Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging

• Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understanding the aging process. Here, using a model carrying a proofreading-defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging, including anemia, lymphopenia, and myeloid lineage skewing. However, in contrast to physiological stem cell aging, rapidly accumulating mitochondrial DNA mutations had little functional effect on the hematopoietic stem cell pool, and instead caused distinct differentiation blocks and/or disappearance of downstream progenitors. These results show that intact mitochondrial function is required for appropriate multilineage stem cell differentiation, but argue against mitochondrial DNA mutations per se being a primary driver of somatic stem cell aging.

Subject headings

NATURVETENSKAP  -- Biologi -- Cellbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Cell Biology (hsv//eng)

Keyword

anemia

animal cell

animal experiment

apoptosis

capacity

cell aging

cell differentiation

cell lineage

controlled study

DNA polymerase

efflux

expression

gene mutation

hematopoiesis

hematopoietic stem cell

lymphocytopenia

mitochondrial DNA

mouse

nonhuman

number

p-glycoprotein

pathways

phenotype

priority journal

proliferation

repopulation

serial transplantation

somatic cell

MEDICINE

MEDICIN

Publication and Content Type

ref (subject category)

art (subject category)