Polymorphisms in the mitochondrial ribosome recycling factor EF-G2mt/MEF2 compromise cell respiratory function and increase atorvastatin toxicity.
Mitochondrial translation, essential for synthesis of the electron transport chain complexes in the mitochondria, is governed by nuclear encoded genes. Polymorphisms within these genes are increasingly being implicated in disease and may also trigger adverse drug reactions. Statins, a class of HMG-CoA reductase inhibitors used to treat hypercholesterolemia, are among the most widely prescribed drugs in the world. However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle. The mitochondria are one of the molecular targets of statins, and these drugs have been known to uncover otherwise silent mitochondrial mutations. Based on yeast genetic studies, we identify the mitochondrial translation factor MEF2 as a mediator of atorvastatin toxicity. The human ortholog of MEF2 is the Elongation Factor Gene (EF-G) 2, which has previously been shown to play a specific role in mitochondrial ribosome recycling. Using small interfering RNA (siRNA) silencing of expression in human cell lines, we demonstrate that the EF-G2mt gene is required for cell growth on galactose medium, signifying an essential role for this gene in aerobic respiration. Furthermore, EF-G2mt silenced cell lines have increased susceptibility to cell death in the presence of atorvastatin. Using yeast as a model, conserved amino acid variants, which arise from non-synonymous single nucleotide polymorphisms (SNPs) in the EF-G2mt gene, were generated in the yeast MEF2 gene. Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity. These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans.
School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
Sylvie
S
Callegari
Philip A
PA
Gregory
Matthew J
MJ
Sykes
Jennifer
J
Bellon
Stuart
S
Andrews
Ross A
RA
McKinnon
Miguel A
MA
de Barros Lopes
D000069059:Atorvastatin; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D019069:Cell Respiration / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D020653:Peptide Elongation Factor G / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010445:Peptide Elongation Factors / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000494:pharmacology*; D034741:RNA, Small Interfering; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism
D006538:Heptanoic Acids; C559871:MEF2 protein, S cerevisiae; D020653:Peptide Elongation Factor G; D010445:Peptide Elongation Factors; D011758:Pyrroles; D034741:RNA, Small Interfering; D029701:Saccharomyces cerevisiae Proteins; D000069059:Atorvastatin