Mitochondrial Dysfunction: A Roadmap for Understanding and Tackling Cardiovascular Aging

Abstract

Cardiovascular aging is a progressive remodeling process constituting a variety of cellular and molecular alterations that are closely linked to mitochondrial dysfunction. Therefore, gaining a deeper understanding of the changes in mitochondrial function during cardiovascular aging is crucial for preventing cardiovascular diseases. Cardiac aging is accompanied by fibrosis, cardiomyocyte hypertrophy, metabolic changes, and infiltration of immune cells, collectively contributing to the overall remodeling of the heart. Similarly, during vascular aging, there is a profound remodeling of blood vessel structure. These remodeling present damage to endothelial cells, increased vascular stiffness, impaired formation of new blood vessels (angiogenesis), the development of arteriosclerosis, and chronic vascular inflammation. This review underscores the role of mitochondrial dysfunction in cardiac aging, exploring its impact on fibrosis and myocardial alterations, metabolic remodeling, immune response remodeling, as well as in vascular aging in the heart. Additionally, we emphasize the significance of mitochondria-targeted therapies in preventing cardiovascular diseases in the elderly.

Figure 1.

The hallmarkers of cardiac aging. Cardiac aging includes seven hallmarks: genomic instability, telomere shortening, chronic inflammation, epigenetic alterations such as protein acetylation, DNA methylation and histone modification, disrupted protein homeostasis, impaired metabolic flexibility, macroautophagy dysfunction, and mitochondrial dysfunction. SASP, senescence-associated secretory phenotype; mTOR, mechanistic target of rapamycin.

Figure 2.

Mitochondrial activity in the heart. Mitochondrial activity in the heart encompasses mitochondrial dynamics, mitophagy, and the production of mitochondrial reactive oxygen species. Mitochondrial dynamics involve both fusion and fission processes, with Drp1 and the Drp1-anchored proteins Fis1, Mff, MiD49, and MiD51 participating in fission, while Mfn1/2 and Opa1 are involved in fusion. In response to ROS or other stimuli, mitochondria experience a collapse of the membrane potential (Δψm), activating the PINK1-Parkin pathway. Mitophagy is initiated through mitochondrial ubiquitination and LC3 receptor-induced entry of WIPI1, DFCP1, and Ulk1 into the mitochondria, a process inhibited by mTORC1. FUNDC1 is involved in mitochondrial fission, fusion, and the receptor-mediated pathway of mitophagy. Increased ROS can induce mitochondrial damage, triggering apoptosis through release of mitochondrial cytochrome c. Injured mitochondria may also contribute to increased ROS production, establishing a vicious cycle that results in more damaged mitochondria. Drp1, dynamin-related protein 1; Fis1, mitochondrial fission 1; Mff, mitochondrial fission factor; MiD49/51, mitochondrial dynamics protein of 49 and 51 kDa; Mfn1/2, mitofusin 1/2; OPA, opacity-associated protein; PINK, PTEN-induced kinase 1; LC3, light chain 3; WIPI1, WD repeat domain, phosphoinositide interacting 1; DFCP1, double FYVE-containing protein 1; Ulk1, unc51-like autophagy activating kinase 1; mTORC1, mechanistic target of rapamycin complex 1; AMPK, AMP-activated protein kinase; Cyt c, Cytochrome c; Nrf2, nuclear factor erythroid related factor 2; COX, cyclooxygenases; FUNDC1, FUN14 domain containing 1; TBK, Tank-binding kinase.

Figure 3.

