mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes.
OBJECTIVE
ALR/Lt, a mouse strain with strong resistance to type 1 diabetes, is closely related to autoimmune type 1 diabetes-prone NOD/Lt mice. ALR pancreatic beta cells are resistant to the beta cell toxin alloxan, combinations of cytotoxic cytokines, and diabetogenic NOD T-cell lines. Reciprocal F1 hybrids between either ALR and NOD or ALR and NON/Lt, showed that alloxan resistance was transmitted to F1 progeny only when ALR was the maternal parent. Here we show that the mitochondrial genome (mtDNA) of ALR mice contributes resistance to diabetes.


METHODS
When F1 progeny from reciprocal outcrosses between ALR and NOD were backcrossed to NOD, a four-fold lower frequency of spontaneous type 1 diabetes development occurred when ALR contributed the mtDNA. Because of the apparent interaction between nuclear and mtDNA, the mitochondrial genomes were sequenced.


RESULTS
An ALR-specific sequence variation in the mt-Nd2 gene producing a leucine to methionine substitution at amino acid residue 276 in the NADH dehydrogenase 2 was discovered. An isoleucine to valine mutation in the mt-Co3 gene encoding COX3 distinguished ALR and NOD from NON and ALS. All four strains were distinguished by variation in a mt-encoded arginyl tRNA polyadenine tract. Shared alleles of mt-Co3 and mt-Tr comparing NOD and ALR allowed for exclusion of these two genes as candidates, implicating the mt-Nd2 variation as a potential ALR-derived type 1 diabetes protective gene.


CONCLUSIONS
The unusual resistance of ALR mice to both ROS-mediated and autoimmune type 1 diabete stresses reflects an interaction between the nuclear and mt genomes. The latter contribution is most likely via a single nucleotide polymorphism in mt-Nd2.
Mathews
C E
CE
Department of Pediatrics, Diabetes Institute, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 3460 5th Ave., Rangos Research Center, Pittsburgh, PA 15213, USA. cem65@pitt.edu
Leiter
E H
EH
Spirina
O
O
Bykhovskaya
Y
Y
Gusdon
A M
AM
Ringquist
S
S
Fischel-Ghodsian
N
N
D000818:Animals; D001483:Base Sequence; D003433:Crosses, Genetic; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D014644:Genetic Variation; D007113:Immunity, Innate; D007668:Kidney / Q000201:enzymology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D008930:Mitochondria, Liver / Q000201:enzymology / Q000235:genetics; D009245:NADH Dehydrogenase / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
D017931:DNA Primers; D004272:DNA, Mitochondrial; D009245:NADH Dehydrogenase; C502385:mt-Nd2 protein, mouse