Failing Mitophagy in the Progression of Aging
Mitochondria, the power plants of the cell, decline in function with age. This contributes to the development of age-related conditions, particularly in energy-hungry tissues such as muscle and brain. An important proximate cause of this failure is disruption of mitophagy, a form of the cellular maintenance process of autophagy that recycles damaged mitochondria. This in turn might be due to an imbalance of fission and fusion of mitochondria, leading to large mitochondria that are resistant to mitophagy. It may also be due to various dysfunctions in mechanisms of autophagy that emerge in old tissues. The underlying causes below that level are poorly understood, but interventions that enhance autophagy are one possible starting point for the development of therapies to improve faltering mitochondrial function in older people.
A decline in mitochondrial function is a hallmark of the aging process and is connected to other aging hallmarks such as telomere dysfunction, genome instability, and cellular senescence. However, it remains largely unclear how these processes are interconnected and finally provoke disruption of the cellular and tissue integrity. There is accumulating evidence that mitophagy impacts health- and lifespan in different model organisms. The effect of changes in mitophagy on health- and lifespan has been particularly demonstrated by using the model organisms C. elegans and D. melanogaster. Several genetic studies in D. melanogaster revealed that the overexpression of mitochondrial and mitophagy genes leads to increased health- and/or lifespan. For instance, the overexpression of the mitochondrial fission protein dynamin-related protein 1 (DRP1) increased the lifespan along with a prolonged healthspan in flies.
An increasing number of human diseases have been associated with impaired mitophagy, thus, interventions that modulate mitophagy may provide the possibility of counteracting disease development or progression. In recent years, multiple small molecules as well as lifestyle interventions have been shown to modulate autophagy, thereby causing health- and lifespan benefits in different organisms. Due to the dependency on core autophagy regulators, mitophagy is modulated by most of the classic autophagy inducers such as the mTOR inhibitor rapamycin, the AMP-activated protein kinase (AMPK) activator AICAR, as well as caloric restriction and exercise.
Mitophagy is emerging as a central process preserving organismal and, especially, neurological health. Since most trials targeting age-associated neurodegeneration in the last decades have been disappointing, new pharmaceutical avenues are direly needed. Here, mitophagy stimulators could play a key role. Indeed, several clinical trials are underway testing the efficacy of mitophagy modulating compounds and the outcome of these studies will undoubtedly prove critical for the future translatability of the field. Nonetheless, the regulatory mechanism of mitophagy and its contribution to age-associated diseases still remains elusive and potential issues with artificially augmenting mitophagy have not been considered. However, given the central role of mitophaging in multiple age-related pathologies it appears highly likely that these new promising approaches may present possible interventions in age-associated diseases. The future is bright!
Something that has never been clear to me, and I am hoping someone would comment on, is what happens to the Mitochondria when a cell undergoes apoptosis? Do the Mitochondria escape and are reabsorbed by other cells, or are all the Mitochondria destroyed with the cell? And if they are reabsorbed by other cells, do the other cells exercise some screening process so they do not absorb defective mitochondria?
@JohnD
the traditional view was they they get collected by macrophages and other cleanup systems. More recently there is indication that at least some of the mitochondria can be picked up by other cells. There even some researches indicating that the cells could "eat" some of their neighbors and either incorporate organelles directly or just use it as raw material. The biology is amazingly complex. And hard to tweak.
I would say that the biggest part of mitochondria get eaten if there is inflammatory environment, and probably if the cell commit apoptosis without inflammation the mitochondria might be packaged in extra cellular vesicles which are easier to absorbed by other cells. Of course , i might be wrong and it could be the other way around.