Mitochondrial and Nuclear DNA Variants in Amyotrophic Lateral Sclerosis: Enrichment in the Mitochondrial Control Region and Sirtuin Pathway Genes in Spinal Cord Tissue

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a progressive disease with prevalent mitochondrial dysfunctions affecting both upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. Despite mitochondria having their own genome (mtDNA), in humans, most mitochondrial genes are encoded by the nuclear genome (nDNA). Our study aimed to simultaneously screen for nDNA and mtDNA genomes to assess for specific variant enrichment in ALS compared to control tissues. Here, we analysed whole exome (WES) and whole genome (WGS) sequencing data from spinal cord tissues, respectively, of 6 and 12 human donors. A total of 31,257 and 301,241 variants in nuclear-encoded mitochondrial genes were identified from WES and WGS, respectively, while mtDNA reads accounted for 73 and 332 variants. Despite technical differences, both datasets consistently revealed a specific enrichment of variants in the mitochondrial Control Region (CR) and in several of these genes directly associated with mitochondrial dynamics or with Sirtuin pathway genes within ALS tissues. Overall, our data support the hypothesis of a variant burden in specific genes, highlighting potential actionable targets for therapeutic interventions in ALS.

L-Theanine Prolongs the Lifespan by Activating Multiple Molecular Pathways in Ultraviolet C-Exposed Caenorhabditis elegans

“…Mitochondria are multi-functional organelles within eukaryotic cells and generate the most energy by producing adenosine 5′-triphosphate (ATP) via oxidative phosphorylation (OxPHOs), which functions in fatty acid oxidation, apoptosis, the cell cycle, and cell signaling [ 1 ]. The majority of enzymes necessary for oxidative phosphorylation (OxPHOs) are encoded by nuclear DNA (nDNA), while a specific subset of 13 essential protein subunits of respiratory complexes I, III, IV, and V, along with two rRNAs and 22 tRNAs, are exclusively encoded by mitochondrial DNA (mtDNA) [ 2 ]. mtDNA is more susceptible to damage compared to nDNA due to its lack of nucleotide excision repair (NER), which typically repairs helix-distorting damage caused by common environmental factors such as polycyclic aromatic hydrocarbons (PAHs), mycotoxins, and ultraviolet C radiation (UVC) [ 3 ].…”