Targeting The Mitochondrial Permeability Transition Pore To Prevent Age-Associated Cell Damage And Neurodegeneration Part 2
Jun 19, 2024
ROS-induced ROS release is observed during aging and after injury. Inflammation, a process typically associated with injury, induces extracellular acidification [57]. This acidification can in turn lead to increased ROS production within the cell [58].
Inflammation is a natural response in the human body, but if it occurs excessively, it can become a health hazard. Recent studies have shown that inflammation not only affects the health of the body but can also hurt our brains, adversely affecting memory and thinking ability. However, here we will focus on the positive side and discuss inflammation and ways to protect memory.
First, some studies have shown that some healthy lifestyles can reduce the extent of chronic inflammation. For example, eating foods rich in antioxidants and anti-inflammatory elements, such as fish, nuts, fruits, and vegetables, can reduce inflammation and help maintain the health of the nervous system. It is also helpful to avoid excessive fat and sugar in the diet, as these foods can aggravate the inflammatory response.
Second, for those who are already affected by certain diseases, drugs that reduce inflammation may be a helpful auxiliary treatment. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce pain and inflammation and can reduce neurodegeneration associated with Alzheimer's disease. However, it should be noted that these drugs need to be used under the guidance of a doctor.
Finally, regular exercise activities are also an important way to maintain brain health. Exercise can reduce inflammation in the body, promote the health of the nervous system, and improve memory and cognitive ability. Whether you are exercising your favorite sports, or walking, running, cycling, etc., it is beneficial to protect memory and brain health.
In general, there is a certain correlation between inflammation and memory, but we can reduce inflammatory responses through healthy living habits, protect our brain health, and improve memory and thinking ability. This is also a positive and healthy attitude towards life. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammation in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of the neural network. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.
Click know ways to improve brain function
Increased ROS production in the cell instigates mROS release from the matrix of the mitochondria [9], specifically using the mPTP [59]. Thus, inflammation can effectively alter the function of the pore by increasing PT.
These effects are not, however, limited to inflammation. Ischemia is also known to decrease extracellular pH [60], in turn launching the same ROS-stimulating pathway described above in which the release of mROS further stimulates the production of ROS leading to a positive feedback mechanism in which normal pore function is disrupted [8].
Intracellular pH, like extracellular pH, plays a role in the interaction between inflammation, ischemia, and mPTP activation. Kerr et al. [61] used 2-deoxy-d-[3H]glucose (2-DG) mitochondrial entrapment to show that recovery of Langendorff-perfused rat hearts from ischemia is accompanied by a reversal of the mitochondrial PT [61].
This connection hinges on pyruvate, which is suggested to inhibit the mPTP by decreasing intracellular pH. The beneficial effects of mPTP inhibition included recovery of left ventricular pressure [61].
When considering the results of their study, it is clear that mPTP function is altered in ischemic injury, specifically using increased permeability. Yet, it is this same alteration of increased permeability that further stimulates injury, as evidenced by the beneficial effects observed upon mPTP inhibition.
The protective effects of mPTP inhibition are further evidenced by Na(+)-H(+) exchanger-1 (NHE-1) inhibition. NHE-1 inhibition in hearts subjected to ischemia/reperfusion using the same 2-DG mitochondrial entrapment method described above is associated with attenuation of mPTP opening [62]. The beneficial effects of mPTP attenuation also included recovery of left ventricular pressure [62].
A careful analysis of these studies shows that increased PT is observed with injury, inhibition of the mPTP can lead to a decrease in PT, and decreased PT can improve cardiac function.
Figure 2: All of the following contribute to ROS production: physiological aging, injury, ischemia, PD, and AD. Injury, ischemia, PD, and AD do so using inducing inflammation. Extracellular acidification is a pathological effect of inflammation.
A decrease in extracellular pH leads to increased ROS production within the cell which in turn instigates DDR. Aging results in oxidative damage to either mtDNA or electron transport complexes.
This instigates defective mROS production. Upon ROS-induced ROS release, ROS can damage nuclear DNA, again inducing DDR. DDR results in proapoptotic pathways that induce mPTP opening and further mROS release.
A positive feedback mechanism is initiated in which mPTP openings allow for mROS release which instigates DDR. Simultaneous to the proapoptotic mechanism are the NAD+-dependent protective pathways.
SIRT3 in particular acts as an inhibitor of mROS release. It is important to note that these mechanisms are opposing and upon depletion of NAD+, the proapoptotic pathways dictate mROS release as the protective pathways are unable to perform their function.
ROS production within the cell leads to mPTP opening and subsequent macOS release. It is thought that the outer membrane anion channel, VDAC, plays a role in allowing the release of ROS from the intramembranous space of the mitochondria [63].
The ROS that is released by VDAC includes superoxide and H2O2, as they are both small enough (less than 1500 kDa) to pass through the channel [64]. Once released into the cytosol, ROS damages nuclear DNA [11] and triggers the DNA damage response (DDR). DDR induces both proapoptotic signaling in postmitotic pathways [12] and protective pathways [11] (Figure 2).
Proapoptotic signals include p53, which targets the mitochondrial matrix, and p66Shc, which targets the intermembrane space. p66Shc induces apoptosis specifically using generating H2O2.
H2O2 reacts with cytochrome c and induces oxidation of the mPTP leading to mitochondrial swelling and ultimately mPTP activation [54–56]. Thus, the increase in ROS production seen as a byproduct of aging initiates mPTP opening, but mPTP opening leads to further ROS production (H2O2) via proapoptotic signals.
