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Amyotrophic lateral sclerosis (ALS) is a heterogeneous progressive neurodegenerative disorder with available treatments such as riluzole and edaravone extending survival by an average of 3-6 months. The lack of highly effective, widely available therapies reflects the complexity of ALS. Omics technologies, including genomics, transcriptomic and proteomics have contributed to the identification of biological pathways dysregulated and targeted by therapeutic strategies in preclinical and clinical trials. Integrating clinical, environmental and neuroimaging information with omics data and applying a systems biology approach can further improve our understanding of the disease with the potential to stratify patients and provide more personalised medicine. This chapter will review the omics technologies that contribute to a systems biology approach and how these components have assisted in identifying therapeutic targets. Current strategies, including the use of genetic screening and biosampling in clinical trials, as well as the future application of additional technological advances, will also be discussed., (Copyright © 2024. Published by Elsevier Inc.)

Astrocytes are the most abundant glial cell in the central nervous system and are involved in multiple processes including metabolic homeostasis, blood brain barrier regulation and neuronal crosstalk. Astrocytes are the main storage point of glycogen in the brain and it is well established that astrocyte uptake of glutamate and release of lactate prevents neuronal excitability and supports neuronal metabolic function. However, the role of lipid metabolism in astrocytes in relation to neuronal support has been until recently, unclear. Lipids play a fundamental role in astrocyte function, including energy generation, membrane fluidity and cell to cell signaling. There is now emerging evidence that astrocyte storage of lipids in droplets has a crucial physiological and protective role in the central nervous system. This pathway links β-oxidation in astrocytes to inflammation, signalling, oxidative stress and mitochondrial energy generation in neurons. Disruption in lipid metabolism, structure and signalling in astrocytes can lead to pathogenic mechanisms associated with a range of neurological disorders., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Reperfusion or reoxygenation of ischaemic or hypoxic cardiac tissue results in increases in total cell calcium and cell lysis both of which are dependent on mitochondrial function. Although changes which occur during this period of exposure of the tissue to hypoxia predispose the heart to take up calcium on reoxygenation, the mechanisms involved are not well understood. In the present study we have investigated the effects of hypoxia and reoxygenation on the concentration of intramitochondrial (matrix) free Ca2+ ([Ca2+]m) using mitochondria loaded in the intact heart with fura-2. During periods of up to 80 min hypoxia, total tissue calcium content was unchanged. Over this period [Ca2+]m rose from an initial value of 156 +/- 26 nM to 360 +/- 33 nM and 574 +/- 62 nM at 50 and 80 min of hypoxia, respectively; values that are within the expected physiological range for [Ca2+]m. Reoxygenation after 50 min hypoxia resulted in no further change in [Ca2+]m whereas reoxygenation after 80 min hypoxia resulted in a 10-fold increase in this parameter. These results provide clear evidence that [Ca2+]m increases during hypoxia and suggest that the ability of the cell to maintain Ca2+ homeostasis is lost on reoxygenation after prolonged hypoxia with the result that [Ca2+]m exceeds the normal physiological range.

When rat hearts were perfused with a medium containing 10 microM fura-2/AM for 1 hr at 37 degrees C a significant amount of the derived fura-2 could be detected in subsequently isolated mitochondria. This procedure allowed the measurement of matrix free Ca2+ concentration ([Ca2+]m) of mitochondria rapidly isolated from whole hearts by a method which avoids artefactual redistribution of Ca2+. [Ca2+]m in mitochondria prepared from control hearts and incubated with respiratory substrates and EGTA was found to be 172 +/- 23 nM (mean +/- S.E.M.). When hearts were subjected to either increased mechanical work or treatment with 1 microM L-epinephrine (for 2 mins) [Ca2+]m increased to 916 +/- 138 nM and 727 +/- 65 nM respectively. The presence of ruthenium red (2.5 microM) in the perfusion medium prior to and during inotropic intervention diminished these increases in [Ca2+]m(to 316 +/- 28 nM and 218 +/- 18 nM respectively) but did not affect control values. Addition of Na+ ions to incubated mitochondria to enhance mitochondrial Ca2+ egress diminished these increases in [Ca2+]m due to pre-treatment with positive inotropes (compared to controls). These changes in [Ca2+]m were broadly parallelled by changes in the active non-phosphorylated form of pyruvate dehydrogenase (PDH) under all circumstances. These results provide further evidence that the activation of PDH by positive inotropes is accomplished by, and at least in part due to, raised mitochondrial matrix free [Ca2+] and that such increases can be maintained in isolated and suitably incubated mitochondria.