Selective Neuron Vulnerability in Common and Rare Diseases—Mitochondria in the Focus

Abstract

Mitochondrial dysfunction is a central feature of neurodegeneration within the central and peripheral nervous system, highlighting a strong dependence on proper mitochondrial function of neurons with especially high energy consumptions. The fitness of mitochondria critically depends on preservation of distinct processes, including the maintenance of their own genome, mitochondrial dynamics, quality control, and Ca2+ handling. These processes appear to be differently affected in common neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, as well as in rare neurological disorders, including Huntington’s disease, Amyotrophic Lateral Sclerosis and peripheral neuropathies. Strikingly, particular neuron populations of different morphology and function perish in these diseases, suggesting that cell-type specific factors contribute to the vulnerability to distinct mitochondrial defects. Here we review the disruption of mitochondrial processes in common as well as in rare neurological disorders and its impact on selective neurodegeneration. Understanding discrepancies and commonalities regarding mitochondrial dysfunction as well as individual neuronal demands will help to design new targets and to make use of already established treatments in order to improve treatment of these diseases.

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

“…The memory loss and cognitive decline characteristic of AD are caused by atrophy of the entorhinal cortex (EC), mainly of neurons in layer II (ECII), and hippocampus, particularly the CA1 region [ 72 ]. Research has shown that neurons in these areas have high energetic demands and are very sensitive to decreased oxygen and glucose supply [ 263 ].…”

“…The pathological hallmark of ALS is degeneration of upper and lower motor neurons, which both have very long axons and, thus, depend on proper mitochondrial function and trafficking [ 72 ]. The large motor unit size imposes high energetic demands on spinal motor neurons to maintain neurotransmission and muscle contraction [ 276 ].…”

“…As such, mitochondrial Ca 2+ concentrations must be finely tuned. A mitochondrial Na + /Ca 2+ exchanger located in the IMM, and termed NCLX because it can also able to exchange Li + for Ca 2+ , extrudes Ca 2+ from the mitochondrial matrix by using the electrochemical gradient of Na + [71], while from the intermembrane space Ca 2+ is extruded by the Na + /Ca 2+ exchanger 3 and VDACs [72]. Figure 1 illustrates the mechanisms involved in cellular calcium homeostasis.…”

“…Abnormal proteins associated with impaired mitochondrial function in the three most frequent neurodegenerative diseases (adapted form Paß et al[72]). ↑ = increases; ↓ = decreases.…”

Changes in Glial Support of the Hippocampus during the Development of an Alzheimer’s Disease-like Pathology and Their Correction by Mitochondria-Targeted Antioxidant SkQ1

“…Undoubtedly, neurogenesis is a highly energyconsuming process that requires healthy mitochondria. Mitochondrial abnormalities, together with synaptic degeneration, are the earliest and most prominent features of vulnerable neurons in the brain of AD patients [33][34][35]. For a decade, we have researched the role of mitochondria in the AD-affected brain using mitochondria-targeted antioxidant SkQ1 [31,32,36].…”