Mitochondrial permeability plays a key role in the recovery of aging and ischemic injury


Researchers at the Massachusetts General Hospital (MGH) have for the first time discovered that mitochondrial permeability determines whether autophagy prolongs or shortens lifespan. These findings suggest that targeting mitochondrial permeability to maximize autophagy becomes a possibility in aging or aging-related diseases such as heart disease and stroke.
The ability of molecules to pass through the mitochondrial membrane (the cellular structure that converts nutrients into energy) may determine whether autophagy (the cellular process that removes damaged and dysfunctional molecules and cellular components) is beneficial or harmful to the health of the organism.

As we age, the body's molecular damage and defective proteins continue to accumulate, and these accumulations will shorten the lifespan. On the contrary, autophagy can prolong life. In fact, genetic mutations or measures such as limiting caloric intake are dependent on autophagy to extend lifespan. However, autophagy may also play a role in ischemia, reperfusion injury caused by cancer, diabetes, neurodegeneration, and restricted blood flow.

Previous studies have shown that inhibition of the mTORC2 pathway shortens lifespan. The mTORC2 pathway is known to control a variety of key metabolic functions. The team found that autophagy also increased or in organisms whose mutations in mTORC2 or in the downstream effector protein SGK1 resulted in a shortened lifespan. Therefore, they began to investigate why beneficial autophagy is detrimental to mTORC2/SGK1 mutant animals in most cases and identifies key cellular determinants of the effects of autophagy on health and longevity.

They have experimentally observed that inhibition of autophagy can restore the normal lifespan of the mTORC2/SGK1 mutant Caenorhabditis elegans. They also discovered that SGK1 regulates the opening of the mitochondrial permeability transition pore (mPTP), which allows very small molecules to pass through the mitochondrial membrane. And by inhibiting the mTORC2/SGK1 pathway or by over-opening mPTP by direct genetic stimulation, autophagy changes from a beneficial function to a detrimental function, resulting in a shortened life span. Based on these results, the team concluded that the beneficial effects of autophagy depend on low levels of mitochondrial permeability.

Autophagy is thought to be one of the causes of ischemic injury, and the researchers looked at the potential role of autophagy in ischemia/reperfusion injury (I/R)—when blood flow returns to restricted tissue, tissue Damage will increase. They also found that mice were more susceptible to I/R damage when the SGK1 gene in the liver of mice was removed. Although both current and previous studies have shown that autophagy and elevated mitochondrial permeability are detrimental in the early stages of reperfusion injury, autophagy can help reduce the severity of tissue damage when damaged cellular components must be removed from the cells. 

Because of the need to temporarily interrupt the blood supply to donor organs during heart attacks and strokes or during organ transplants, researchers believed that this work is important to prevent ischemic damage in these processes. And these processes share characteristics with the research model, meaning that targeting mitochondrial permeability through mTORC2, SGK1 or mPTP has great potential to reduce the potentially damaging outcome of these events.

For the first time, the current study directly demonstrates that increasing mitochondrial permeability can reduce longevity and prevent the beneficial effects of autophagy. They also provide direct genetic evidence that low levels of mitochondrial permeability are required to prolong life and improve health, and SGK1 has been identified as an important regulatory molecule whose regulation can help prolong life and reduce age-related diseases.

Understanding the mechanisms that increase mPTP openness in all aspects of aging-related changes and age-related declines and diseases can further learn about how mitochondrial permeability can cause problems during aging. Successfully reducing the mitochondrial permeability through the health promotion pathway may provide new insights into promoting healthy aging.
 
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