The Multi-Faceted Nature of Renalase for Mitochondrial Dysfunction Improvement in Cardiac Disease

Abstract

The cellular mechanisms and signaling network that guide the cardiac disease pathophysiology are inextricably intertwined, which explains the current scarcity of effective therapy and to date remains the greatest challenge in state-of-the-art cardiovascular medicine. Accordingly, a novel concept has emerged in which cardiomyocytes are the centerpiece of therapeutic targeting, with dysregulated mitochondria as a critical point of intervention. Mitochondrial dysfunction pluralism seeks a multi-faceted molecule, such as renalase, to simultaneously combat the pathophysiologic heterogeneity of mitochondria-induced cardiomyocyte injury. This review provides some original perspectives and, for the first time, discusses the functionality spectrum of renalase for mitochondrial dysfunction improvement within cardiac disease, including its ability to preserve mitochondrial integrity and dynamics by suppressing mitochondrial ΔΨm collapse; overall ATP content amelioration; a rise of mtDNA copy numbers; upregulation of mitochondrial genes involved in oxidative phosphorylation and cellular vitality promotion; mitochondrial fission inhibition; NAD⁺ supplementation; sirtuin upregulation; and anti-oxidant, anti-apoptotic, and anti-inflammatory traits. If verified that renalase, due to its multi-faceted nature, behaves like the "guardian of mitochondria" by thwarting pernicious mitochondrial dysfunction effects and exerting therapeutic potential to target mitochondrial abnormalities in failing hearts, it may provide large-scale benefits for cardiac disease patients, regardless of the underlying causes.

Keywords: MAPK; NAD+; apoptosis; cardiac disease; mitochondrial dysfunction; oxidative stress; renalase; sirtuins.

