Mitochondrial Dysfunction as a Feature of Neurodegenerative Conditions
Increasing dysfunction of mitochondria, the power plants of the cell, is a feature of aging. It is also strongly connected to neurodegenerative conditions. The brain is an energy-hungry organ, and anything that interferes with the supply of nutrients and their processing to power cellular operations is going to cause issues. In this review paper, researchers discuss the link between mitochondrial dysfunction and neurodegeneration, and go on to note a few of the efforts underway to produce pharmacological treatments capable of restoring greater mitochondrial function in aged tissues. Sadly all too few of these treatments can outpace the beneficial effects of exercise on mitochondrial function. More and better approaches are needed, such as transplantation of functional mitochondria.
The decline in mitochondrial function during aging and associated disorders like neurodegeneration has received much attention, and there are extensive efforts underway to develop pharmacological treatments that can restore the potential and integrity of these crucial organelles. A large number of pharmacological modulators, both natural and synthetic, are being studied for their ability to reduce mitochondrial stress by targeting different pathways, including mitochondrial OXPHOS, ROS homeostasis, and metabolic processes. Furthermore, several other pathways, such as mitochondrial biogenesis, dynamics, and degradation, are also considered in developing therapeutics against mitochondria-associated disorders.
The depleted energy production by mitochondria due to various cellular stresses such as increased ROS levels and calcium dyshomeostasis, significantly affects energy-intensive cells like neurons. Scientists have explored various molecules that could potentially improve the functioning of the electron transport chain (ETC). For example, riboflavin and idebenone enhance the transfer of electrons, while others, such as thiamine and dichloroacetate, increase the availability of ETC substrates.
In addition, researchers have studied various natural compounds for their ability to regulate mitochondrial oxidative stress. For example, saponins derived from Panax japonicus and Panax notoginseng show neuroprotective effects by reducing mitochondrial damage through the induction of antioxidant responses. Besides this, several mitochondrial antioxidants, including MitoQ, Mitotempo, and Mito apocynin, protects mitochondria from oxidative damage.
Another approach to address energy deficiency involves increasing the number of mitochondria in cells by targeting transcription factors participating in formation of new mitochondria, such as PGC-1α. Pioglitazone, a type of thiazolidinedione, has been shown to have protective effects in several neurological diseases by targeting transcription factors such as PGC-1α. Furthermore, various studies show the protective effects of directly or indirectly activating mitochondrial biogenesis with compounds such as bezafibrate, resveratrol, and AICAR. It is evident that mitochondrial dynamics are altered in various neurodegenerative diseases, and different pharmacological interventions that can modulate the proteins involved in this process are investigated. Echinacoside (ECH) treatment shows neuroprotective effects by inducing mitochondrial fusion via increased transcription of Mfn2. Treatment with liquiritigenin, a flavonoid, has been found to induce mitochondrial fusion and protects against amyloid-β cytotoxicity.
Various modulators of mitophagy that have shown beneficial effects by removing damaged or altered mitochondria are identified. Urolithin A induces autophagic removal of altered mitochondria and extended lifespan in C. elegans. Spermidine treatment was found to induce both the mitophagy as well as biogenesis of mitochondria in aged mice heart cells. Metformin, a drug used in treating type 2 diabetes, has been found to enhance mitochondrial function by restoring ETC proteins and promoting mitophagy.