicator. They are reminiscent of a perfect companion, who always picks up on your signals, takes in your emotions when you feel overwhelmed, is present whenever and wherever they are needed, and power you up when you are drained… While nature has offered such a wise system intrinsically in our body, it is still hard for us, the advanced and intelligent human-beings to be such a perfect creature, isn’t it?