Investigating the causal and consequential role of the nuclear encoded mitochondrial genome in Amyotrophic Lateral Sclerosis

Mitochondrial central dogma pathways—especially mitochondrial translation and the mitoribosome—show modest enrichment for ALS genetic risk (Padj = 0.044) in a European GWAS.

• Why it matters: It remains unclear which mitochondrial processes relate to ALS risk and whether mitochondrial pathway changes reflect cause, consequence, or both.
• What they did: Using MAGMA on 27,205 ALS cases and 110,881 controls, the study tested MitoCarta3.0 pathways hierarchically and integrated TWAS/SMR directionality with cell type–adjusted GSEA/GSVA in >1,500 post-mortem motor cortex and spinal cord samples plus iPSC-derived motor neurones.
• The result: ALS tissue showed higher mitochondrial gene expression in motor cortex, with OXPHOS and mitoribosome enriched beyond a global shift (PFDR = 0.027), while nuclear–mtDNA co-expression was more negative in ALS post-mortem tissues but opposite in iPSC-derived motor neurones.

AI summary of the abstract · may contain errors · not medical advice · read the paper.