Mitochondrial Dysfunctions: A Red Thread across Neurodegenerative Diseases

Abstract

Mitochondria play a central role in a plethora of processes related to the maintenance of cellular homeostasis and genomic integrity. They contribute to preserving the optimal functioning of cells and protecting them from potential DNA damage which could result in mutations and disease. However, perturbations of the system due to senescence or environmental factors induce alterations of the physiological balance and lead to the impairment of mitochondrial functions. After the description of the crucial roles of mitochondria for cell survival and activity, the core of this review focuses on the "mitochondrial switch" which occurs at the onset of neuronal degeneration. We dissect the pathways related to mitochondrial dysfunctions which are shared among the most frequent or disabling neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. Can mitochondrial dysfunctions (affecting their morphology and activities) represent the early event eliciting the shift towards pathological neurobiological processes? Can mitochondria represent a common target against neurodegeneration? We also review here the drugs that target mitochondria in neurodegenerative diseases.

Keywords: cellular homeostasis; mitochondria; mitochondria biogenesis and dynamics; mitochondria targeting drugs; motor neuron diseases; neurodegeneration; neurodegenerative diseases; oxidative stress.

Figure 1

The mitochondrial switch. The sketch shows the appearance and the features of a mitochondrion before and after the accumulation of damage responsible for its impairment. At the onset of the neurodegenerative process the increase of reactive oxygen species (ROS), mitochondrial DNA (mtDNA) mutations and altered proteins determines the swelling of mitochondria and the disruption of their membranes and cristae. Such an altered morphology heavily impacts on function determining, among others, decreases ATP production, increased ROS, leading to neuronal death. Created with BioRender software.

Figure 2

The process of neurodegeneration in the central nervous system (CNS), in the periphery and across diseases. Neurodegeneration is a progressive process taking place not only in the CNS but also in the periphery. After the accumulation of damage at the cellular and, in particular, mitochondrial level, the switch from physiology to pathology is fast and rarely reversible and it is occurring in many cell types. Indeed, it occurs in the CNS but also in the periphery, in particular the neuromuscular junction (NMJ), the skeletal muscles, blood cells, and fibroblasts. Moreover, the major pathways involved are linked to ROS and free radical formation, alterations in ATP formation, calcium homeostasis, apoptosis, mitochondrial turnover and dynamics, and neuroinflammation in terms of microglia and astrocytes activation. These pathways are affected in all the neurodegenerative diseases discussed in this review. Increase of ROS is represented by the black arrow pointing up and reduction in energy production by the black arrow pointing down. Created with BioRender software.