Altered FoF1 ATP synthase and susceptibility to mitochondrial permeability transition pore during ischaemia and reperfusion in aging cardiomyocytes

Abstract

Aging is a major determinant of the incidence and severity of ischaemic heart disease. Preclinical information suggests the existence of intrinsic cellular alterations that contribute to ischaemic susceptibility in senescent myocardium, by mechanisms not well established. We investigated the role of altered mitochondrial function in the adverse effect of aging. Isolated perfused hearts from old mice (> 20 months) displayed increased ischaemia-reperfusion injury as compared to hearts from adult mice (6 months) despite delayed onset of ischaemic rigor contracture. In cardiomyocytes from aging hearts there was a more rapid decline of mitochondrial membrane potential (Δψm) as compared to young ones, but ischaemic rigor shortening was also delayed. Transient recovery of Δψm observed during ischaemia, secondary to the reversal of mitochondrial FoF1 ATP synthase to ATPase mode, was markedly reduced in aging cardiomyocytes. Proteomic analysis demonstrated increased oxidation of different subunits of ATP synthase. Altered bionergetics in aging cells was associated with reduced mitochondrial calcium uptake and more severe cytosolic calcium overload during ischaemia-reperfusion. Despite attenuated ROS burst and mitochondrial calcium overload, mitochondrial permeability transition pore (mPTP) opening and cell death was increased in reperfused aged cells. In vitro studies demonstrated a significantly reduced calcium retention capacity in interfibrillar mitochondria from aging hearts. Our results identify altered FoF1 ATP synthase and increased sensitivity of mitochondria to undergo mPTP opening as important determinants of the reduced tolerance to ischaemia-reperfusion in aging hearts. Because ATP synthase has been proposed to conform mPTP, it is tempting to hypothesise that oxidation of ATP synthase underlie both phenomena.

Mitochondria and aging: A role for the mitochondrial transition pore?

“…An increased sensitivity to calcium overload was observed in mitochondria isolated from senescent rat heart (Fernandez‐Sanz et al., 2015; Jahangir, Ozcan, Holmuhamedov, & Terzic, 2001; Ljubicic, Menzies, & Hood, 2010; Petrosillo, Moro, Paradies, Ruggiero, & Paradies, 2010). This effect was confirmed in permeabilized cardiomyocytes (Picard, Wright, Ritchie, Thomas, & Hepple, 2012) but may be restricted to interfibrillar mitochondria (Fernandez‐Sanz et al., 2015; Hofer et al., 2009).…”

“…This effect was confirmed in permeabilized cardiomyocytes (Picard, Wright, Ritchie, Thomas, & Hepple, 2012) but may be restricted to interfibrillar mitochondria (Fernandez‐Sanz et al., 2015; Hofer et al., 2009). An enhanced susceptibility to mPTP opening was also found in brain (Krestinina et al., 2015; Marques‐Aleixo et al., 2012; Mather & Rottenberg, 2000) and appeared to depend on the brain area tested (Brown, Geddes, & Sullivan, 2004; LaFrance, Brustovetsky, Sherburne, Delong, & Dubinsky, 2005), in the liver (Goodell & Cortopassi, 1998; Mather & Rottenberg, 2000), and in lymphocytes (Rottenberg & Wu, 1997).…”

“…Aging could decrease the maximal ATP synthase activity and impact the available ATP concentration in vivo but can also contribute to mPTP activation. An increased number of oxidized cysteine residues and a nitration of specific tyrosines was found in the ATP synthase of aged mouse hearts (Fernandez‐Sanz et al., 2015) and in the liver of aging rats (Haynes, Traaseth, Elfering, Fujisawa, & Giulivi, 2010), respectively.…”

“…mPTP is thought to be a key factor in these processes, and the mechanism responsible for this loss of effectiveness may result from an activation of mPTP. Indeed, mPTP opening and cell death are increased in reperfused aged cardiomyocytes (Fernandez‐Sanz et al., 2015). This may be the consequence of the oxidative stress due to the increase in ROS production coupled with a decline in antioxidant defenses (Ferrara et al., 2008; Judge, Jang, Smith, & Hagen, 2005; Meng, Wong, Chen, & Ruan, 2007) prevailing in the aging heart.…”

Antioxidant and antitumor activities of Capparis spinosa L. and the related mechanisms

“…The formation of ROS which could harm membrane lipids, reduces the fluidity of membrane and increases the cell membrane permeability, causing Δψm decrease (48)(49)(50). This could cause oxidative damage to proteins, resulting in protein denaturation and crosslink, and a change in enzyme activity (51).…”