Aging in mammals leads to reduction in genes encoding the 45-subunit mitochondrial electron
transport chain complex I. It has been hypothesized that normal aging and age-related diseases such
as Parkinson’s disease are in part due to modest decrease in expression of mitochondrial complex I
subunits. By contrast, diminishing expression of mitochondrial complex I genes in lower organisms
increases lifespan. Furthermore, metformin, a putative complex I inhibitor, increases healthspan in
mice and humans. In the present study, we investigated whether loss of one allele of Ndufs2, the
catalytic subunit of mitochondrial complex I, impacts healthspan and lifespan in mice. Our results
indicate that Ndufs2 hemizygous mice (Ndufs2+/−) show no overt impairment in aging-related
motor function, learning, tissue histology, organismal metabolism, or sensitivity to metformin in a
C57BL6/J background. Despite a signifcant reduction of Ndufs2 mRNA, the mice do not demonstrate
a signifcant decrease in complex I function. However, there are detectable transcriptomic changes
in individual cell types and tissues due to loss of one allele of Ndufs2. Our data indicate that a
50% decline in mRNA of the core mitochondrial complex I subunit Ndufs2 is neither benefcial nor
detrimental to healthspan
