Defective mitochondrial respiration and ATP production Reductions in cellular respiration and ATP production are well documented in ALS (Fig. 1). In post-mortem spinal cord of sporadic ALS patients the activity of all ETC complexes, complex I, II, III, and IV was found to be reduced [52,53]. In addition, the activity of complexes I and IV were reported to be impaired in skeletal muscle [54–56] while complex I activity and ATP levels were reduced in lymphocytes of sporadic ALS patients [57]. Counterintuitively, in fibroblasts obtained from skin biopsies of sporadic ALS patients the mitochondrial membrane potential (MMP) was increased compared to healthy controls. Possibly the increased MMP observed in fibroblasts reflects an attempt to rescue inefficient ATP synthesis or the metabolic differences between skin fibroblasts and central nervous system (CNS) cells [58]. Indeed, similar to fibroblasts obtained from sporadic patients, MMP was increased in C9orf72 patient fibroblasts [31] but was significantly decreased in iPSC-derived motor neurons reprogrammed from C9orf72 patient fibroblasts [32]. In SOD1 G93A transgenic mice impaired ATP synthesis and
depressed mitochondrial respiration rates in the brain and spinal cord were found well before disease onset and they persist throughout the course of the disease [39,45]. Associated with these changes, decreased complex I + III, II + III and IV activity was observed in the spinal cord of 17-week old symptomatic SOD1 G93A transgenic mice [45] and complex IV activity was reduced in forebrain mitochondria isolated from presymptomatic, symptomatic and end-stage SOD1 G93A transgenic mice [39,45]. Analysis of regional changes in ETC complex activities further showed a selective decrease of complex I and IV activity in the ventral horn of the spinal cord of these mice prior to the onset of disease which further declined as disease progressed [59]. In these cases, the reduced activity of complex IV may relate to impaired association of cytochrome c with the IMM [39,45]. A decrease in complex I activity was also confirmed in ex vivo motor cortex slices from SOD1 G93A mice [60] (Fig. 1). Analysis of mutant SOD1 ALS cell models recaptured the defects
found in SOD1 G93A mice. SOD1 I113T patient fibroblast lines showed reduced oxidative phosphorylation compared to nondisease controls [61]. Stable low level expression of SOD1 G93A or G37R in NSC-34 motor neuron-like cell lines reduced the activity of complex II and IV [62,63] accompanied by reduced MMP [64] while doxycycline-induced expression of SOD1 G93A, A4V, H46R, H80R, D90A, or D123H in the same cell line caused a decrease in complex I, II + III and IV activity which was accompanied by reduced cellular ATP levels [46]. In N2A neuroblastoma cells overexpression of SOD1 G37R resulted in reduced complex I activity which correlated with a drop in MMP and reduced levels of cytosolic ATP, but complex II, III and IV activities were unaffected [63]. In contrast to these studies, Bowling et al. found increased com-
plex I activity in post-mortem frontal cortex of familial ALS patients with an SOD1 A4V mutation [65] and the same group reported an increase in complex I activity in the forebrain of SOD1 G93A transgenic mice [66]. Furthermore, when they assessed mitochondrial respiration solely via complex II, the mitochondrial respiration rate was not different in SOD1 G93A transgenic mice compared to wild type SOD1 transgenic mice [67]. Similarly, others found no evidence for reduced mitochondrial respiration via complex I or II in
presymptomatic SOD1 G93A transgenic mice [68]. It is not readily  apparent what accounts for the discrepancy between these studies, but these measurements are particularly sensitive to variations in experimental conditions and differences between the SOD1 G93A mouse strains cannot be excluded. Nevertheless, despite differences between studies and cell mod-
els, the overarching trend is that ALS mutant SOD1 decreases ETC activity and causes impaired ATP production. Moreover, the presymptomatic occurrence of oxidative phosphorylation disruption in SOD1 G93A transgenic mice suggests it may have a causative role in this ALS model. Defective mitochondrial respiration and ATP production have