Fatty acid metabolism in cardiomyocytes. LCFAs bound to albumin in the circulation undergo dissociation by FABP on the cellular membrane. The resultant free LCFAs are then transported into the cytosol by FATP and FAT/CD36. Within the cytosol, LCFAs are converted into Acyl-CoAs, which can enter the mitochondrial matrix via the carnitine shuttle system to participate in β-oxidation. This process generates NADH and FADH₂ for OXPHOS, as well as Acetyl-CoAs for various biochemical processes. On the other hand, after passing into the cytoplasm, FA such as SCFA and MCFA are stored in the dynamic organelle LD, and when Hsp70 on the LD binds to the mitochondrial Mfn2 to form MLC, the FA is transferred to the mitochondria for metabolism, where they are converted into Acyl-CoAs by SACSs and MACSs. When activated by free fatty acids, PPARs, especially PPARα/δ can promote the expression of multiple proteins involved in lipid catabolism. Under the influence of many factors, activated mTOR pathway inhibits PPARα/δ while activating PPARγ and SREBP pathways, promoting lipogenesis. SIRT1 plays a pivotal role in this system by activating PGC-1α to enhance mitochondrial biogenesis. Simultaneously, SIRT1 can translocate to the inner mitochondrial membrane to produce NAMs from NAD+, as well as recruiting SIRT3, which promotes β-oxidation. LCFA(SCFA/MCFA), long chain(short chain/medium chain) fatty acid; FABP, fatty acid binding protein; FAT, fatty acid translocase; FATP, fatty acid transport protein; LACS(SACS/MACS), long chain(short chain/medium chain) acyl-CoA synthetase; CPT1/2, carnitine palmityl transferase 1/2; CACT, carnitine-acylcarnitine translocase; TCA, tricarboxylic acid cycle; CLS, cardiolipin synthase; NAM, nicotinamide; PPAR, peroxisome proliferators-activated receptor; Sirt1/Sirt3, silent information regulator 1/3; mTOR, mechanistic target of rapamycin; SREBP, sterol-regulatory element binding protein; PGC-1α, peroxisome proliIerators-activated receptor γ coactivator 1α; PPAR, peroxisome proliferator-activated receptor; PG, phosphatidylglycerol; LD, lipid droplets; MLC, mitochondria-LD membrane contact; Hsc70, heat shock cognate protein 70.

Figure 4.

Glucose, amino acid and ketone metabolism in cardiomyocytes. Glucose transport into the cytosol is facilitated by GLUT1 and GLUT4. Within the cytosol, glucose undergoes conversion to G6P by HK and subsequently pyruvate through a series of reactions. Pyruvate can either produce energy and lactate via glycolysis or enter the mitochondria through MPC. PDH in the mitochondrial matrix converts pyruvate into Acetyl-CoA, which can participate in the TCA cycle. AAT transports circulating amino acids into cytosol, where they are converted into α-ketoacids, serving as building blocks for amino acid, lipid, and glucose synthesis. Glutamate and pyruvate interact to form α-KG, which also participates in the TCA cycle. BHB enters the cytosol through MCT1/2 and can permeate into the mitochondria to replenish Acetyl-CoA. Insulin and IGF promote the translocation of GLUT4 from the cytosol to the membrane, either directly or by activating Akt. The insulin receptor also upregulates PDH through Akt to promote glucose oxidation. PPAR influences the activity and expression of proteins in glucose transport and glycolysis. BHB activates PGC-1α in the nucleus, initiating a cascade of events leading to mitochondrial biogenesis. Calcium ions regulate metabolism by entering the mitochondria through mtCU. The uptake capacity of mitochondrial calcium ions can be regulated by MICU1/2 through the adjustment of calcium ion thresholds. ATP generated by oxidative phosphorylation combines with Cr to form PCr under the activation of CK and enters the cytoplasm to be utilized as a functional substance. GLUT1/GLUT4, glucose transported type 1/4; HK, hexokinase; G6P, Glucose-6-Phosphate; MPC, mitochondrial pyruvate carrier; LDH, Lactate dehydrogenase; PDH, pyruvate dehydrogenase; mtCU, mitochondrial calcium uniporter; AAT, amino acid transporter; BHB, β-Hydroxybutyrate; MCT1/2, Monocarboxylate transporters 1/2; IGF, Insulin-like growth factor; IR, insulin receptor; Akt, Protein Kinase B; HIF1, hypoxia-inducible factor 1; Akt, protein kinase B; MICU1/2, mitochondrial calcium uptake 1/2; CK, creatine kinase; Cr, creatine; PCr, creatine phosphate.

