Cellular Senescence, Mitochondrial Dysfunction, and Their Link to Cardiovascular Disease

Abstract

Cardiovascular diseases (CVDs), a group of disorders affecting the heart or blood vessels, are the primary cause of death worldwide, with an immense impact on patient quality of life and disability. According to the World Health Organization, CVD takes an estimated 17.9 million lives each year, where more than four out of five CVD deaths are due to heart attacks and strokes. In the decades to come, an increased prevalence of age-related CVD, such as atherosclerosis, coronary artery stenosis, myocardial infarction (MI), valvular heart disease, and heart failure (HF) will contribute to an even greater health and economic burden as the global average life expectancy increases and consequently the world's population continues to age. Considering this, it is important to focus our research efforts on understanding the fundamental mechanisms underlying CVD. In this review, we focus on cellular senescence and mitochondrial dysfunction, which have long been established to contribute to CVD. We also assess the recent advances in targeting mitochondrial dysfunction including energy starvation and oxidative stress, mitochondria dynamics imbalance, cell apoptosis, mitophagy, and senescence with a focus on therapies that influence both and therefore perhaps represent strategies with the most clinical potential, range, and utility.

Keywords: cardiac cardiomyocyte; cardiac ischemia reperfusion; mitochondrial dysfunction; senescence.

Figure 1

Common characteristics that define mitotic and post-mitotic senescent cells. DNA Damage Response (DDR) and Cyclin Dependant Kinase Inhibitors (Cdkis).

Figure 2

Illustrates mitochondrial reactive oxygen species (mtROS) production within the electron transport chain (ETC). Electrons, initially provided by NADH in complex I and FADH2 in complex II, traverse through ubiquinone to reach complex III. Subsequently, they move to complex IV via cytochrome c, where they combine with molecular oxygen to generate water. Proton-pumping activities by complex I, complex III, and complex IV into the intermembrane space establish a proton gradient crucial for ATP synthesis. During oxidative phosphorylation, electron leakage occurs, leading to the interaction with molecular oxygen and the formation of superoxide (O₂^−·). Complex I and complex III serve as the primary sites for ROS production within the mitochondria, while complex II also contributes. Complex III directs superoxide production both towards the matrix and the intermembrane space, whereas complex I and complex II exclusively produce ROS towards the matrix. Key components and molecules involved include coenzyme Q (CoQ), cytochrome c (Cyt c), electrons (e−), protons (H+), adenosine diphosphate (ADP), adenosine triphosphate (ATP), reduced (NADH) and oxidized (NAD+) nicotinamide adenine dinucleotide, flavin adenine dinucleotide (FAD), oxygen (O₂).

Figure 3

Mitochondrial dysfunction contributes to cardiovascular disease through apoptosis and senescence. Mitochondrial dysfunction and increased ROS production promote DNA damage, both chromosomal and mitochondrial. DNA damage leads to p53 activation and a cell-fate decision between apoptosis and senescence. In apoptotic cells p53 induces mitochondrial outer membrane permeabilization via formation of the apoptotic pore which allows cytochrome c release, activation of the caspase cascade, and cell death. While not yet completely understood, but perhaps as a result as less severe stress, DNA damage and p53 can lead to expression of the p21 (a negative regulator of apoptosis and the cell cycle), activation of the p16 pathway, or activation of both p21 and p16 pathways resulting in cellular senescence. Upregulation of pro-survival pathways in senescent cells suppresses apoptotic pore formation leading to miMOMP, sublethal apoptosis and the release of mtDNA into the cytoplasm. mtDNA fragments are sensed by the cGAS-STING pathway, upregulating expression of inflammatory mediators. Sublethal activation of the caspase cascade may also promote additional DNA damage. A combination of apoptosis and senescence will drive pathological myocardial remodelling.