Partial loss of succinate dehydrogenase reduces high red cell distribution width and promotes healthy survival in chronically hypoxic mice

Increased red cell distribution width (RDW), which measures erythrocyte size variability (anisocytosis), has been linked to early mortality in many diseases and normal aged population through unknown mechanisms. Hypoxia has been proposed to increase both RDW and mortality. However, experimental evidence, especially in animal models, is lacking. Here, we show that chronic hypobaric hypoxia (~10% O 2 ) increases erythrocyte numbers, hemoglobin and RDW, while reducing longevity in male mice. Compound heterozygous knockout (chKO) mutations in succinate dehydrogenase (Sdh; mitochondrial complex II) genes Sdhb, Sdhc and Sdhd reduce high RDW and immature reticulocyte fraction, and increase healthy lifespan in chronic hypoxia. Hemoglobin and erythrocyte numbers in hypoxia do not show statistically significant differences between Sdh chKO and WT mice. These results identify a mitochondrial mechanism regulating both RDW and organismal adaptation to chronic hypoxia, and suggest SDH as a potential therapeutic target to reduce high RDW-associated clinical mortality.