Targeting ER stress and calpain activation to reverse age-dependent mitochondrial damage in the heart

https://doi.org/10.1016/j.mad.2020.111380Get rights and content

Highlights

  • Aging leads to increased ER stress that contributes to mitochondrial dysfunction.

  • ER stress-mediated calpain activation impairs the mitochondrial respiratory chain.

  • The damaged respiratory chain leads to increased injury in aged hearts during ischemia-reperfusion.

  • Intervention to restore mitochondrial function in aged hearts decreases cardiac injury during ischemia-reperfusion.

Abstract

Severity of cardiovascular disease increases markedly in elderly patients. In addition, many therapeutic strategies that decrease cardiac injury in adult patients are invalid in elderly patients. Thus, it is a challenge to protect the aged heart in the context of underlying chronic or acute cardiac diseases including ischemia-reperfusion injury. The cause(s) of this age-related increased damage remain unknown. Aging impairs the function of the mitochondrial electron transport chain (ETC), leading to decreased energy production and increased oxidative stress due to generation of reactive oxygen species (ROS). Additionally, ROS-induced oxidative stress can increase cardiac injury during ischemia-reperfusion by potentiating mitochondrial permeability transition pore (MPTP) opening. Aging leads to increased endoplasmic reticulum (ER) stress, which contributes to mitochondrial dysfunction, including reduced function of the ETC. The activation of both cytosolic and mitochondrial calcium-activated proteases termed calpains leads to mitochondrial dysfunction and decreased ETC function. Intriguingly, mitochondrial ROS generation also induces ER stress, highlighting the dynamic interaction between mitochondria and ER. Here, we discuss the role of ER stress in sensitizing and potentiating mitochondrial dysfunction in response to ischemia-reperfusion, and the promising potential therapeutic benefit of inhibition of ER stress and / or calpains to attenuate cardiac injury in elderly patients.

Introduction

Cardiac mitochondria are the primary source to meet the energy demand for a constantly beating heart (Lesnefsky et al., 2016). There are two distinct populations of cardiac mitochondria: subsarcolemmal mitochondria (SSM), which reside under the sarcolemma, and interfibrillar mitochondria (IFM), present between myofibrils (Palmer et al., 1985). Although SSM are more sensitive to ischemia-mediated mitochondrial damage (Lesnefsky et al., 1997), IFM are the population mainly affected in aged hearts (Fannin et al., 1999). Aging-induced mitochondrial defects lead to decreased ATP production and increased ROS generation that potentiate cardiac injury during ischemia-reperfusion (Lesnefsky et al., 2001a). Moreover, most cardiac protective strategies are relatively ineffective in aged hearts (Peart et al., 2014). This review focuses on the potential of novel approaches targeting ER stress and calpain activation to decrease age-related exacerbation of cardiac injury following ischemia-reperfusion.

Section snippets

ETC damage in aged hearts

A detailed description of aging-induced mitochondrial defects can be found in several excellent reviews (Lesnefsky et al., 2016, 2017; Lesnefsky et al., 2001c). In brief, the rate of oxidative phosphorylation is decreased in IFM isolated from 24 month old Fisher 344 rat hearts. In contrast, oxidative phosphorylation is not markedly altered in SSM from aged rat hearts (Fannin et al., 1999). Direct measurement of enzyme activities shows that aging leads to decreased activities of electron

Role of oxidative stress in mitochondrial damage during aging

Oxidative stress plays a key role in aging-induced mitochondrial dysfunction (Moghaddas et al., 2003). Over expression of mitochondria-targeted catalase protects aged hearts, supporting the idea that mitochondrial ROS generation contributes to the mitochondrial dysfunction observed in aged hearts (Bhuiyan and Fukunaga, 2009). The ETC is a key source of ROS generation in cardiac mitochondria (Chen et al., 2003). Decreased complex III activity contributes to increased ROS generation in aged IFM

Impairment of endogenous signal transduction in aged hearts

Aged hearts are more susceptible to cardiac injury during ischemia-reperfusion (D’ Annunzio et al., 2016; Lesnefsky et al., 1994, 1996). Classical cardio-protective approaches including ischemic pre/post-conditioning are not effective in aged hearts (D’ Annunzio et al., 2016; Wojtovich et al., 2012). Ischemic preconditioning (IPC) activates a number of protective signaling cascades that eventually converge at the mitochondria. The potential mechanisms underlying the loss of IPC protection in

