Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function is an upstream driver or a downstream modifier of neurotoxicity. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial DNA copy number (mtCN). Across three cohorts including 6,437 ALS patients, we discovered that a set of mitochondrial haplotypes, chosen because they are linked to measurements of mitochondrial function, are a determinant of ALS survival following disease onset, but do not modify ALS risk. One particular haplotype appeared to be neuroprotective and was significantly over-represented in two cohorts of long-surviving ALS patients. Causal inference for mitochondrial function was achievable using mitochondrial haplotypes, but not autosomal SNPs in traditional Mendelian randomization (MR). Furthermore, rare loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to ∼50 % shorter ALS survival; both proteins are implicated in mitochondrial function. Both mtCN and cellular vulnerability are linked to DNA2 function in ALS patient-derived neurons. Finally, MtCN responds dynamically to the onset of ALS independently of mitochondrial haplotype, and is correlated with disease severity. We conclude that, based on the genetic measures we have employed, mitochondrial function is a therapeutic target for amelioration of disease severity but not prevention of ALS.
Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Michael P Snyder reports a relationship with Personalis Inc that includes: board membership. Michael P Snyder reports a relationship with Q Bio that includes: board membership. Michael P Snyder reports a relationship with SensOmics that includes: board membership. Michael P Snyder reports a relationship with January that includes: board membership. Michael P Snyder reports a relationship with Protos that includes: board membership. Michael P Snyder reports a relationship with Mirvie that includes: board membership. Michael P Snyder reports a relationship with NiMo that includes: board membership. Michael P Snyder reports a relationship with Onza that includes: board membership. Michael P Snyder reports a relationship with Oralome that includes: board membership. Michael P Snyder reports a relationship with Danaher that includes: board membership. Michael P Snyder reports a relationship with GenapSys Inc that includes: board membership. Michael P Snyder reports a relationship with Jupiter that includes: board membership.
(© 2024 The Authors.)