This positive feedback mechanism is a means by which continued opening of the mPTP leads to a destruction of the membrane potential, swelling, and rupture of the outer mitochondrial membrane.
The mPTP exacerbates the effects of aging as the rupture of the outer mitochondrial membrane leads to the release of ROS, Ca2+, and other metabolites which can, in turn, induce oxidative damage to proteins, transporters, and nuclear DNA ultimately disrupting cellular homeostasis [9, 50].
The frequency of mPTP opening is further increased by Ca2+ overloading in the matrix [49, 50, 65] Ca2+ concentration within the mitochondria is driven by cytosolic Ca2+ levels and mediated by the Ca2+ uniporter MCU [66, 67].
It is known that aging disrupts Ca2+ homeostasis [68, 69] and interferes with the interaction between ER and mitochondria [70]. The disruption in Ca2+ homeostasis is thought to be a byproduct of oxidative damage to Ca2+ transporters which increases the leak of Ca2+ into the cytosol and subsequently increases Ca2+ overload of the mitochondria [71, 72] (Figure 3).
Since oxidative damage to Ca2+ transporters is a byproduct of increased ROS levels, the continued opening of the mPTP would lead to further damage first initiated by cellular aging. In addition to damaged Ca2+ transporters, the direct transfer of calcium from the ER to the mitochondria increases Ca2+ overloading within the matrix [73].
To counter calcium overloading resulting from mPTP openings, MICU1, a subunit of MCU, limits calcium accumulation in the matrix as it maintains a threshold for calcium uptake [66, 74].
In aged cells, however, cytosolic free calcium often exceeds the MICU1 threshold for calcium uptake while the calcium threshold controlling mPTP activation is lower than the normal threshold [75].
This would indicate that more Ca2+-induced mPTP openings are to be observed in aged cells.
Since ROS release can lead to oxidative damage of Ca2+ transporters and consequently Ca2+ overloading, increased mPTP sensitivity with age can be seen as a byproduct of both Ca2+ overloading and ROS release. Furthermore, mPTP opening can be seen as a key driver of the processes (oxidative damage to Ca2+ transporters, etc.) first initiated by aging.
Figure 3: The components of the mPTP are of great controversy. However, despite this, CyPD and the controversial F1F0 (F)-ATP synthase are shown as pore constituents.
VDAC, while not considered to be part of the mPTP, is thought to be how mROS, Ca2+, etc. are shuttled from the intermembrane space to the cytosol. mROS release through the mPTP leads to DNA and Ca2+ transporter damage.
DNA damage induces DDR or DNA damage response. DDR subsequently induces both proapoptotic signals and protective pathways. Proapoptotic signals recruit p53 and p66Shc which act upon the mPTP (p53 specifically interacts with CypD, and p66Shc targets the intermembrane space generating ROS) to further induce mPTP openings.
Oxidative damage to Ca2+ transporters can lead to calcium overloading and subsequent increased mPTP openings. MCU in particular can be affected by oxidative damage, leading to a disruption in mitochondrial Ca2+ levels.
Protective pathways such as PARP1 aid in DNA repair, and SIRT3 inhibits mROS production. As further oxidative damage to DNA takes place, both protective pathways continue to utilize NAD+.
NAD+ depletion can result, leading to an inactivation of protective pathways. In turn, the proapoptotic signals are left unchallenged and mPTP openings become more frequent.
1.3. Protective Pathways Involving PARP1 and SIRT3 Can Inhibit mPTP Opening.
Although aging can increase ROS production, ROS do not always invoke damaging effects. This is because protective pathways exist to counter oxidative damage by ROS.
Thus, due to the dual nature of ROS, which can have both protective and damaging effects, it is necessary to address the interplay between both to examine the overall effects of mPTP opening.
Before the interplay can be discussed regarding aging, it is necessary to examine the protective pathways stimulated by mROS that exist to maintain cellular homeostasis.
One of the most important pathways begins with the intranuclear protein PARP1. When DNA is damaged through oxidative stress, PARP1 repairs DNA in a manner that is dependent on NAD+ [76].
Working in conjunction with PARP1 are the sirtuins, which are similarly classified as NAD-dependent deacetylases [77]. It is thought that SIRT3 plays a particularly important role in inhibiting ROS production and mPTP activation in stem cells [78].
Through metabolic reprogramming, SIRT3 is suggested to effectively increase efficient electron transport away from carbohydrate catabolism, resulting in reduced ROS production [79, 80]. Thus, because ROS production is decreased and mPTP activation is inhibited, the protective pathways above antagonize the mPTP from exacerbating the processes initiated by aging.
With this in mind, it is clear that any downregulation of the protective pathways described above through the depletion of NAD+ would lead to the domination of mPTP openings and subsequent positive feedback regarding the release and production of mROS.
As aging proceeds, NAD+ depletion, mPTP openings, and mROS production and release lead to DNA damage. The protective pathways noted above, as well as activation of nuclear factor erythroid 2-related factor 2 (Nrf2), are initiated to counter oxidative damage; however, the continued activation of these pathways leads to a depletion of NAD+.
Since both the PARP1 and sirtuin protective pathways are dependent upon NAD+, they are no longer able to perform their function as an inhibitor of mPTP opening and subsequent mROS release and production [81, 82].
Ultimately, as aging progresses, oxidative damage to nuclear DNA results in the activation of protective pathways which in turn leads to depletion of NAD+. Without NAD+, the protective pathways involving PARP1 and SIRT3 are unable to perform their function as an mPTP opening inhibitor.
As a consequence, the mPTP can effectively exacerbate processes initiated by aging.
For more information:1950477648nn@gmail.com
