Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Abstract

Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating CVD in the older population combined with indirect costs, secondary to lost wages, are predicted to reach $1.1 trillion by 2035. Therefore, there is an eminent need to discover novel therapeutic targets and identify new interventions to delay, lessen the severity, or prevent cardiovascular complications associated with advanced age. Protein and organelle quality control pathways including autophagy/lysosomal and the ubiquitin-proteasome systems, are emerging contributors of age-associated myocardial dysfunction. In general, two findings have sparked this interest. First, strong evidence indicates that cardiac protein degradation pathways are altered in the heart with aging. Second, it is well accepted that damaged and misfolded protein aggregates and dysfunctional mitochondria accumulate in the heart with age. In this review, we will: (i) define the different protein and mitochondria quality control mechanisms in the heart; (ii) provide evidence that each quality control pathway becomes dysfunctional during cardiac aging; and (iii) discuss current advances in targeting these pathways to maintain cardiac function with age.

Keywords: aging; chaperone-mediated autophagy; heart; macroautophagy; mitophagy; protein quality control; ubiquitin proteasome system.

Figure 1

Schematic illustration of different types of protein degradation pathways. Left: Ubiquitin Proteasome System (UPS) employs three different enzymes, E1, E2 and E3 to target and tag proteins with four or more ubiquitin molecules. The 26S proteasome is a large protein complex that is comprised of approximately 33 different subunits which form the 20S proteolytic core particle capped by the 19S regulatory lid particle. The 20S core has six catalytic sites that cleave protein substrates. The ubiquitinated proteins are recognized and degraded by the 20S core particle into smaller peptides and the free ubiquitin is available for recycling. Middle: Macroautophagy and mitophagy require the formation of double-membrane vesicles called autophagosomes to engulf proteins and damaged mitochondria, for eventual fusion with, and degradation by, the lysosome. Right: Chaperone Mediated Autophagy (CMA) functions independently of autophagosomes and employs a co-chaperone complex, Hsc70, and the lysosomal receptor, LAMP2A, for the recognition and degradation of proteins bearing a unique KFERQ-like motif.

Figure 2

Decline in protein quality control in the aging heart. The heart exhibits a progressive decline in the intracellular protein quality control (PQC) pathways during the aging process. Macroautophagy, mitophagy and chaperone mediated autophagy (CMA) are lysosomal-dependent protein degradation pathways. Strong evidence exists that macroautophagy and mitophagy are decreased in old hearts. At present it is unclear how aging regulates CMA function in the heart. Enzymatic activities of the proteasome are severely reduced in the aging heart. As a consequence of impaired protein quality control, the aging heart accumulates misfolded protein aggregates (proteotoxicity), cell death proteins, and dysfunctional mitochondria. This cardio/proteo-toxic profile is associated with heightened fibrosis, collagen deposition, and cardiac hypertrophy.

Figure 3

Interventions to upregulate protein quality systems in the aging heart. Nutraceutical (e.g., spermidine), pharmacological (e.g., rapamycin, SIRT1 activators), and dietary and lifestyle (e.g., exercise training, intermittent fasting) approaches have been used to boost protein quality control systems in the heart, in an effort to lessen the severity, delay the onset, or prevent age-associated proteotoxicity and cardiovascular dysfunction. Evidence for the degree of efficacy afforded by each procedure is described in the text. Upregulating the protein quality control mechanisms can prove to be beneficial against various age-related cardiac pathologies. mTOR: mammalian target of rapamycin; PMI: p62-mediated mitophagy inducer; SIRT1: silent mating type information regulation 2 homolog; RARα: retinoic acid receptor alpha; PD169316: p38 MAPK inhibitor; CRMs: caloric restriction mimetics.