As shown in , the aging heart is more sensitive to IR injury (Lesnefsky et al., 2006
; Lesnefsky et al., 2001b
). In addition, a significant decline in cardiac mitochondrial function is seen in aging, and this appears to differ between IFM and SSM (Judge et al., 2005
; Fannin et al., 1999
). This section will focus on two mitochondrial commonalties between aging and IR injury: (i) mitochondrial Ca2+
handling and (ii) mitochondrial ROS generation/oxidative damage.
insult associated with pathology of cardiac IR injury results in mitochondrial Ca2+
overload and ultimately cell death (Lemasters et al., 2009
; Murphy et al., 2008
; Brookes et al., 2004
). In this regard, it is notable that mitochondria from the aged heart display a decreased capacity to accumulate and retain Ca2+
, resulting in a decreased tolerance to Ca2+
insult (Jahangir et al., 2001
). This inability to handle a pathological Ca2+
insult may predispose the aged myocardium to IR injury.
The molecular mechanisms underlying defects in Ca2+
and ROS homeostasis find their roots at the level of the respiratory chain. Both aging and IR injury result in damage to the Ox-Phos machinery (Kwong et al., 2000
; Fannin et al., 1999
; Lenaz et al., 1997
; Guerrieri et al., 1993
), raising the possibility that an already age-diminished Ox-Phos may be susceptible to further decline with IR.
Alterations in complex III activity have been reported in both IR injury (Lesnefsky et al., 2001a
) and aging (Lesnefsky et al., 2001b
), although the molecular mechanisms may be distinct; complex III’s cytochrome c
binding site is the target of functional decline in aging, while ischemic damage is primarily at the iron-sulfur center within the complex (Lesnefsky et al., 2001a
). Notably, both of these mechanisms manifest in increased ROS production. While this review focuses on changes in ROS production at the level of the Ox-Phos machinery, other mitochondrial ROS modulating components such as monoamine oxidase and p66Shc
are also associated with aging. The inhibition of monoamine oxidase and p66Shc
result in protection from IR injury (Carpi et al., 2009
), their expression levels increase with age (Pandolfi et al., 2005
; Saura et al., 1994
), and genetic deletion of p66Shc
increases life span (Migliaccio et al., 1999
In addition to changes in ROS generation by the respiratory chain, a state of oxidative stress can also be precipitated by a decrease in antioxidant defenses. In this regard, IR injury is known to decrease the activity of enzymes involved in ROS removal, such as manganese superoxide dismutase and glutathione peroxidase (Shlafer et al., 1987
). Antioxidant defenses are similarly compromised with aging (Ferrara et al., 2008
; van der Loo et al., 2005
; Moghaddas et al., 2003
The increased mitochondrial ROS generation associated with aging and IR injury can have a profound impact on the formation mitochondrial permeability transition (PT) pore. The induction of the mitochondrial PT pore is associated with irreversible damage and the initiation of cell death (Lemasters et al., 2009
). The increased ROS and altered calcium handling conditions set forth in the aged myocardium may be interrelated and ultimately sensitize the heart to the induction of mitochondrial PT pore opening.
It is not clear whether differences in mitochondrial ROS generation are an underlying factor in the differential responses to IR injury that occur between animals of varying aging rates. It is known that mitochondria from short-lived animals generate more ROS (Lambert et al., 2007
). Interestingly, these animals also develop myocardial infarction more quickly (Downey et al., 2009
; Manintveld et al., 2007
; Gersh et al., 2005
; Barja et al., 2000
). While this connection between the rate of aging and infarct development is appealing, other hemodynamic parameters (e.g. collateral flow) should be taken into consideration when comparing different species. In addition, there have been a number of recent observations that ROS can be beneficial as well as detrimental and that ROS signaling may be important for adaptive responses to ischemia (see below). Hence, the role of ROS depends upon the context in which it is presented, including that of aging.
Collectively, a dysregulation of mitochondrial Ox-Phos, Ca2+ handling and ROS generation occurs in both IR injury and aging, and it is logical to suggest that the molecular mechanisms underlying these phenomena may be shared.