Summary

The presence of dysfunctional mitochondria in aged hearts increases cardiac injury during ischemia-reperfusion. Targeting mitochondrial function in aged hearts by acute intervention at the onset of reperfusion can decrease cardiac injury during ischemia-reperfusion. Obviously, a better approach is to restore mitochondrial function in aged hearts before injury. This approach not only eliminates mitochondrial dysfunction-induced cell injury, but also may enable traditional therapeutic approaches

Declaration of Competing Interest

The authors state they have no conflict of interest or financial interests to disclose.

Acknowledgements

The critical review of this manuscript by Dr. Edward Lesnefsky (Pauley Heart Center, Virginia Commonwealth University and Medical Service, McGuire Veterans Affairs Medical Center) is greatly appreciated. This work was supported by R21 AG049461 (Q.C.) from the National Institute on Aging, the Department of Veterans Affairs Office of Research and Development, Medical Research Service Merit Review Award (2IO1BX001355-01A2) (QC, EJL), and a Pauley Heart Center Pilot Project from Virginia

References (126)

  • M. Chen et al.

    Calpain and mitochondria in ischemia/reperfusion injury

    J. Biol. Chem.

    (2002)
  • Q. Chen et al.

    Production of reactive oxygen species by mitochondria: central role of complex III

    J. Biol. Chem.

    (2003)
  • Q. Chen et al.

    Isolating the segment of the mitochondrial electron transport chain responsible for mitochondrial damage during cardiac ischemia

    Biochem. Biophys. Res. Commun.

    (2010)
  • Q. Chen et al.

    Activation of mitochondrial mu-calpain increases AIF cleavage in cardiac mitochondria during ischemia-reperfusion

    Biochem. Biophys. Res. Commun.

    (2011)
  • Q. Chen et al.

    Metformin attenuates ER stress-induced mitochondrial dysfunction

    Transl. Res.

    (2017)
  • Q. Chen et al.

    Cardiac specific knockout of p53 decreases ER stress-induced mitochondrial damage

    Front. Cardiovasc. Med.

    (2019)
  • Q. Chen et al.

    Endoplasmic reticulum stress-mediated mitochondrial dysfunction in aged hearts

    Biochim Biophys Acta Mol Basis Dis.

    (2020)
  • K.B. Choksi et al.

    Age-related increases in oxidatively damaged proteins of mouse kidney mitochondrial electron transport chain complexes

    Free Radic. Biol. Med.

    (2007)
  • V. D’Annunzio et al.

    Role of thioredoxin-1 in ischemic preconditioning, postconditioning and aged ischemic hearts

    Pharmacol. Res.

    (2016)
  • S.W. Fannin et al.

    Aging selectively decreases oxidative capacity in rat heart interfibrillar mitochondria

    Arch. Biochem. Biophys.

    (1999)
  • M.L. Genova et al.

    Functional role of mitochondrial respiratory supercomplexes

    Biochim. Biophys. Acta

    (2014)
  • M. Giorgio et al.

    Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis

    Cell.

    (2005)
  • L.A. Gomez et al.

    Supercomplexes of the mitochondrial electron transport chain decline in the aging rat heart

    Arch. Biochem. Biophys.

    (2009)
  • A.B. Gustafsson et al.

    Recycle or die: the role of autophagy in cardioprotection

    J. Mol. Cell. Cardiol.

    (2008)
  • D. Han et al.

    Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol

    J. Biol. Chem.

    (2003)
  • A. Jahangir et al.

    Increased calcium vulnerability of senescent cardiac mitochondria: protective role for a mitochondrial potassium channel opener

    Mech. Ageing Dev.

    (2001)
  • J.S. Kim et al.

    Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers

    Toxicol. Appl. Pharmacol.

    (2013)
  • L.K. Kwong et al.

    Substrate and site specificity of hydrogen peroxide generation in mouse mitochondria

    Arch. Biochem. Biophys.

