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Upregulation of Mitophagy as an Approach to Treat Age-Related Disease


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Posted 28 September 2020 - 10:09 AM


Mitophagy is a cellular housekeeping process that removes damaged mitochondria. Mitochondria are the power plants of the cell, crucial in all tissues, but particularly so in the energy-hungry brain and muscles. Mitochondrial function declines with age throughout the body, and failing mitophagy is a proximate contributing cause of this issue, allowing dysfunctional mitochondria to accumulate in cells. Why this happens is a topic for study; various important genes relating to mitochondrial structure and mitophagy have alterations in expression levels, a maladaptive reaction to the damaged environment of aged tissues, perhaps. But it is not well understood. Boosting the operation of mitophagy in old tissues may be a useful approach to therapy for age-related conditions, and may also be an important mechanism by which exercise can improve health and reduce mortality older individuals.

Macroautophagy, hereafter referred to as "autophagy," is an evolutionarily conserved pathway involving the engulfment of cytosolic contents by a lipid membrane for recycling of nutrients or removal of harmful aggregates, microbes, and organelles. Mitophagy is one form of macroautophagy that involves selectively targeting and engulfing mitochondria for removal through lysosomal degradation. Activation of this pathway is a result of mitochondria being damaged beyond the capabilities of other quality control methods or in instances in which the cell needs to get rid of mitochondria for metabolic or developmental purposes.

Mitophagy is important for any cell that contains mitochondria. When moving from this idea of a nondescript eukaryotic cell to differentiated, specific cells that make up our body's organs, certain tissues become focal points for discussion. These include muscle cells and neurons because of their specific functions, metabolism, and energy requirements. These cells make up organs with high energy consumption and vulnerability, and slight perturbations in homeostasis can lead to pronounced effects. Although we focus on these two cell types, mitophagy is important in all organs where mitochondria play important roles.

The deep molecular understanding of mitophagy we have stems from the thorough investigation into PINK1 and Parkin, which are both major recessive risk factors for developing early onset Parkinson's disease (PD). The unique structure of the neuron creates an environment where not only does the mitochondrial pool have to be healthy, but it also must be properly transported down the axon to quite distant sites where ATP production and calcium buffering are its two most important functions. An aged nervous system coupled with a decline in mitophagy leads to accumulation of bad mitochondria and is a hallmark of neurodegeneration.

Until recently, surprisingly little evidence directly linked mitophagy to the most common neurodegenerative disease, Alzheimer's disease (AD). Historically, PD etiology was more focused on defective mitophagy, whereas investigation of AD has focused on accumulation of amyloid-β (Aβ) plaques and phospho-tau neurofibrillary tangles. Recent studies have shown that mitophagy is, in fact, affected in AD and, more important, that inducing mitophagy could benefit the pathological and cognitive outcomes. Models of toxic Aβ and tau were shown to impair mitophagy, and increasing mitophagy helped to reduce the plaque and neurofibrillary tangle burden in Caenorhabditis elegans and mouse models.

As with most therapeutics that control a biological process, increasing levels of mitophagy must be carefully controlled because passing an upper limit would induce cell death, so careful modulation rather than constitutive activation would be ideal for this style of treatment. Physiologically relevant stimulation through NAD+ supplementation has been effective in mouse and C. elegans studies in AD. By supplementing with a molecule that is already present in the body, the safety concerns are greatly reduced. Alternatively, by removing the brakes on the mitophagy system, such as the deubiquitinating enzymes, we would also increase levels of basal mitophagy. Regardless of the treatment approach, the ideal therapy will be targeted to the dysfunctional organ because affecting the balance of mitophagy in off-target organs that do not have mitochondrial dysfunction will create additional problems.

Link: https://doi.org/10.1083/jcb.202004029


View the full article at FightAging




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