Mitochondrial defects in the respiratory complex I contribute to impaired translational initiation via ROS and energy ho
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RESEARCH
Mitochondrial defects in the respiratory complex I contribute to impaired translational initiation via ROS and energy homeostasis in SMA motor neurons Maximilian Paul Thelen1,2 , Brunhilde Wirth1,2,3 and Min Jeong Kye1,2*
Abstract Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of lower motor neurons, which leads to proximal muscle weakness and atrophy. SMA is caused by reduced survival motor neuron (SMN) protein levels due to biallelic deletions or mutations in the SMN1 gene. When SMN levels fall under a certain threshold, a plethora of cellular pathways are disturbed, including RNA processing, protein synthesis, metabolic defects, and mitochondrial function. Dysfunctional mitochondria can harm cells by decreased ATP production and increased oxidative stress due to elevated cellular levels of reactive oxygen species (ROS). Since neurons mainly produce energy via mitochondrial oxidative phosphorylation, restoring metabolic/oxidative homeostasis might rescue SMA pathology. Here, we report, based on proteome analysis, that SMA motor neurons show disturbed energy homeostasis due to dysfunction of mitochondrial complex I. This results in a lower basal ATP concentration and higher ROS production that causes an increase of protein carbonylation and impaired protein synthesis in SMA motor neurons. Counteracting these cellular impairments with pyruvate reduces elevated ROS levels, increases ATP and SMN protein levels in SMA motor neurons. Furthermore, we found that pyruvate-mediated SMN protein synthesis is mTOR-dependent. Most importantly, we showed that ROS regulates protein synthesis at the translational initiation step, which is impaired in SMA. As many neuropathies share pathological phenotypes such as dysfunctional mitochondria, excessive ROS, and impaired protein synthesis, our findings suggest new molecular interactions among these pathways. Additionally, counteracting these impairments by reducing ROS and increasing ATP might be beneficial for motor neuron survival in SMA patients. Keywords: Spinal muscular atrophy, SMN, SMN1, SMN2, Mitochondria, Reactive oxygen species, Translation initiation Background Spinal muscular atrophy (SMA) is an inherited neuromuscular disease that is characterized by loss of lower motor neurons (MNs) due to reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein *Correspondence: min.kye@uk‑koeln.de 1 Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931 Cologne, Germany Full list of author information is available at the end of the article
[1]. The incidence of SMA varies between 1 per 6000– 10,000 newborns in the human population [2]. In 96% of SMA patients, homozygous deletions, or mutations in SMN1, the gene encoding for full-length SMN, have been described [2]. Interestingly, the human genome contains an almost identical gene - SMN2 -, that mainly produces a transcript lacking exon 7 due to a single silent mutation [3]. Hence, SMN2 produces approximately 10% of the full-length
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