Mitochondrial Dysfunction: An Emerging Link in the Pathophysiology of Cardiorenal Syndrome

Abstract

The crosstalk between the heart and kidney is carried out through various bidirectional pathways. Cardiorenal syndrome (CRS) is a pathological condition in which acute or chronic dysfunction in the heart or kidneys induces acute or chronic dysfunction of the other organ. Complex hemodynamic factors and biochemical and hormonal pathways contribute to the development of CRS. In addition to playing a critical role in generating metabolic energy in eukaryotic cells and serving as signaling hubs during several vital processes, mitochondria rapidly sense and respond to a wide range of stress stimuli in the external environment. Impaired adaptive responses ultimately lead to mitochondrial dysfunction, inducing cell death and tissue damage. Subsequently, these changes result in organ failure and trigger a vicious cycle. In vitro and animal studies have identified an important role of mitochondrial dysfunction in heart failure (HF) and chronic kidney disease (CKD). Maintaining mitochondrial homeostasis may be a promising therapeutic strategy to interrupt the vicious cycle between HF and acute kidney injury (AKI)/CKD. In this review, we hypothesize that mitochondrial dysfunction may also play a central role in the development and progression of CRS. We first focus on the role of mitochondrial dysfunction in the pathophysiology of HF and AKI/CKD, then discuss the current research evidence supporting that mitochondrial dysfunction is involved in various types of CRS.

Keywords: cardiorenal syndrome; heart failure; inflammation; kidney failure; mitochondrial dysfunction; oxidative stress.

Figure 1

A schematic depiction of the cardiorenal connectors in CRS. The cardiorenal connectors, including hemodynamic factors, RAAS, SNS, inflammation, and oxidative stress are core mechanisms of CRS, all of which synergize and activate each other, leading to further deterioration of cardiac and renal function. CO, Cardiac Output; CVP, central venous pressure.

Figure 2

Diagrammatic representation shows the relationship between pathological alterations in CRS and mitochondrial dysfunction mechanisms. Intrinsic and extrinsic stress signals, such as hemodynamic alteration, RAAS overactivation, SNS dysfunction, inflammation or oxidative stress, can activate mitochondrial responses, including mitochondrial metabolism, antioxidant defense imbalance, abnormal dynamics, mitophagy and biogenesis. Impaired adaptive responses ultimately lead to mitochondrial dysfunction, include ATP synthesis reduction, excessive ROS, aberrant calcium signaling, (de) differentiation or cell death (apoptosis or necrosis). These changes in cardiomyocytes or renal tubular epithelial cells induce energy deprivation, oxidative stress, inflammation and fibrosis.

Figure 3

Mitochondrial Dysfunction Plays a Central and Multifaceted Role in HF and AKI/CKD. Mitochondria from cardiomyocytes and renal proximal tubular cells preferentially use fatty acyl-CoA, the primary substrate for mitochondrial FAO, rather than pyruvate to generate ATP. The hallmarks of metabolic remodeling are FAO downregulation and increased glucose utilization, which are observed in both early-stage heart and kidney injury. ROS were initially thought to be by-products of mitochondrial OXPHOS, the balance between mtROS production and scavenging is critical for maintaining mitochondrial function and cell viability. Mitochondrial dynamics contribute to the functional integrity of mitochondria. Fusion allows mixing of contents within the mitochondrial network and protects the mitochondria from stress. Damaged mitochondria undergo selective mitochondrial autophagy via Parkin, Fundc1, through autophagosome formation and lysosome-mediated degradation. Upregulation of PGC1α and activation of NRF1/2 initiate mitochondrial biogenesis, followed by mtDNA amplification and synthesis of nuclear-encoded mitochondrial proteins. After severe mitochondrial damage, increased fission leads to mitochondrial fragmentation, depolarization of the mitochondrial membrane potential inhibits fusion, and frequent abnormal fission events will affect mitochondrial autophagy, leading to abnormal degradation of damaged mitochondria, along with a decrease in the number and quality of nascent mitochondria mediated by mitochondrial biosynthesis. NRFs, nuclear respiratory factors, PGC1α, PPARγ coactivator-1α. FAO, fatty acid β-oxidation, OXPHOS, oxidative phosphorylation.

Figure 4

Mitochondrial functions and the effects of mitochondrial damage. Mitochondria play a key role in producing energy in the form of ATP. NADPH are formed by the oxidation of fatty acids and the cycle of TCA in the mitochondrial matrix, and their electrons are transferred to O₂ through the electron transport chain (including COX I and IV). This results in the generation of a proton gradient across the IMM to produce ATP. Cyto C exists in free form in the IMS, or is anchored in the IMM by interaction with cardiolipin, acting as an electron carrier COX III and COX IV. Mitochondria are the main source of ROS. Mitochondria also play an important role in maintaining calcium balance in cells. Mitochondrial damage reduces ATP production and can result in the energetic failure of cells. An increase in mitochondrial ROS production by damaged mitochondria may also induce other forms of cell death, including necroptosis, pyroptosis and ferroptosis, as well as inflammation. NADH, nicotinamide adenine dinucleotides; TCA, tricarboxylic acids; IMM, mitochondrial intima; Cyto C, Cytochrome C; IMS, intermembrane space; IMM, intermembrane space; COX I, mitochondrial respiratory complex I; NLRs, nucleotide-binding and oligomerization domain-like receptors.