TY  - JOUR
AU  - Harvey, Calum
AU  - Weinreich, Marcel
AU  - Lee, James A K
AU  - Shaw, Allan C
AU  - Ferraiuolo, Laura
AU  - Mortiboys, Heather
AU  - Zhang, Sai
AU  - Hop, Paul J
AU  - Zwamborn, Ramona A J
AU  - van Eijk, Kristel
AU  - Julian, Thomas H
AU  - Moll, Tobias
AU  - Iacoangeli, Alfredo
AU  - Al Khleifat, Ahmad
AU  - Quinn, John P
AU  - Pfaff, Abigail L
AU  - Kõks, Sulev
AU  - Poulton, Joanna
AU  - Battle, Stephanie L
AU  - Arking, Dan E
AU  - Snyder, Michael P
AU  - Veldink, Jan H
AU  - Kenna, Kevin P
AU  - Shaw, Pamela J
AU  - Cooper-Knock, Johnathan
TI  - Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis.
JO  - Heliyon
VL  - 10
IS  - 3
SN  - 2405-8440
CY  - London [u.a.]
PB  - Elsevier
M1  - DKFZ-2024-00284
SP  - e24975
PY  - 2024
AB  - 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 
LB  - PUB:(DE-HGF)16
C6  - pmid:38317984
C2  - pmc:PMC10839612
DO  - DOI:10.1016/j.heliyon.2024.e24975
UR  - https://inrepo02.dkfz.de/record/287630
ER  -