PMC:6610326 / 90511-95066 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6610326","sourcedb":"PMC","sourceid":"6610326","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6610326","text":"Mitochondria and Energy Metabolism\nNeurons utilize most of their energy at the synapse, which consumes more than a third of the overall cellular ATP (Harris et al., 2012; Niven, 2016). The properties and types of ion channels expressed in a MN influence the energy required to generate an action potential, and the Na+/K+ pump is estimated to account for 20–40% of the brain’s energy consumption (Purves et al., 2001). The size and shape of a MN also affects its electrical properties, and the distance over which signals must spread. MNs have particularly high energetic demands, even compared to other neurons. They also have large numbers of NMJs as well as high intracellular Ca2+ flux as discussed above.\nMore than 90% of ATP generation in the CNS occurs via mitochondrial oxidative phosphorylation (Hyder et al., 2013; Vandoorne et al., 2018). Reductions in energy metabolism have been reported in ALS (Vandoorne et al., 2018) and mitochondrial abnormalities, such as swelling and morphological changes, are among the earliest signs of pathology in SOD1G93A and SOD1G37R mice (Wong et al., 1995; Kong and Xu, 1998), FUSR521C rats (Huang et al., 2012; So et al., 2018) and wild type TDP-43 mice (Shan et al., 2010; Xu et al., 2010). Moreover, mitochondrial abnormalities are also present in MNs of ALS patient tissues (Fujita et al., 1996; Sasaki and Iwata, 1996; Swerdlow et al., 1998; Dhaliwal and Grewal, 2000; Sasaki et al., 2007). Furthermore, mutant SOD1 specifically associates with mitochondria and interferes with their function (Liu et al., 2004; Pasinelli et al., 2004; Ferri et al., 2006; Sotelo-Silveira et al., 2009; Vande Velde et al., 2011). Decreased activity of mitochondrial respiratory chain complexes was also present in spinal cord sections (Borthwick et al., 1999) and homogenates (Wiedemann et al., 2002) from ALS patients. Consistent with these findings, genes involved in mitochondrial function were upregulated in rat oculomotor neurons compared to hypoglossal and cervical spinal cord MNs. However, it should be noted that the higher firing rate of the former might confer some resistance to energy imbalance (Hedlund et al., 2010; Brockington et al., 2013).\nIn vulnerable MNs lacking Ca2+-binding proteins calbindin and parvalbumin, Ca2+ is largely taken up by mitochondria (Lautenschläger et al., 2013). As a result, extensive mitochondrial transport to the dendritic space is required to maintain Ca2+ homeostasis. The normal distribution of mitochondria is also perturbed in ALS patient MNs. Whereas they are depleted in distal dendrites and axons, mitochondria also accumulate in the soma and proximal axon hillock (Sasaki et al., 2007). Disturbed mitochondrial dynamics were also described in MNs in mutant SOD1G93A (De Vos et al., 2007; Sotelo-Silveira et al., 2009; Bilsland et al., 2010; Magrané et al., 2014) and TDP-43A315T (Magrané et al., 2014) mice. In addition, iPSC-derived A4V MNs exhibit disturbances in mitochondrial morphology and motility within the axon (Kiskinis et al., 2014). Similarly, expression of mutant TDP-43 in spinal cord primary neurons leads to abnormal distribution of mitochondria (Wang et al., 2013). Dysfunctional Ca2+ uptake by mitochondria may therefore result in elevated intracellular Ca2+ levels, thus contributing to neurodegeneration.\nCompared to FF-MNs, S-MNs have smaller soma and axons, less dendritic branching, and fewer neuromuscular terminals (Kanning et al., 2010). This results in higher input resistance and therefore less energy is required to initiate an action potential in comparison. Moreover, S-MNs contain more mitochondria compared to FF-MNs (Kanning et al., 2010). These two properties may therefore render FF-MNs more vulnerable to depletion of energy than S-MNs. Indeed, a computational analysis study estimated that the energy requirements of FF-MNs are considerably larger than S-MNs for a similar discharge (Le Masson et al., 2014), rendering the former more sensitive to ATP imbalance. Furthermore, the muscle fiber types associated with FF- and S-MNs differ in their major energy source. The slow twitch muscles use mainly oxidative metabolism, whereas the fast-twitch fibers use glycolysis. Hence, the heightened vulnerability of MN subpopulations may relate to their bioenergetic and morphological characteristics. Both the direct interaction of misfolded ALS mutant proteins with mitochondria and the secondary overload of ion uptake could account for mitochondrial metabolism failure, leading to reduced ATP availability (Israelson et al., 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