StemCell Therapy

Highlights

Mitochondrial ROS (mtROS) signaling increases longevity in the nematode C.elegans

mtROS act through the intrinsic apoptosis pathway

mtROS signaling requires the alternative BH3-only protein CED-13

mtROS signaling induces a unique pattern of gene expression

The increased longevity of the C.elegans electron transport chain mutants isp-1 and nuo-6 is mediated by mitochondrial ROS (mtROS) signaling. Here weshow that the mtROS signal is relayed by theconserved, mitochondria-associated, intrinsic apoptosis signaling pathway (CED-9/Bcl2, CED-4/Apaf1, and CED-3/Casp9) triggered by CED-13, an alternative BH3-only protein. Activation of the pathway by an elevation of mtROS does not affect apoptosis but protects from the consequences of mitochondrial dysfunction by triggering a unique pattern of gene expression that modulates stress sensitivity and promotes survival. In vertebrates, mtROS induce apoptosis through the intrinsic pathway to protect from severely damaged cells. Our observations in nematodes demonstrate that sensing of mtROS by the apoptotic pathway can, independently of apoptosis, elicit protective mechanisms that keep the organism alive under stressful conditions. This results in extended longevity when mtROS generation is inappropriately elevated. These findings clarify the relationships between mitochondria, ROS, apoptosis, and aging.

The observed association of the aging process with the biology of reactive oxygen species (ROS), in particular ROS originatingfrom mitochondria (mtROS), has led to the formulation of the oxidative stress theory of aging. Recently, however, more nuanced interpretations have been proposed to explain the basic observations that led to the formulation of the theory (Lapointe and Hekimi, 2010andSena and Chandel, 2012). One possibility is that ROS damage is not causally involved in the aging process but that ROS levels are correlated with the aged phenotype because they modulate signal transduction pathways that respond to cellular stresses brought about by aging (Hekimi etal., 2011). In other words, ROS generation may be enhanced by the aging process because, in their role as signaling molecules, ROS help to alleviate the cellular stresses caused by aging. This hypothesis is supported by findings in a variety of organisms, in particular in C.elegans where changes in ROS generation or detoxification can be uncoupled from any effect on lifespan ( Doonan etal., 2008, Van Raamsdonk and Hekimi, 2009, Van Raamsdonk and Hekimi, 2010andYang etal., 2007). Most strikingly, moderate mitochondrial dysfunction ( Felkai etal., 1999, Feng etal., 2001andYang and Hekimi, 2010b), severe loss of mtROS detoxification ( Van Raamsdonk and Hekimi, 2009), and elevated mtROS generation ( Yang and Hekimi, 2010a), as well as treatments with pro-oxidants ( Heidler etal., 2010, Lee etal., 2010, Van Raamsdonk and Hekimi, 2012andYang and Hekimi, 2010a), can all lengthen rather than shorten lifespan. In addition, the pro-longevity effects of both dietary restriction ( Schulz etal., 2007), and reduced insulin signaling in C.elegans ( Zarse etal., 2012), appear to involve an increase in ROS levels. Such observations are not limited to C.elegans. For example, mtROS signaling can act to extend chronological lifespan of the yeast S.cerevisiae ( Pan etal., 2011).

The longevity phenotype of isp-1(qm150) ( Feng etal., 2001) and nuo-6(qm200) ( Yang and Hekimi, 2010b) mutants is most unequivocally connected to mtROS generation ( Yang and Hekimi, 2010a). isp-1 encodes the Rieske iron sulfur protein, one of the major catalytic subunits of mitochondrial complex III, and nuo-6 encodes the mitochondrial complex I subunit NDUFB4. The qm150 and qm200 mutations are missense mutations that do not lead to a full loss of protein function. Mitochondria isolated from both mutants show elevated superoxide generation, as measured by fluorescence sorting of purified mitochondria incubated with the dye MitoSox ( Yang and Hekimi, 2010a). This is a very specific phenotype that is not accompanied by an increase in overall mitochondrial oxidative stress, nor by a measurable increase in overall oxidative damage. The long-lived phenotype can also be phenocopied by treatment of the wild-type with a very low level (0.1mM) of the superoxide generator paraquat (PQ). In contrast, treatment of the mitochondrial mutants with PQ has no effect, suggesting that treatment with PQ extends lifespan by the same mechanisms as the mitochondrial mutations ( Yang and Hekimi, 2010a).

Increased longevity can also result from induction of the mitochondrial unfolded protein stress response (mtUPR), which can be triggered by RNA interference knockdown of mitochondrial components (Dillin etal., 2002, Durieux etal., 2011andLee etal., 2003). This response is however distinct from the response to elevated mtROS as the lifespan increases produced by the elevated mtROS in the mutants and by the activated mtUPR are fully additive (Yang and Hekimi, 2010b).

How might elevated mtROS promote longevity? ROS are well known to act as modulators in signal transduction pathways, andit is as such that they might be enhancing longevity. One candidate signaling pathway that could include potential mtROS sensors as well as a mechanism of downstream signaling is the intrinsic apoptosis pathway. Apoptosis is a highly controlled process that in mammals is sensitive to mitochondrial function, including mtROS, via the intrinsic apoptosis signaling pathway (Wang and Youle, 2009). In C.elegans the intrinsic apoptotic machinery consists of the BH3-only protein EGL-1, CED-9 (Bcl2-like), CED-4 (Apaf1-like), and CED-3 (Casp9-like). CED-9 is tethered to the outer mitochondrial membrane and binds CED-4. However, in contrast to vertebrates, there is no evidence for any role for mtROS in regulating apoptosis in C.elegans.

The rest is here:
The Intrinsic Apoptosis Pathway Mediates the Pro-Longevity ...

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