Mitochondria are the power plants of the cell, generating the chemical energy store molecule adenosine triphosphate (ATP) that powers cellular processes. Every cell possesses a herd of mitochondria, replicating like bacteria, and monitored by quality control mechanisms. Damaged, potentially harmful mitochondria are removed and dismantled for raw materials through a variant of autophagy called mitophagy. A mountain of evidence links mitochondrial function to aging, just as a mountain of evidence links the cellular recycling mechanisms of autophagy to aging. Both mitochondrial function and autophagic activity decline with age, producing downstream consequences that contribute to age-related diseases. There is the strong suspicion, with evidence to back it up, that it is the quality control of mitochondria, and thus maintenance of mitochondrial function without harmful side-effects resulting from damaged mitochondria, that is the common factor here.
Enhanced autophagy is a feature common to many of the methods by which aging can be slowed and life span extended in short-lived laboratory species. Most of these work via upregulation of cellular stress responses - to heat, lack of nutrients, oxidative damage, and so forth - and autophagy is an important stress response mechanism, making cells more resilient. Minor or short stresses lead to a longer upregulation of the response to stress, and thus the overall result is an improvement in health and longevity. This is called hormesis, and is a major part of the way in which intermittent fasting or calorie restriction work. Researchers have in the past demonstrated that calorie restriction actually fails to extend life in animals in which autophagy is disabled.
The topic for today is specifically the permeability of the mitochondrial membrane and its role in the relationship between mitochondrial function and autophagy. A fair amount of attention has been directed in recent years towards the mitochondrial permeability transition pore structures in the mitochondrial membrane, and their role in mitochondrial dysfunction. Clearly greater pore activity and thus greater permeability are a feature of aging, alongside mitochondrial dysfunction, but joining the dots on what is cause and what is consequence in our biochemistry is far from simple. It is known that mitophagy falters in later life, and it is known that this appears to be at least partly a consequence of reduced levels of mitochondrial fission - but consider how long it took to join just those two items. Why do mitochondrial fission rates fall? How does that relate to permeability and the membrane structures that support it? The complexity is overwhelming, which is perhaps why the path forward towards near term therapies is usually to cut the Gordian knot in some way, bypass the system that is poorly understood. Many of the SENS-style proposed rejuvenation therapies based on repair of underlying damage are of this form.
The ability of molecules to pass through the membrane of mitochondria - the cellular structures that convert nutrients into energy - may determine whether or not autophagy, a cellular process that removes damaged and dysfunctional molecules and cellular components, is beneficial or detrimental to the health of an organism. As the accumulation of damaged molecules and defective proteins is considered a hallmark of aging, autophagy has been associated with increased longevity. In fact, model organisms in which gene mutations or measures such as calorie restriction lead to lifespan extension depend on autophagy for their beneficial effects. However, autophagy can also play a role in cancer, diabetes, neurodegeneration and in the ischemia/reperfusion injury caused by restricted blood flow.
Previous studies have suggested that inhibition of the mTORC2 molecular pathway, which controls several critical metabolic functions, shortens lifespan. Organisms in which mutations in mTORC2 or in the gene encoding its downstream effector protein SGK-1 have reduced lifespan also show increased autophagy. Experiments revealed that inhibition of autophagy can restore a normal lifespan in mTORC2/SGK1 mutant C. elegans roundworms. The researchers also found that SGK-1 can regulate the opening of the mitochondrial permeability transition pore (mPTP), which allows very small molecules to pass through the mitochondrial membrane. Excessive opening of the mPTP, either by inhibition of the mTORC2/SGK-1 pathway or by direct genetic stimulation, transforms autophagy from a beneficial to a detrimental function, resulting in a shortened lifespan. Overall, the results indicate that the beneficial effects of autophagy depend on low levels of mitochondrial permeability.
Since autophagy is believed to contribute to ischemic injury, the investigators looked at its potential role in ischemia/reperfusion (I/R) injury - the exacerbation of tissue damage that occurs when blood flow is restored to tissue to which it had been restricted. They found that mice in which expression of the gene for SGK-1 was knocked out in the liver were more susceptible to I/R injury of the liver than were unmutated animals. While both current and previous research has indicated that elevated autophagy and mitochondrial permeability are harmful in the early phases of reperfusion injury, autophagy may help reduce the severity of tissue damage at later stages when damaged cellular components must be cleared from the cell.
Autophagy is required in diverse paradigms of lifespan extension, leading to the prevailing notion that autophagy is beneficial for longevity. However, why autophagy is harmful in certain contexts remains unexplained. Here, we show that mitochondrial permeability defines the impact of autophagy on aging. Elevated autophagy unexpectedly shortens lifespan in C. elegans lacking serum/glucocorticoid regulated kinase-1 (sgk-1) because of increased mitochondrial permeability. In sgk-1 mutants, reducing levels of autophagy or mitochondrial permeability transition pore (mPTP) opening restores normal lifespan.
Remarkably, low mitochondrial permeability is required across all paradigms examined of autophagy-dependent lifespan extension. Genetically induced mPTP opening blocks autophagy-dependent lifespan extension resulting from caloric restriction or loss of germline stem cells. Mitochondrial permeability similarly transforms autophagy into a destructive force in mammals, as liver-specific Sgk knockout mice demonstrate marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury. Targeting mitochondrial permeability may maximize benefits of autophagy in aging.