Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities

Abstract

The prevalence of cardiovascular disease increases with advancing age. Although long-term exposure to cardiovascular risk factors plays a major role in the etiopathogenesis of cardiovascular disease, intrinsic cardiac aging enhances the susceptibility to developing heart pathologies in late life. The progressive decline of cardiomyocyte mitochondrial function is considered a major mechanism underlying heart senescence. Damaged mitochondria not only produce less ATP but also generate increased amounts of reactive oxygen species and display a greater propensity to trigger apoptosis. Given the postmitotic nature of cardiomyocytes, the efficient removal of dysfunctional mitochondria is critical for the maintenance of cell homeostasis, because damaged organelles cannot be diluted by cell proliferation. The only known mechanism whereby mitochondria are turned over is through macroautophagy. The efficiency of this process declines with advancing age, which may play a critical role in heart senescence and age-related cardiovascular disease. The present review illustrates the putative mechanisms whereby alterations in the autophagic removal of damaged mitochondria intervene in the process of cardiac aging and in the pathogenesis of specific heart diseases that are especially prevalent in late life (eg, left ventricular hypertrophy, ischemic heart disease, heart failure, and diabetic cardiomyopathy). Interventions proposed to counteract cardiac aging through improvements in macroautophagy (eg, calorie restriction and calorie restriction mimetics) are also presented.

Figure 1. Schematic representation of the macroautophagy machinery

Macroautophagy begins with the formation of a double-layered isolation membrane (phagophore) around the molecules and/or organelles to be degraded. The phagophore grows in size and completely engulfs the cargo, forming an autophagosome. The autophagosome subsequently fuses with a lysosome evolving into an autolysosome wherein the cargo is digested.

Figure 2. Schematic overview of the molecular regulation of macroautophagy in the context of mitochondrial homeostasis

In the presence of nutrients and growth factors, the PKB/Akt (protein kinase B) pathway is activated, which blocks the TSC1/TSC2 (tuberous sclerosis complex 1/2), thus relieving its inhibitory effect on RHEB (Ras homolog enriched in brain). The latter, in turn, activates mTORC1 [mammalian target of rapamycin (mTOR) complex 1]. mTORC1 inhibits macroautophagy by blocking the ULK1-Atg13-FIP100 complex through Atg13 hyperphosphorylation. In cases of energy depletion, the cellular AMP:ATP ratio increases and AMPK (AMP-activated protein kinase) becomes activated, which in turn stimulates macroautophagy through multiple mechanisms. For instance, AMPK can phosphorylate and activate TSC1/TSC2, thereby relieving the mTORC1-mediated inhibition of macroautophagy. In addition, AMPK can phosphorylate Ulk1 at specific serine residues leading to the initiation of macroautophagy. AMPK can also inhibit the mTORC1 complex by phosphorylating Raptor (mTORC1 containing rapamycin-associated TOR protein), the binding partner required for mTORC1 activity. Once activated, macroautophagy provides to several tasks, including the clearance of damaged mitochondria. In addition AMPK induces mitochondrial biogenesis by activating PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) either directly or through SIRT1(sirtuin-1). SIRT1 can also deacetylate and activate several autophagy-related proteins, such as Atg5, Atg7 and LC3. The autophagic removal of damaged mitochondria coupled with mitochondrial biogenesis is essential for the maintenance of mitochondrial homeostasis.

Figure 3. Lipofuscinogenesis inside a lysosome

Damaged mitochondria engulfed within an autolysosome generate hydroxyl radicals (^˙OH) via Fenton reactions. Hydrogen peroxide (H₂O₂) participating in these reactions is generated by the action of SOD2 on superoxide anion (O₂^˙−) produced by the electron transport chain. ^˙OH causes crosslinking between intralysosomal proteins, lipids and/or proteins, forming an indigestible polymer, called lipofuscin.