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.
Highlights
The Peculiarity of MitochondriaClassically, mitochondria were considered the “powerhouse” of the cell, the energetic core generating ATP for cell activities [1]
Neurodegenerative diseases consist of a group of heterogeneous disorders, but, they are all characterized by the progressive loss of specific neuronal populations and circuits in the central nervous system (CNS) triggered by mitochondria dysfunctions [23,24]
Accumulation of mitochondrial DNA (mtDNA) defects occurs early in HD to the point of being suggested as a potential biomarker of the disease [82,83]. These mitochondria-derived defects recall pro-inflammatory activated innate immune cells; in HD, a remarkable neuroinflammation has been observed in brains from HD patients and positron emission tomography (PET) imaging showed that microglia activation correlates with the pathology progression
Summary
Mitochondria were considered the “powerhouse” of the cell, the energetic core generating ATP for cell activities [1] Intensive research on their morphology and functions showed that mitochondria play several different roles. Mitochondria buffer calcium ions regulate, in turn, calcium homeostasis [7,8] This is a crucial mitochondrial function impacting many cellular pathways such as the neurotransmitters’ release from neurons and glial cells [9]. The number and the size of cristae, which are dynamic bioenergetic compartments of the inner mitochondrial membrane where the respiratory chain occurs, adapt to the needs Their plasticity guarantees a constant turnover to assure the balance between regeneration, biogenesis, and elimination of damaged mitochondria [13]. Mitochondria are able to protect cell integrity by preventing the damage induced by viral infection [16]; they can stimulate the innate immune response against these insults [17]
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