    (1998)
  • E.J. Lesnefsky et al.

    Increased left ventricular dysfunction in elderly patients despite successful thrombolysis: the GUSTO-I angiographic experience

    J. Am. Coll. Cardiol.

    (1996)
  • E.J. Lesnefsky et al.

    Ischemic injury to mitochondrial electron transport in the aging heart: damage to the iron-sulfur protein subunit of electron transport complex III

    Arch. Biochem. Biophys.

    (2001)
  • E.J. Lesnefsky et al.

    Aging decreases electron transport complex III activity in heart interfibrillar mitochondria by alteration of the cytochrome c binding site

    J. Mol. Cell. Cardiol.

    (2001)
  • E.J. Lesnefsky et al.

    Mitochondrial dysfunction in cardiac disease: ischemia-reperfusion, aging, and heart failure

    J. Mol. Cell. Cardiol.

    (2001)
  • S. Moghaddas et al.

    Aging defect at the Qo site of complex III augments oxyradical production in rat heart interfibrillar mitochondria

    Arch. Biochem. Biophys.

    (2003)
  • A.A. Mohsin et al.

    Endoplasmic reticulum stress-induced complex I defect: central role of calcium overload

    Arch. Biochem. Biophys.

    (2020)
  • S.B. Ong et al.

    Calpain inhibition restores autophagy and prevents mitochondrial fragmentation in a human iPSC model of diabetic endotheliopathy

    Stem Cell Reports

    (2019)
  • J.W. Palmer et al.

    Biochemical differences between subsarcolemmal and interfibrillar mitochondria from rat cardiac muscle: effects of procedural manipulations

    Arch. Biochem. Biophys.

    (1985)
  • J. Pang et al.

    SIRT1 protects cochlear hair cell and delays age-related hearing loss via autophagy

    Neurobiol. Aging

    (2019)
  • J.N. Peart et al.

    Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium

    Exp. Gerontol.

    (2014)
  • A. Picca et al.

    Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions: useful insights from aging and calorie restriction studies

    Mitochondrion.

    (2015)
  • N. Quan et al.

    Sestrin2 prevents age-related intolerance to post myocardial infarction via AMPK/PGC-1alpha pathway

    J. Mol. Cell. Cardiol.

    (2018)
  • P. Abete et al.

    Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats

    Am. J. Physiol. Heart Circ. Physiol.

    (2002)
  • T. Adam et al.

    Loss of cardioprotection with ischemic preconditioning in aging hearts: role of sirtuin 1?

    J. Cardiovasc. Pharmacol. Ther.

    (2013)
  • M. Aldakkak et al.

    Inhibited mitochondrial respiration by amobarbital during cardiac ischaemia improves redox state and reduces matrix Ca2+ overload and ROS release

    Cardiovasc. Res.

    (2008)
  • G. Ambrosio et al.

    Effects of the superoxide radical scavenger superoxide dismutase, and of the hydroxyl radical scavenger mannitol, on reperfusion injury in isolated rabbit hearts

    Cardiovasc. Drugs Ther.

    (1992)
  • E. Balsa et al.

    ER and nutrient stress promote assembly of respiratory chain supercomplexes through the PERK-eIF2α Axis

    Mol. Cell

    (2019)
  • G. Barja

    Mitochondrial free radical production and aging in mammals and birds

    Ann. N. Y. Acad. Sci.

    (1998)
  • I. Belaya et al.

    Long-term exercise protects against cellular stresses in aged mice

    Oxid. Med. Cell. Longev.

    (2018)
  • M.S. Bhuiyan et al.

    Stimulation of sigma-1 receptor signaling by dehydroepiandrosterone ameliorates pressure overload-induced hypertrophy and dysfunctions in ovariectomized rats

    Expert Opin. Ther. Targets

    (2009)
  • T. Cao et al.

    Increased calpain-1 in mitochondria induces dilated heart failure in mice: role of mitochondrial superoxide anion

    Basic Res. Cardiol.

    (2019)
  • Q. Chen et al.

    Ischemic damage to the mitochondrial electron transport chain favors opening of the permeability transition pore

    FASEB J.

    (2008)
  • Cited by (0)

    View full text