Altered glucose catabolism in the presynaptic and perisynaptic compartments of SOD1^G93A mouse spinal cord and motor cortex indicates that mitochondria are the site of bioenergetic imbalance in ALS

Abstract

Amyotrophic lateral sclerosis is an adult-onset neurodegenerative disease that develops because of motor neuron death. Several mechanisms occur supporting neurodegeneration, including mitochondrial dysfunction. Recently, we demonstrated that the synaptosomes from the spinal cord of SOD1 G93A mice, an in vitro model of presynapses, displayed impaired mitochondrial metabolism at early pre-symptomatic stages of the disease, whereas perisynaptic astrocyte particles, or gliosomes, were characterized by mild energy impairment only at symptomatic stages. This work aimed to understand whether mitochondrial impairment is a consequence of upstream metabolic damage. We analyzed the critical pathways involved in glucose catabolism at presynaptic and perisynaptic compartments. Spinal cord and motor cortex synaptosomes from SOD1 G93A mice displayed high activity of hexokinase and phosphofructokinase, key glycolysis enzymes, and of citrate synthase and malate dehydrogenase, key Krebs cycle enzymes, but did not display high lactate dehydrogenase activity, the key enzyme in lactate fermentation. This enhancement was evident in the spinal cord from the early stages of the disease and in the motor cortex at only symptomatic stages. Conversely, an increase in glycolysis and lactate fermentation activity, but not Krebs cycle activity, was observed in gliosomes from the spinal cord and motor cortex of SOD1 G93A mice although only at the symptomatic stages of the disease. The cited enzymatic activities were enhanced in spinal cord and motor cortex homogenates, paralleling the time-course of the effect observed in synaptosomes and gliosomes. The observed metabolic modifications might be considered an attempt to restore altered energetic balance and indicate that mitochondria represent the ultimate site of bioenergetic impairment.

Decreased Mitochondrial Function, Biogenesis, and Degradation in Peripheral Blood Mononuclear Cells from Amyotrophic Lateral Sclerosis Patients as a Potential Tool for Biomarker Research

“…In fact, lactate augmentation accounts for a compensatory glycolytic response to favor ATP synthesis [ 185 ]. Although the synthesis of ATP through lactate is not efficient and is less cost-effective than through OXPHOS, metabolic modifications might be an attempt to restore energy homeostasis [ 186 ] since ATP depletion contributes to ALS progression [ 187 ]. Furthermore, the accumulation of lactate can be a strategy to convert NADH (reduced form of nicotinamide adenine dinucleotide) into NAD+ (oxidized form of nicotinamide adenine dinucleotide), reverting reductive stress in order to compensate for an oxidative phosphorylation deficiency [ 186 , 188 ].…”

Abnormal Mitochondrial Quality Control in Neurodegenerative Diseases

“…Point mutations in the gene that encodes SOD1 are one of the earliest discovered genetic causes related to fALS. There is an increment of glucose catabolic activity upstream of the mitochondrial aerobic respiration in SOD1G93A mice, indicating that mitochondrial dynamics represent the crucial site of the synaptic bioenergetic impairment in ALS (Ravera et al, 2019). Superoxide dismutase 1 mutations affect protein folding, which is a potential source of the toxicity that leads to mitochondria degeneration (Wright et al, 2019).…”

A multistationary loop model of ALS unveils critical molecular interactions involving mitochondria and glucose metabolism

“…Moreover, neurons also display a high rate of the pentose phosphate pathway (PPP), while astrocytes are known to provide neurons with lactate that is then converted to pyruvate and contributes to satisfy the needs for mitochondrial metabolism [23,24]. Given these premises, another important piece of evidence for the building of our model is the apparent inversion of MN energetic metabolism in SOD1 G93A mice, from prevalently oxidative under healthy conditions to prevalently glycolytic during pathogenesis [17,18]. Moreover, as observed for mutant SOD1 binding to mitochondria, also the metabolism inversion occurs in the spinal cord at an early stage of the disease and then appears in the motor cortex at a later symptomatic stage [18].…”

“…Despite a bulk of data collected through years at the molecular, cellular, and organism levels, on both animal models and human subjects, and a number of hypotheses put forward about pathogenesis, the identification of a bona fide primary event for the onset of the disease is still lacking, thus making pharmacological and clinical strategies disappointedly weak [16]. By considering previous published data from our laboratory [17,18], as well as, at present, unpublished data, and combining them with other inputs from literature, in this study we propose a model based on interactive feedback loops mainly focused on the SOD1 G93A mouse model. In particular, we envisage a feedback loop interaction between mitochondria and glucose metabolism in MNs.…”