Succinate dehydrogenase inversely regulates red cell distribution width and healthy life span in chronically hypoxic mice.

Increased red cell distribution width (RDW), which measures erythrocyte mean corpuscular volume (MCV) variability (anisocytosis), has been linked to early mortality in many diseases and in older adults through unknown mechanisms. Hypoxic stress has been proposed as a potential mechanism. However, experimental models to investigate the link between increased RDW and reduced survival are lacking. Here, we show that lifelong hypobaric hypoxia (~10% O2) increased erythrocyte numbers, hemoglobin, and RDW, while reducing longevity in male mice. Compound heterozygous knockout (hKO) mutations in succinate dehydrogenase (Sdh; mitochondrial complex II) genes Sdhb, Sdhc, and Sdhd reduced Sdh subunit protein levels, reduced RDW, and increased healthy life span compared with WT mice in chronic hypoxia. RDW-SD, a direct measure of MCV variability, and the SD of MCV showed the most statistically significant reductions in Sdh hKO mice. Tissue metabolomic profiling of 147 common metabolites showed the largest increase in succinate with elevated succinate/fumarate and succinate/oxoglutarate (2-ketoglutarate) ratios in Sdh hKO mice. These results demonstrate that mitochondrial complex II level is an underlying determinant of both RDW and healthy life span in hypoxia and suggest that therapeutic targeting of Sdh might reduce high RDW-associated clinical mortality in hypoxic diseases.

Loci affecting male fertility in hybrids between Mus macedonicus and C57BL/6.

Male F1 hybrids between inbred strains and Mus macedonicus have very small testes and are sterile. Cytological analysis of testes shows very few meioses. To determine the genetic basis for this sterility, (C57BL/6J x Mus macedonics) F1 females were mated to males from C57BL/10J. In about half the male progeny no meiosis I was observed. About half of the animals that progressed through meiosis I showed other indications of low fertility and the balance appeared fertile. QTL analysis of the progeny suggested that loci on proximal Chrs 17 and X were involved in the sterility and a locus on Chr X in variation of body weight. There is also evidence that X//Y dissociation of the pseudo-autosomal region occurs. The QTLs on Chrs X and 17 together account for about 37% of the variance for testis weight. Congenic lines B.MAC-X(1-38), and B.MAC-17(1-23) have been constructed using a modified speed congenic approach. Testis tubules from B.MAC-X(1-38) are narrow and vacuolated. They contain only Sertoli cells and mitotically dividing spermatogonia. Very occasionally a meiotic metaphase can be observed, but no sperm are produced. Homozygous males from B.MAC-17(1-23) are sterile, producing sperm heads but no complete sperm.