Mitochondria: The Powerhouse Driver of Fitness, Wellness and Health
Energy supply is the driver of metabolic activities and sustainability of life. It is no surprise, therefore, that development, growth, mental and physical acivities all rely on an adequate, ready-to-use energy source, the ATP. Since the mitochondrion is the major source of this, its well-being lies at the root of optimal body function and its poor state at the heart of most diseases.
Mitochondrial gene expression is conditioned by the peroxisome proliferation genes, driven by factors such as, fibrate drugs, free fatty acids and arachidonic acids. Peroxisome activated receptors form heterodimers with vitamins A and D receptors. It goes without saying that any stress, such as sudden nutritional overload from food intake; exercise, fasting, with energy exhaustion or low supplies that call for mobilization from stores, activates the peroxisome proliferator-activated receptor, increases mitochondrial function and promotes metabolism. The receptors are nuclear genes that upregulate mitochodrial; and nuclear genes that, in turn, regulate mitochondrial function.
However, with increasing metabolic function, there is increased oxygen free radical production and with it increased mitochondrial damage; which mitochondria, being of bacterial ancestory, are more susceptible to free radical damage. Cross-linking of mitochondrial membrane by malonyldialdehyde, a product of inflammation and an end-product of lipid peroxidation, and advanced glycation end-products(AGEs)-- a ubiquitous cross-linking, seeding, component of amyloid--further compromise mitochondrial intergrity. This oxidative stress again compromises protein folding--that engenders amyloid--and this leads to endoplastic reticulum(ER) stress.
The initial reaction is transient stress granules formation to preserve proteins from further damage. Metabolic activity is slowed down. Anti-oxidation pathways are activated. On stress recovery or removal, stress granules disassemble. Protein folding is engaged. Mitochondria fusion begins to take place to compensate for damaged mitochondrial structures, to try and stave off further damage.
In the case of a no-return damage, there is mitochondrial fission and autophagy, including mitophagy. Autophagy is a damage response, primarily a survival one, at that. It ensures cell survival, in the case of low damage.The cell may survive with a low number of and less effective mitochondria. Damage- or pathogen-sensing inflammasomes are activated. These mitochondria release further reactive oxygen species and the cycle continues. It is these cells that are less functional(low metabolic, in want of ATP) that produce pathologies such as neuritis, fatigue, foggy brain, fatty liver disease.
In the event of severely damaged mitochondria, apoptosis is activated through further porosity in the mitochondrial membrane that allows heme to leak out and activate caspases in the cytosol. Much more severe damage leads to frank necroptosis or even necrosis with inflammatory outcomes.
Apoptosis may be the best outcome, if through stem cell division, the tissue cell is renewable, but an awful event if not, as is the case with cells of the nigrostriatal pathway that regulate movement in the brain and which are implicated in Parkinson's. The same goes for islet cells in diabetes. Necroptosis from reperfusion damage, following a heart attack, has dire consequences for the patient. It has been suggested the mitochondrial membrane cross-linking by AGEs accounts for the most damage, with calcium entry and release of heme from the mitochondria to engage caspases, which calcium also phosphorylates kinases and activates hydrolyases, including plasma and mitochondrial membrane lipases.
Once a cell differentiates, itself a mild stress-conditioning process, it begins a time-sensitive journey, through apoptosis, to death, unless a well orchestrated heat shock response and autophagy, with or without inflammation, steps in or stands in the way to delay or put a stop to the process. Excessive autophagy will, however, break down vital functional and structural molecules of life and precipitate apoptosis. Dimorphism is an in-built regulatory phenomenon in all biological species.
Dr. Oliver Verbe Birnso, MD.
Mitochondrial gene expression is conditioned by the peroxisome proliferation genes, driven by factors such as, fibrate drugs, free fatty acids and arachidonic acids. Peroxisome activated receptors form heterodimers with vitamins A and D receptors. It goes without saying that any stress, such as sudden nutritional overload from food intake; exercise, fasting, with energy exhaustion or low supplies that call for mobilization from stores, activates the peroxisome proliferator-activated receptor, increases mitochondrial function and promotes metabolism. The receptors are nuclear genes that upregulate mitochodrial; and nuclear genes that, in turn, regulate mitochondrial function.
However, with increasing metabolic function, there is increased oxygen free radical production and with it increased mitochondrial damage; which mitochondria, being of bacterial ancestory, are more susceptible to free radical damage. Cross-linking of mitochondrial membrane by malonyldialdehyde, a product of inflammation and an end-product of lipid peroxidation, and advanced glycation end-products(AGEs)-- a ubiquitous cross-linking, seeding, component of amyloid--further compromise mitochondrial intergrity. This oxidative stress again compromises protein folding--that engenders amyloid--and this leads to endoplastic reticulum(ER) stress.
The initial reaction is transient stress granules formation to preserve proteins from further damage. Metabolic activity is slowed down. Anti-oxidation pathways are activated. On stress recovery or removal, stress granules disassemble. Protein folding is engaged. Mitochondria fusion begins to take place to compensate for damaged mitochondrial structures, to try and stave off further damage.
In the case of a no-return damage, there is mitochondrial fission and autophagy, including mitophagy. Autophagy is a damage response, primarily a survival one, at that. It ensures cell survival, in the case of low damage.The cell may survive with a low number of and less effective mitochondria. Damage- or pathogen-sensing inflammasomes are activated. These mitochondria release further reactive oxygen species and the cycle continues. It is these cells that are less functional(low metabolic, in want of ATP) that produce pathologies such as neuritis, fatigue, foggy brain, fatty liver disease.
In the event of severely damaged mitochondria, apoptosis is activated through further porosity in the mitochondrial membrane that allows heme to leak out and activate caspases in the cytosol. Much more severe damage leads to frank necroptosis or even necrosis with inflammatory outcomes.
Apoptosis may be the best outcome, if through stem cell division, the tissue cell is renewable, but an awful event if not, as is the case with cells of the nigrostriatal pathway that regulate movement in the brain and which are implicated in Parkinson's. The same goes for islet cells in diabetes. Necroptosis from reperfusion damage, following a heart attack, has dire consequences for the patient. It has been suggested the mitochondrial membrane cross-linking by AGEs accounts for the most damage, with calcium entry and release of heme from the mitochondria to engage caspases, which calcium also phosphorylates kinases and activates hydrolyases, including plasma and mitochondrial membrane lipases.
Once a cell differentiates, itself a mild stress-conditioning process, it begins a time-sensitive journey, through apoptosis, to death, unless a well orchestrated heat shock response and autophagy, with or without inflammation, steps in or stands in the way to delay or put a stop to the process. Excessive autophagy will, however, break down vital functional and structural molecules of life and precipitate apoptosis. Dimorphism is an in-built regulatory phenomenon in all biological species.
Dr. Oliver Verbe Birnso, MD.
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