also been observed in models of non-SOD1 related familial ALS. Depolarisation of mitochondria was described in NSC-34 cells expressing wild type or mutant TDP-43 (Q331K and M337V) and primary motor neurons expressing TDP-43 M337V [21,23,69,70]. In NSC-34 cells TDP-43-associated MMP reduction was accompanied by decreased complex I activity [70]. Similarly, in TDP-43 G298S and A382T patient fibroblasts reduced MMP was accompanied by decreased complex I activity, reduced oxygen consumption and decreased ATP levels [42]. However, this may not always be the case as others reported reduced MMP, but no changes in mitochondrial respiration or ATP content in 3 independent TDP-43 A382T patient fibroblast lines [31]. As was the case for TDP-43, overexpression of wild type or
mutant FUS P525L caused a reduction in MMP in HEK293 cells [29] and ATP production was impaired upon expression of wild type or ALS mutant FUS R521C or R518K in NSC-34 cells [51]. Similarly overexpression of the sigma non-opioid intracellular receptor 1 (Sig1R) E102Q mutant in N2A cells reduced ATP production [71]. Decreased MMP was further observed in SQSTM1 knockout MEFs and in SH-SY5Y, mouse cortical neurons and astrocytes in which VCP/p97 expression was ablated using siRNA to model ALSassociated loss of function mutants in p62/Sequestosome1 and VCP/p97, respectively [72,73]. In case of VCP/p97 the same results were obtained in VCP/p97 R155C, R155H and R191Q ALS patient fibroblast lines [73]. In these cell models of VCP/p97-associated ALS the decrease in MMP was accompanied by a decrease in ATP levels but an increase in the rate of mitochondrial respiration and oxygen consumption, suggesting that depletion of MMP is due to uncoupling rather than ETC activity deficits [73]. Finally, analysis of fibroblasts from patients with mutations in the mitochondrial protein CHCHD10 revealed impaired ETC activity at complexes I, II, III and IV which was accompanied by a severe bioenergetics deficit [36,37].
Neurons do not operate as isolated units, but depend on the surrounding cellular environment and supporting cells such as microglia and astrocytes for survival and function. Accordingly, it is now clear that ALS is a non-cell-autonomous disease with astrocytes in particular associated with disease progression [74, reviewed in Refs. [12,75]]. One way in which glia support neurons is by shuttling of lactate, produced by conversion of the glycolysis product pyruvate, to the neighbouring neuron where it is converted back to pyruvate which is subsequently converted to acetyl-CoA and enters the Krebs cycle [76,reviewed in Ref. [77]]. In fact, evidence suggests that glial lactate is the main energy source of neurons (i.e. the Astrocyte-Neuron Lactate Shuttle Hypothesis (ANLSH)). Several lines of evidence suggest that impairment of the ANLSH may be involved in the bioenergetics deficits observed in ALS. The expression of phosphoglycerate kinase 1 (PGK1) which transfers phosphate from 1,3-bisphosphoglycerate (1,3-BPG) to ADP to produce 3-phosphoglycerate (3-PG) and ATP during glycolysis, as well as of the monocarboxylate transporter 4 (MCT4; Slc16a4), which is involved in the transport of lactate are downregulated in SOD1 G93A astrocytes [78]. Similarly, MCT1 (Slc16a1) expression is downregulated in oligodendrocytes in the spinal cord
of SOD1 G93A transgenic mice. Furthermore, consistent with a pos-sible role in neurodegeneration knock down of MTC1 caused motor neuron death in vivo [79]. Hence reductions in neuronal respiration and ATP production may be caused by failure of glia to provide respiratory substrates. Despite differences in mechanisms and specific observations depending on the models studied, decreased ETC activity and ATP levels emerge as a common feature in ALS. It is conceivable that, in line with the high energy demands of neurons, gradual depletion
of ATP due to reduced respiration may trigger degeneration. Por favor, hazme ideas principales del texto?