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.

The molecular mechanisms and intervention strategies of mitophagy in cardiorenal syndrome

“…This metabolic flux shifts are also termed energy metabolism remodeling (Razeghi et al, 2002) (Huang et al, 2020a). Growing evidences, including ours, have suggested damaged mitochondria as a vital contributor to energy metabolism remodeling in CRS (Huang et al, 2020a) (Mapuskar et al, 2019;Tirichen et al, 2021;Shi et al, 2022). Mitophagy is an essential machinery for the removal of damaged mitochondria, maintaining mitochondrial quality control and cellular homeostasis (Pickles et al, 2018).…”

“…The main pathological changes of kidney in CKD include glomerulosclerosis, tubular atrophy, interstitial fibrosis and inflammatory cell infiltration ( Webster et al, 2017a ; Wang X. H. et al, 2022 ), while a growing body of evidence observes cardiac interstitial fibrosis, cardiomyocyte hypertrophy, and mitochondrial swelling and damage in the heart ( Bigelman et al, 2018 ). Of note, mitochondrial injury has been identified as the common pathological change in both kidney and heart in the state of CKD ( Shi et al, 2022 ). Recent studies have reported that modulating mitophagy may reverse the above pathological changes in the injured kidney and heart through eliminating damaged mitochondria and maintaining mitochondrial homeostasis ( Quiles and Gustafsson, 2022 ), hinting that mitophagy might link these pathological changes between the heart and kidney.…”

A comprehensive review of acute cardio-renal syndrome: need for novel biomarkers

“…The natriuretic peptide system (NPS) and RAAS function as opposing regulators in maintaining kidney and cardiovascular homeostasis ( Peoples et al, 2019 ). The paracrine effect of RAAS and NPS is also associated with salt and water homeostasis through the kidney ( Peoples et al, 2019 ; Shi et al, 2022 ). Three natriuretic peptides central to the NPS, atrial (ANP), and brain (BNP), as well as another non-natriuretic protein C-type natriuretic peptide (CNP), act as counter-regulators to the RAAS activities ( Ronco et al, 2012a ; Peoples et al, 2019 ).…”

Emodin alleviates CRS4‐induced mitochondrial damage via activation of the PGC1α signaling

“…This pathologic process is referred to as cardiorenal syndrome type 4 (CRS4) (Shi et al, 2022). In these patients, the estimated glomerular filtration rate (eGFR) declines greatly, while the mortality rate resulting from heart failure (HF) increases from 56% to 131% (Thompson et al, 2015;Wheeler et al, 2021).…”

“…Approximately 10%–47% of CKD patients undergo pathologic cardiac remodeling, such as diastolic dysfunction and left ventricular hypertrophy, which can result in death. This pathologic process is referred to as cardiorenal syndrome type 4 (CRS4) (Shi et al, 2022). In these patients, the estimated glomerular filtration rate (eGFR) declines greatly, while the mortality rate resulting from heart failure (HF) increases from 56% to 131% (Thompson et al, 2015; Wheeler et al, 2021).…”