As organisms age, they accumulate cellular damage. Stem cells are needed to replenish tissues, but the damage they sustain over time compromises their ability to maintain healthy tissue function. A number of recent papers further our understanding of how stem cells are vulnerable to or protected from damage.

Katajisto et al., 2015 Katajisto P.

Döhla J.

Chaffer C.L.

Pentinmikko N.

Marjanovic N.

Iqbal S.

Zoncu R.

Chen W.

Weinberg R.A.

Sabatini D.M. Young and old mitochondria. Image by Kip Lyall. Stem cells may possess intrinsic protective mechanisms that keep them healthy. For instance, one possibility is that upon dividing, they favor one of their progeny by bestowing it with the newest and healthiest cellular components. Now a recent study by David Sabatini and colleagues presents evidence in support of this idea (). By using various labeling methods to distinguish between old and young organelles in human mammary stem-like cells, they find that unlike other organelles examined, mitochondria are divvied up unequally, with young mitochondria going preferentially to the daughter cell that retains stem-cell-like properties. Live imaging shows that even before division, old and new mitochondria are separated, with old mitochondria sticking close to the nucleus, but young ones venturing further out. Inhibiting mitochondrial fission prevents this partitioning, so mitochondria have to stay nimble for this process to occur. But how exactly do how young and old mitochondria get asymmetrically segregated to promote stemness?

Higuchi et al., 2013 Higuchi R.

Vevea J.D.

Swayne T.C.

Chojnowski R.

Hill V.

Boldogh I.R.

Pon L.A. The answer isn’t clear, but it’s tempting to look to yeast for some possible clues. When yeast cells divide, the new cell that buds off gets the younger, less damaged mitochondria, while the mother keeps the less desirable ones for herself. It appears that retrograde flow of actin cables toward the mother cell acts as a filter to keep oxidized mitochondria out of the bud, as healthy mitochondria are more effective at fighting their way upstream against this conveyer belt than their more sluggish, damaged counterparts (). Interestingly, the aging-related deacetylase SIR2 increases actin cable abundance and regulates mitochondrial partitioning between mother and daughter. However, it remains to be seen whether a similar cytoskeletal flow-based mechanism occurs in asymmetric stem cell division.

Moussaieff et al., 2015 Moussaieff A.

Rouleau M.

Kitsberg D.

Cohen M.

Levy G.

Barasch D.

Nemirovski A.

Shen-Orr S.

Laevsky I.

Amit M.

et al. Vilchez et al., 2012 Vilchez D.

Boyer L.

Morantte I.

Lutz M.

Merkwirth C.

Joyce D.

Spencer B.

Page L.

Masliah E.

Berggren W.T.

et al. Zhou et al., 2014 Zhou C.

Slaughter B.D.

Unruh J.R.

Guo F.

Yu Z.

Mickey K.

Narkar A.

Ross R.T.

McClain M.

Li R. Whatever the partitioning mechanism may be, a key question raised by this study is why young mitochondria promote stemness. Pluripotential stem cells generally have more immature mitochondria and higher rates of glycolysis, and when they differentiate, they shift to oxidative phosphorylation. As a result, they produce less of the glycolytic product acetyl-coA, which is needed for histone acetylation () and potentially for epigenetic control of pluripotency genes. So one possibility is that having young mitochondria metabolically biases cells to maintain stem cell properties. Or perhaps it has to do with cellular stress responses and proteostasis, since high proteasome activity is needed in stem cells to maintain pluripotency (). Here again, it may be worth turning to yeast for some inspiration. Unfolded proteins cause proteotoxic stress and form aggregates that must be disposed of by proteasomes. Interestingly, unfolded protein aggregates are tethered to mitochondria in yeast, with the mother cell keeping the garbage-covered mitochondria and sending the pristine ones to the baby bud cell (). It isn’t known whether these protein aggregates are targeted to old mitochondria, but perhaps mitochondrial segregation is a way to reduce proteotoxic stress in stem cells.

Mohrin et al., 2015 Mohrin M.

Shin J.

Liu Y.

Brown K.

Luo H.

Xi Y.

Haynes C.M.

Chen D. Indeed, proteotoxic stress in the mitochondria themselves seems to be linked to stem cell aging. One way adult stem cells preserve themselves is by staying in a metabolically quiescent state until needed. Adult stem cells generally possess few mitochondria, but when they’re deployed to proliferate and replenish tissues, their metabolism revs up and mitochondrial biogenesis increases. Danica Chen and colleagues now show that this checkpoint involves a mitochondrial stress response and regulates hematopoietic stem cell (HSC) aging (). They find that the histone deacetylase SIRT7 promotes HSC quiescence and maintenance, likely by preventing NRF1 from activating mitochondrial translation machinery genes and from promoting mitochondrial proliferation. By keeping the demand on mitochondrial protein synthesis low, mitochondria experience less protein folding stress. Remarkably, reintroduction of SIRT7 or inhibiting NRF1 is able to reduce the mitochondrial unfolded protein response and restore regenerative function to aged HSCs in mice. This suggests that it may be possible to rejuvenate old stem cells by targeting mitochondrial proteostasis pathways.

Walter et al., 2015 Walter D.

Lier A.

Geiselhart A.

Thalheimer F.B.

Huntscha S.

Sobotta M.C.

Moehrle B.

Brocks D.

Bayindir I.

Kaschutnig P.

et al. So what causes HSCs to exit quiescence, and how might the resulting mitochondrial stress affect cells in the longer term? As shown in a study from Michael Milsom and colleagues, a variety of physiological stresses in mice, such as induction of the infectious immune response and chronic blood loss, cause HSCs to transition out of quiescence to a proliferative state (). While deployment of HSCs may be necessary to respond to an immediate crisis, this isn’t without negative consequences; mitochondria in the proliferative HSCs produce more reactive oxygen species, which cause DNA damage. When HSCs are repeatedly forced to exit dormancy in mice lacking the Fanconi anemia DNA repair mechanism, the ultimate effects are dire; HSCs can no longer be maintained, and the whole hemotopoietic system collapses. This suggests that over time, the accumulation of DNA damage in response to various infections and stresses may hamper HSC maintenance.

Together, these studies point to the centrality of mitochondrial metabolism and function in stem cell maintenance and aging. Understanding how these processes are regulated and coordinated with other cellular functions will be key for developing stem cell rejuvenation approaches that may someday allow us to stave off detrimental effects of aging.

Cindy Lu