Figure 1

A schematic view of anticipated mechanisms of renalase in regard to mitochondrial protection upon various cardiomyocyte injuries. Renalase gene expression is regulated by a range of transcription factors, including STAT3, NF-κB, TNF-α, and HIF-1α, to acquire multi-faceted roles for renalase action. Evidence shows that renalase provides a state of antioxidation by suppressing cellular and mitochondrial ROS content and silencing its consequences (mtROS-induced epithelial to mesenchymal transition); upregulating GSH and SOD expression and abolishing MDA; downregulating NADPH oxidase components (gp91^phox, p47^phox, and p67^phox) and a state of anti-apoptosis specifically by suppressing cytochrome C liberation, Bax expression, and cleaved caspase-3; and downregulating Bcl-2 expression. At the same time, renalase obtains the competence to enhance the phosphorylation of Drp-1 (the major fission protein) at serine 637 and to impede its translocation and its accumulation into mitochondria, thereby preventing mitochondrial fission. By that means, renalase efficiently prevents a mitochondrial ΔΨm collapse, ameliorates the overall ATP content, and increases mtDNA copy numbers to maintain mitochondrial integrity and dynamics. Moreover, renalase functions as an NADH oxidase (the amine oxidase domain is denoted in orange) by converting α-NAD(P)H to β-NAD(P)⁺, thereby ameliorating the cellular NAD⁺ levels and NAD⁺/NADH ratio and upregulating the activity of sirtuins (NAD⁺-dependent type III deacetylases). In that manner, renalase presumably provides an indirect role for promoting SIRT1-dependent mitochondrial biogenesis and mitophagy. For instance, SIRT1 promotes the nuclear accumulation of PGC-1α for the transcription of genes required for mitochondrial function and biogenesis. SIRT1 also activates (FOXO, NRF2, LKB1) or inhibits (p53) some signaling pathways to further inhibit oxidative stress, improve anti-oxidant protection, lessen inflammation, decrease inflammasome activity and IL-1β production, promote mitophagy, and suppress apoptosis for mitochondria quality control preservation and presumed cardioprotection against many cardiac stressors. Moreover, renalase promotes the activity of SIRT3, which, through deacetylation, regulates fatty acid oxidation; glucose and ketone body metabolism; amino acid catabolism; regulates oxidative phosphorylation and increases ATP production; governs oxidative stress by negative regulation of ROS production; preserves ΔΨm by increasing GSH and SOD levels; negatively regulates the mPTP opening; and stimulates mitophagy. SIRT3, for instance, similar to SIRT1, upregulates the expression of PGC1-α for mitochondrial function preservation and detoxification pathway activation; promotes mitochondrial FOXO3a for the transcription of anti-oxidative genes and genes necessary for mitochondrial biogenesis safety; and enhances the LKB1 pathway for ATP production. Collectively, by functioning as a mitochondrial homeostasis guardian, SIRT3 ameliorates the mitochondrial function of cardiomyocytes and increases energy production; hence, it is implicated in heart protection against myocardial ischemia, cardiac fibrosis, hypertrophy, atherosclerosis, dilated cardiomyopathy, and heart failure. However, extracellular renalase or its recombinant peptide, Rp-220 (denoted as red), upon targeting its receptor PMCA4b, elicits mediation of the vast downstream network, including PI3K/Akt, p38, JNK, ERK1/2, to obtain renalase-mediated cytoprotection, irrespective of the injury. The MAPKs signaling (ERK1/2, p38, JNK), specifically, mediate the activities of multiple cardiac stressors, being highly involved in cardiac development, metabolism, physiology, and pathogenesis. In terms of the implication of MAPK-mitochondria signaling in diverse cardiac pathologies (myocardial ischemia and infarction, hypertrophy, and heart failure), it may be that its modulation by renalase, at different levels, occurs in a context-dependent manner to provide some renalase-mediated mitochondria-induced cardiac protection. STAT3: signal transducer and activator of transcription 3; NF-κB: nuclear factor kappa B; HIF-1α: hypoxia-1α; ROS: reactive oxygen species; GSH: glutathione; SOD: superoxide dismutase; MDA: malondialdehyde; NADPH: nicotinamide adenine dinucleotide phosphate; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; Drp-1: dynamic-related protein-1; ΔΨm, changes in mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; NAD+: nicotinamide adenine dinucleotide; SIRT: sirtuin; NLRP3: NOD-like receptor family, pyrin domain containing 3; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator-1α; FOXO: forkhead box O; NRF2: nuclear factor erythroid 2-related factor 2; LKB1: liver kinase B1; PMCA4b: plasma membrane calcium-ATPase 4b; ERK1/2, extracellular regulated protein kinases 1/2; PI3K/Akt, phosphatidylinositol 3-kinase/protein kinase B; JNK, c-Jun N-terminal kinases; MAPKs: mitogen-activated protein kinases.

Figure 2

A schematic view of the potential anti-inflammatory effects of renalase against impaired mitochondrial homeostasis and cardiac inflammation upon cardiac injury. Diverse cardiac stressors (ischemia, hypoxia, and oxidative stress) significantly disrupt mitochondrial function, resulting in impaired mitochondrial homeostasis, which is characterized by suppressed mitophagy, reduced mitochondrial biogenesis, and dysregulated mitochondrial dynamics (fission and fusion). Such a setting triggers an innate inflammatory response as evidenced by myocardial accumulation of pro-inflammatory macrophages (M1), enhanced M1/M2 polarization, and assembly of the NLRP3 inflammasome, thereby aggravating cardiac inflammation and disease progression. Renalase regulates mitochondrial biogenesis, preserves mitochondrial integrity and dynamics, and, by upregulating the activity of sirtuins (Figure 1), provides an indirect role in sirtuin-dependent mitophagy and finally recovers mitochondrial quality control mechanisms. Renalase thwarts pro-inflammatory macrophage (M1) tissue accumulation and their polarization (M1/M2) and hinders inflammasome activation and IL-1β secretion, thereby mediating anti-inflammatory tissue protection. The multi-faceted nature of renalase suggests a proof of principle for the therapeutic potential of targeting mitochondrial abnormalities in failing hearts. NLRP3: NOD-like receptor family, pyrin domain containing 3.