Abstract
Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients’ skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients’ skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes.
Highlights
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurological disease characterized by the gradual degeneration and death of motor neurons, followed by global muscle wasting
The inhibition of the respiratory chain system was previously explained by the blockade of VDAC by the misfolded mutated form of SOD12, and the altered oxidative phosphorylation (OXPHOS) coupling was thought to result from the perturbation of mitochondrial structure[39]
We observed an increased fragmentation of the mitochondrial network in amyotrophic lateral sclerosis (ALS) mice motor neurons, as well as a reduced mitochondrial transmembrane electric potential. This is totally consistent with the dependency of mitochondrial morphology and dynamics on mitochondrial bioenergetics[29] and on transmembrane electric potential[30]
Summary
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurological disease characterized by the gradual degeneration and death of motor neurons, followed by global muscle wasting. Further bioenergetic and biochemical analyses showed that UCP2 does not uncouple OXPHOS as expected[8,9,10,11,12,13,14] but rather accommodates a metabolic shift from glucose to fatty acid oxidation (FAO)[15] and induce ketone body formation by exporting C4 metabolites as oxaloacetate out of mitochondria[16] In line with this view, a metabolic shift toward FAO and ketogenesis was observed in the skeletal muscle of ALS patients[17] and a genetic mouse model[4], and UCP2 expression itself was shown to depend upon the activation of fatty acid metabolism[18]. Our results unraveled the specificities of metabolic remodeling in ALS mouse motor neurons and patients’ skin fibroblasts
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