Sandbox Reserved 1626: Difference between revisions

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=== Diabetes ===

In healthy individuals, the [https://en.wikipedia.org/wiki/Beta_cell 𝛽-cells] in the pancreas are responsible for sensing the concentration of glucose in the bloodstream and releasing the appropriate amount of [https://en.wikipedia.org/wiki/Insulin 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 [https://en.wikipedia.org/wiki/Glycolysis glycolysis]~~vin~~ 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 <ref name="Giorgi" />.

In healthy individuals, the [https://en.wikipedia.org/wiki/Beta_cell 𝛽-cells] in the pancreas are responsible for sensing the concentration of glucose in the bloodstream and releasing the appropriate amount of [https://en.wikipedia.org/wiki/Insulin 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 [https://en.wikipedia.org/wiki/Glycolysis glycolysis] in the cell, which increases the amount of [http://proteopedia.org/wiki/index.php/ATP 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 activating [http://proteopedia.org/wiki/index.php/PKC 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 <ref name="Giorgi" />.

INSULIN SIGNALLING PICTURE

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.

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=== 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.<ref name="Giorgi" />

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 [https://en.wikipedia.org/wiki/Cellular_respiration 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 ([http://proteopedia.org/wiki/index.php/Voltage-gated_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 [https://en.wikipedia.org/wiki/Troponin 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 [https://en.wikipedia.org/wiki/Cardiac_muscle_cell cardiomyocyte] contraction. The MCU favors rapid calcium intake which increases heartbeat frequency.<ref name="Giorgi" />

CARDIAC CYCLE PICTURE?

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.<ref name="Woods" />

Sandbox Reserved 1626: Difference between revisions

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@@ Line 22: / Line 22: @@
 === Diabetes ===
-In healthy individuals, the [https://en.wikipedia.org/wiki/Beta_cell 𝛽-cells] in the pancreas are responsible for sensing the concentration of glucose in the bloodstream and releasing the appropriate amount of [https://en.wikipedia.org/wiki/Insulin 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 [https://en.wikipedia.org/wiki/Glycolysis glycolysis]vin 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 <ref name="Giorgi" />.
+In healthy individuals, the [https://en.wikipedia.org/wiki/Beta_cell 𝛽-cells] in the pancreas are responsible for sensing the concentration of glucose in the bloodstream and releasing the appropriate amount of [https://en.wikipedia.org/wiki/Insulin 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 [https://en.wikipedia.org/wiki/Glycolysis glycolysis] in the cell, which increases the amount of [http://proteopedia.org/wiki/index.php/ATP 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 activating [http://proteopedia.org/wiki/index.php/PKC 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 <ref name="Giorgi" />.
+INSULIN SIGNALLING PICTURE
 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.
@@ Line 28: / Line 30: @@
 === 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.<ref name="Giorgi" />
+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 [https://en.wikipedia.org/wiki/Cellular_respiration 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 ([http://proteopedia.org/wiki/index.php/Voltage-gated_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 [https://en.wikipedia.org/wiki/Troponin 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 [https://en.wikipedia.org/wiki/Cardiac_muscle_cell cardiomyocyte] contraction.  The MCU favors rapid calcium intake which increases heartbeat frequency.<ref name="Giorgi" />
+CARDIAC CYCLE PICTURE?
 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.<ref name="Woods" />