Mitochondrial Dynamics in Aging Heart

Abstract

Aging is a major risk factor for cardiovascular disease, driving progressive structural and functional decline of the myocardium. Mitochondria, the primary source of ATP through oxidative phosphorylation, are essential for cardiac contractility, calcium homeostasis, and redox balance. In the aging heart, mitochondria show morphological alterations including cristae disorganization, swelling, and fragmentation, along with reduced OXPHOS efficiency. These defects increase proton leak, lower ATP production, and elevate reactive oxygen species (ROS), causing oxidative damage. Concurrent disruptions in mitochondrial fusion and fission further impair turnover and quality control, exacerbating mitochondrial dysfunction and cardiac decline. Serum response factor (SRF) signaling, a crucial regulator of cytoskeletal and metabolic gene expression, plays a key role in modulating mitochondrial function during cardiac aging. Dysregulation of SRF impairs mitochondrial adaptability, contributing to dysfunction. Additionally, reduced levels of nicotinamide adenine dinucleotide (NAD⁺) hinder sirtuin-dependent deacetylation, further compromising mitochondrial efficiency and stress resilience. These cumulative defects activate regulated cell death pathways, leading to cardiomyocyte loss, fibrosis, and impaired diastolic function. Mitochondrial dysfunction therefore serves as both a driver and amplifier of cardiac aging, accelerating the transition toward heart failure. This narrative review aims to provide a comprehensive overview of mitochondrial remodeling in the aging myocardium, examining the mechanistic links between mitochondrial dysfunction and myocardial injury. We also discuss emerging therapeutic strategies targeting mitochondrial bioenergetics and quality control as promising approaches to preserve cardiac function and extend cardiovascular health span in the aging population.

Keywords: apoptosis; cardiac aging; interventions; mitochondria; mtDNA; sirtuins.

Figure 1

Mitochondrial fusion and fission in cardiac aging. This schematic illustrates how alterations in mitochondrial fusion and fission contribute to cardiac aging. On the left, decreased mitochondrial fusion, mediated by downregulation of Opa1, Mfn1, and Mfn2, disrupts cardiolipin integrity, leading to decreased ATP production and impaired cardiac energy supply. On the right, altered mitochondrial fission, characterized by upregulation of Drp1, Fis1, and Drp1 translocation, increases reactive oxygen species (ROS) generation, contributing to oxidative stress. These changes collectively result in mitochondrial dysfunction, which underlies cardiac dysfunction, manifested as enlarged left ventricle and weakened heart muscle.

Figure 2

Transcriptional regulation of cellular stress responses: Role of SRF, PGC-1α, and related pathways. Transcription factors such as SRF and P49 regulate gene expression in response to cellular stress and mutations. Their interaction with PGC-1α/β coordinates the activity of key regulators including Parkin, Pink1, and mTOR, which control mitochondrial function and stress responses. PERK signaling and changes in calcium (Ca²⁺) levels contribute to ER stress, while AMPK, p38MAPK, and p53 pathways are involved in metabolic regulation and inflammation. Mutations in mitochondrial DNA, accumulation of reactive oxygen species (ROS), and disruptions in the TCA cycle can impair normal cellular functions.

Figure 3

Mitochondrial dysfunction-driven cell death pathways in cardiac aging. This schematic illustrates the interconnected mitochondrial cell death pathways contributing to cardiac aging. Mitochondrial dysfunction and increased ROS generation initiate a cascade of events including reduced mitochondrial membrane potential (↓MMP), impaired mitophagy, mitochondrial permeability transition pore (mPTP) opening, and altered ion homeostasis. These stressors activate multiple regulated cell death pathways: apoptosis (via BCL-2 family proteins and cytochrome c release), necroptosis (via RIPK1/RIPK3/MLKL signaling), pyroptosis (via inflammasome activation and GSDMD cleavage), ferroptosis (via GPX4 inactivation and lipid peroxidation), disulfidptosis (via oxidative protein cross-linking), and cuproptosis (via copper-induced proteotoxicity). These mechanisms collectively lead to increased cell death and declining cardiac function during aging.

Figure 4

Schematic depicting the roles of Mitochondrial sirtuins (SIRT3, SIRT4, SIRT5) in regulating mitochondrial metabolism, oxidative stress, and aging-related cardiac function. SDHA: Succinate dehydrogenase; OSCP: Oligomycin-Sensitivity Conferring Protein; OTC: Ornithine Transcarbamylase; AceCS: Acetyl-CoA Synthetase; ETC: Electron Transport Chain; GDH: Glutamate Dehydrogenase; PARP1: poly (ADP-ribose) polymerase-1; LCAD: Long-chain Acyl coenzyme A dehydrogenase.

Figure 5

Schematic representation of BCAA metabolism and mitochondrial function in young versus old hearts. In young hearts, efficient BCAA catabolism via BCKDH fuels the TCA cycle, boosting ATP production, mitochondrial integrity, and cardiac function, supported by glutamine, PGC-1α, and SIRT1. However, in old hearts, reduced BCKDH activity impairs BCAA catabolism, causing BCKA accumulation, TCA cycle disruption, ROS production, and mitochondrial damage, with decreased PGC-1α and SIRT1.

Figure 6

Therapeutic strategies targeting mitochondrial dysfunction in cardiac aging. Cardiac aging is associated with mitochondrial dysfunction, which can be addressed through multiple approaches: promoting mitochondrial biogenesis (via PGC-1, AMPK/SIRT1 pathways, resveratrol), enhancing mitophagy (urolithin A, spermidine, VL-004), mitochondrial transplantation (mtZFN, mitoTALENs), mitochondria-targeted antioxidants (MitoQ, Mito TEMPO), and novel or adjunctive therapies such as mitochondrial gene editing.