Mitochondrial dysfunctions in neurodegenerative diseases: role in disease pathogenesis, strategies for analysis and therapeutic prospects

Abstract

Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes, the mitochondria are required for multiple pivotal processes that include the production of biological energy, the biosynthesis of reactive oxygen species, the control of calcium homeostasis, and the triggering of cell death. The disruption of anyone of these processes has been shown to impact strongly the function of all cells, but especially of neurons. In this review, we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis, Parkinson's disease and Alzheimer's disease. We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle: fusion, fission, production of reactive oxygen species and energy failure. Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes. Therefore, in order to get in depth insights into their health status in neurodegenerative diseases, we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes. Current techniques include Mitostress, Mitotracker, transmission electron microscopy, oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health. We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction. These include canonical drugs, natural compounds, supplements, lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy. In conclusion, because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases, it is critical to develop novel methods to measure the mitochondrial state, and novel therapeutic strategies aimed at improving their health.

Keywords: Alzheimer’s disease; Mitostress; Mitotracker; Parkinson’s disease; amyotrophic lateral sclerosis; mitochondria; mitochondria modulation; mitochondrial dysfunction; mitochondrial health; neurodegenerative disease.

Figure 1

Neurodegenerative diseases impact mitochondrial health at different stages. The altered processes may affect the mitochondria life cycle (biogenesis, fusion, fission and mitophagy), calcium homeostasis, cell death, mtDNA, ATP production and ROS production. ATP: Adenosine triphosphate; mtDNA: mitochondrial DNA; ROS: reactive oxygen species. Created with BioRender.com.

Figure 2

Techniques for mitochondria analyses. Innovative techniques are needed in order to assess degeneration status and potential repair strategies. The figure reports the main techniques used with the respective advantages and disadvantages. OCR: Oxygen consumption rate. Created with BioRender.com.

Figure 3

Summary of therapeutic strategies to protect mitochondria health. These include canonical drugs, nutrients, herbal extracts and alternative approaches as gene therapy, exercise, caloric restrictions and mitochondria transplantation. Drp-1: Dynamin related protein-1; OPA1: optic athropy 1 gene. Created with BioRender.com.