Figure 5.

mitochondrial dysfunction in cardiac immune remodeling. Chronic stimulation and TNF-β induces the production of cellular mtROS, triggering cellular conversion into DAMPs. This process involves the expression of HMGB1, HSP, dsRNA, and the secretion of mtDNA, initiating a chronic inflammatory response through the activation of the TLR-NFκB pathway and NLRP3. mtDNA induces SASP through the cGAS-STING-IFR3 pathway and produces IFN 1, which recruits neutrophils and causes an inflammatory response, in addition to activating TLR-9 and causing NFκB activation. Furthermore, increased mtROS also activates the cGAS-STING pathway through the JNK-53BP1 pathway by causing nuclear CCF spillover. MAVS and the cGAS-STING pathway jointly regulate the activity of ZBP1. MAVS can both inhibit the NFκB pathway to suppress the inflammatory response and activate IFN 1 to induce an antiviral response. Additionally, decreased calcium entry into mitochondria in macrophages during aging also leads to NFκB activation, contributing to the inflammatory response. Moreover, excessive activation of cellular autophagy can result in ‘autophagic depletion’, causing macrophage depletion and the loss of the macrophage exophore receptor MerTK. This, in turn, impairs exophore elimination, leading to the accumulation of functionally impaired mitochondria and the activation of NLRP3, resulting in chronic inflammatory responses. NETs formations are induced by increased mtROS in neutrophils. These traps not only cause chronic inflammation upon mtDNA binding, but they also increase mtROS in cardiomyocytes, creating a vicious cycle. mtROS, mitochondrial reactive oxygen species; DAMP, damage-associated molecular patterns; TNF-β, Tumour necrosis factor beta; mtDNA, mitochondrial DNA; TLR, Toll-like receptor; NFκB, nuclear factor kappaB; NLRP3, NOD-like receptor protein 3; MerTK, Mer tyrosine kinase; NETs, Neutrophil traps, cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes; JNK, c-Jun N-terminal kinase; 53BP1, JNK-p53-binding protein 1; CCFs, cytoplasmic chromatin fragments; ZBP1, Z-DNA binding protein 1;IFN, interferon; MAVS, mitochondrial antiviral-signalling protein.

Figure 6.

mitochondrial dysfunction in cardiac fibrosis. Cardiac fibrosis ensues when fibroblasts undergo differentiation into myofibroblasts, leading to increased ECM secretion that exacerbates the condition. Dysfunction of the mitochondrial calcium channel, mtCU, impairs calcium ion uptake, promoting fibroblast differentiation through NFATc1, gluconeogenesis, and ketone body metabolism pathways. Additionally, reduced mitochondrial fusion coupled with increased fission contributes to myofibroblast proliferation. Activation of the MAPK pathway by mitochondrial ROS induces fibroblast differentiation and increases ECM secretion, a process inhibited by SOD. Excess mitophagy can also lead to increased ECM secretion. MiR-24-3p targets this pathway, offering a potential avenue for alleviating cardiac fibrosis. ECM, extracellular matrix; mtCU, mitochondrial calcium uniporter; NFATc1, nuclear factor of activated T cells c1; MAPK, mitogen-activated protein kinases; ROS, reactive oxygen species; SOD, superoxide dismutase; Mfn2, mitofusin 2; TGFβ, transforming growth factors-beta; Drp1, dynamin-related protein 1; PHB, prohibitin 2.

Figure 7.

mitochondrial dysfunction in cardiac vascular remodeling. Cardiac aging involves vascular remodeling, which includes vascular metabolic aging, vascular stiffness, vascular tone dysregulation, impaired angiogenesis, atherosclerosis, and chronic vascular inflammatory responses. The aging of vascular endothelial cells results in an increase in both glycolysis and oxidative phosphorylation ratios. Vascular sclerosis is characterized by vascular fibrosis, extracellular matrix remodeling, and vascular calcification. Diminished endothelial NO production capacity, increased ONOO-, and decreased eNOS activity are promoted by increased mitochondrial ROS and impaired mitochondrial dynamics, leading to vascular senescence. Impaired angiogenesis is also contributed by downregulated mitochondrial fusion proteins. ROS plays a role in fostering vascular inflammation, LDL deposition, cardiolipin oxidation, and mtDNA damage during atherosclerosis. The activation of the NFκB pathway primarily stems from the chronic inflammatory response. LDL, low-density lipoprotein; ECM, extracellular matrix; SOD, superoxide dismutase; Mfn1/2, mitofusin 1/2; COX, cyclooxygenases; Drp1, dynamin-related protein 1; ROS, reactive oxygen species; ONOO-, peroxynitrite; NOS, nitric oxide synthase.