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Overview

Reference practice ^[3]

Structure

Selectivity Filter

Common Mutations

Medical Relevance

A number of medical conditions all over the body are caused by disruption of the homeostasis of mitochondrial calcium. Diabetes, heart failure, and cancer are just a few members of this broad group of conditions.

Diabetes

In healthy individuals, the 𝛽-cells in the pancreas are responsible for sensing the concentration of glucose in the bloodstream and releasing the appropriate amount of insulin in response. While the mechanism of this activation isn't entirely understood, we can explain a large portion of it in the context of mitochondrial calcium homeostasis. Increased concentration of glucose causes glycolysis in the cell, which increases the amount of ATP. This increase of ATP closes potassium channels in the membrane of the 𝛽-cell which causes depolarization of the membrane. When a certain threshold potential is reached, calcium channels open and create microdomains of calcium below the plasma membrane which allows insulin release by activatin PKC 𝛽-type II. Furthermore, there is a pool of mitochondria in 𝛽-cells near the calcium channels which take in the calcium through the MCU. The mitochondria then create more ATP which sustains and amplifies insulin secretion ^[3].

Any defect in the MCU affects the homeostasis of calcium in the mitochondria. In this case, it can cause insulin secretion to be diminished which can be a causal factor for diabetes I and II.

Heart Failure

Calcium impacts cardiac function in many ways. It is a key modulator of the cardiac functional cycle made up of excitation, contraction (diastole), and relaxation (systole). It also has an impact in cardiac cell death. Mitochondrial calcium contributes to control of oxidative metabolism in excitation-metabolism (EM) coupling which generates the ATP needed for cardiac excitation and contraction in each heartbeat. In sinoatrial nodal cells, an action potential is created by opening of sodium channels to increase the positive charge of the membrane potential. This opens calcium channels (TTCCs and LTCCs) to increase cytosolic calcium levels which activates mitochondrial function and ATP production. This also causes calcium-induced calcium release (CICR) in which the presence of calcium causes the release of more calcium. This initiates muscle contraction by binding troponin C on microfilaments and promotes calcium uptake into the mitochondria. In summary, mitochondrial calcium uptake provides the link between ATP supply and demand during cardiomyocyte contraction. The MCU favors rapid calcium intake which increases heartbeat frequency.^[3]

Ischemia/reperfusion injury (IRI) is caused by the rapid restoration of oxygen to ischemic (oxygen-deficient) tissues. In ischemic conditions, cells undergo anaerobic glycolysis. Because of the cessation of oxidative phosphorylation, the mitochondrial membrane potential is diminished. Additionally, the cytosolic pH is decreased. This drop in pH causes an increase in calcium concentration in the cytoplasm. When oxygen returns, there's a rapid restoration of membrane potential as oxidative phosphorylation resumes. This provides a strong driving force for the entry of calcium into the mitochondria which triggers mitochondrial calcium overload and cell death.^[4]

Therefore, certain issues with the MCU that cause an imbalance in mitochondrial calcium can lead to heart failure. Additionally, even if there is nothing wrong with the MCU, it can have an impact in conditions like IRI. This makes the MCU an interesting target for therapies for both cardiac conditions and many other ailments.

Cancer

Cancer is another condition that can impacted by the MCU, though not much is known about the exact mechanisms. It has mostly been studied in the context of breat and colorectal cancers. Overexpression or overactivation of the MCU complex was shown to promote cancer proliferation. Additionally, the overexpression of MICU1 and MICU2 was shown to decrease mitochondrial calcium levels and prevent apoptosis in cancer cells.^[4] Again, not much is known about the connection between the MCU and cancer cell growth, but the MCU's control over apoptosis and cell growth indicates that mitochondrial calcium regulation is fundamental to cancer cell growth and migration.

Regulation/Inhibition

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