Mitochondria are the power plants of the cell, a herd of bacteria-like organelles responsible for packaging energy store molecules used to power the chemistry of life. With age, mitochondria become dysfunctional throughout the body, for reasons that are not yet fully understood, but which clearly contribute to the onset of age-related declines and diseases. There is certainly stochastic damage to mitochondrial DNA that can lead to a small but significant number of pathological cells dumping oxidizing molecules into the surrounding tissue, but the general malaise of mitochondria is more sweeping than this.
One important contribution to this universal mitochondrial dysfunction appears to be a progressive failure of mitophagy. Mitophagy is a specialized form of autophagy, a quality control process responsible for flagging and then destroying worn and damaged mitochondria. Researchers have shown that specific component parts of the autophagy process can become less efficient with age, but the culprit here may be that mitochondria change in structure and size, becoming larger and more resilient to clearance by mitophagy. Why exactly this happens is, again, quite unclear at the detail level. Many of the research groups interested in the mitochondrial contribution to aging are focused on mitophagy, however, so we shall see, given time.
The brain is an energy-hungry organ, and, like muscle tissue, more profoundly affected by loss of mitochondrial function than is the case elsewhere in the body. Loss of mitochondrial function is a prominent feature of many neurodegenerative diseases, and is thought to be a noteworthy contributing cause of these conditions. Today's open access paper discusses this topic in the context of mitophagy, and possible approaches to upregulation of mitophagy in old tissues, in order to better maintain mitochondrial function in later life.
In Alzheimer's disease (AD), mitochondrial dysfunction and the bioenergetic deficit contribute to the amyloid-β (Aβ) and phosphorylated Tau (p-Tau) pathologies; in turn, these two pathologies promote mitochondrial defects. As a consequence, a fundamental characteristic of AD is the impairment of mitochondria. Pharmacological agents, fasting, physical exercise, and caloric restriction can reverse this impairment. The main target of these methods is to enhance autophagy and mitophagy. Mitophagy plays a fundamental role in mitochondrial quality control and homeostasis, and the pathological consequences of its misregulation demonstrate its importance. However, the exact positions of mitophagy in AD etiology are still unclear as multiple steps are affected. Cells regulate mitochondrial degradation not only through control of the mitophagy machinery but also through delicate tuning of mitochondrial fusion and fission. It remains to see whether other cellular processes linked with mitochondria also have a role to play in mitophagy regulation.
Accumulating studies suggest that dysfunctional mitochondria are mainly due to impaired mitophagy in neurons in AD. The 'vicious cycle' hypothesis proposed that loss-of-function mitophagy and Aβ and p-Tau, the biomarkers in AD pathophysiology, strongly influence each other. Moreover, the 'vicious cycle' experiments state that Aβ-dependent neuronal hyperactivity supports circuit dysfunction in the early stages of AD. Recently, researchers successfully stimulated mitophagy and reversed memory impairment using NAD+ supplementation, urolithin A, and action in both Aβ and tau Caenorhabditis elegans models. In human neurons derived from the hippocampus of AD patients and in AD animal models, enhanced mitophagy can even diminish insoluble Aβ and prevent cognitive impairment in AD mouse model through the suppression of neuroinflammation and microglial phagocytosis of Aβ plaques. These findings predict that enhancing mitophagy could be a novel approach to delay or even treat AD. To this end, plentiful pharmacological agents have been examined in preclinical studies.
In the past 20 years, most of the drugs tested in the clinic for AD have targeted the Aβ accumulation; however, none of these anti-Aβ therapies overcome the central problem. Today, a promising alternative option for AD therapeutics is to maintain mitochondrial homeostasis by enhancing autophagy and stimulating mitophagy. Dysfunctional mitophagy can increase Aβ and Tau pathologies, while aggregating Aβ can impair neuronal mitophagy in reverse. These outcomes indicate pivotal roles for mitophagy dysfunction, both upstream and downstream of Aβ and Tau pathways.