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Alterations in mitochondrial structure and function are commonly observed in adult-onset neurodegenerative diseases. In ALS, mitochondrial dysfunction impairs the efficiency of electron transport chain (ETC) activity and ATP production and leads to the accumulation of reactive oxygen and nitrogen species, abnormal handling of intracellular calcium and cytochrome C release and apoptosis. The extent to which these alterations in mitochondrial functionimpair cellular operations is unclear. Therapeutic intervention based on combating these mitochondrial abnormalities have displayed variable success in mouse models of ALS and humans, as reviewed in Vandoorne et al.

Sean-Patrick Riechers, Jelena Mojsilovic-Petrovic, Tayler B. Belton, Ram P. Chakrabarty, ... Robert G. Kalb

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Current Issue

Neurons undergo pathogenic metabolic reprogramming in models of familial ALS

Sean-Patrick Riechers, Jelena Mojsilovic-Petrovic, Tayler B. Belton, Ram P. Chakrabarty, ... Robert G. Kalb

Objectives

Normal cellular function requires a rate of ATP production sufficient to meet demand. In most neurodegenerative diseases (including Amyotrophic Lateral Sclerosis [ALS]), mitochondrial dysfunction is postulated raising the possibility of impaired ATP production and a need for compensatory maneuvers to sustain the ATP production/demand balance. We investigated intermediary metabolism of neurons expressing familial ALS (fALS) genes and interrogated the functional consequences of glycolysis genes in fitness assays and neuronal survival.

Methods

We created a pure neuronal model system for isotopologue investigations of fuel utilization. In a yeast platform we studied the functional contributions of glycolysis genes in a growth fitness assay iafter expressing of a fALS gene.

Results

We find in our rodent models of fALS, a reduction in neuronal lactate production with maintained or enhanced activity of the neuronal citric acid cycle. This rewiring of metabolism is associated with normal ATP levels, bioenergetics, and redox status, thus supporting the notion that gross mitochondrial function is not compromised in neurons soon after expressing fALS genes. Genetic loss-of-function manipulation of individual steps in the glycolysis and the pentose phosphate pathway blunt the negative phenotypes seen in various fALS models.

Conclusions

We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated alteration in mitochondrial function in a baleful manner and targeting this process can be healthful.

Neurons undergo pathogenic metabolic reprogramming in models of familial ALS

Sean-Patrick Riechers, Jelena Mojsilovic-Petrovic, Tayler B. Belton, Ram P. Chakrabarty, ... Robert G. Kalb

Objectives

Normal cellular function requires a rate of ATP production sufficient to meet demand. In most neurodegenerative diseases (including Amyotrophic Lateral Sclerosis [ALS]), mitochondrial dysfunction is postulated raising the possibility of impaired ATP production and a need for compensatory maneuvers to sustain the ATP production/demand balance. We investigated intermediary metabolism of neurons expressing familial ALS (fALS) genes and interrogated the functional consequences of glycolysis genes in fitness assays and neuronal survival.

Methods

We created a pure neuronal model system for isotopologue investigations of fuel utilization. In a yeast platform we studied the functional contributions of glycolysis genes in a growth fitness assay iafter expressing of a fALS gene.

Results

We find in our rodent models of fALS, a reduction in neuronal lactate production with maintained or enhanced activity of the neuronal citric acid cycle. This rewiring of metabolism is associated with normal ATP levels, bioenergetics, and redox status, thus supporting the notion that gross mitochondrial function is not compromised in neurons soon after expressing fALS genes. Genetic loss-of-function manipulation of individual steps in the glycolysis and the pentose phosphate pathway blunt the negative phenotypes seen in various fALS models.

Conclusions

We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated alteration in mitochondrial function in a baleful manner and targeting this process can be healthful.

2021 impact factor: 7.422

The 60 Second Metabolist

In this section authors briefly report on their work recently published in Molecular Metabolism.

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