Abstract
Mitochondria are heterogeneous and highly dynamic organelles, playing critical roles in adenosine triphosphate (ATP) synthesis, metabolic modulation, reactive oxygen species (ROS) generation, and cell differentiation and death. Mitochondrial dysfunction has been recognized as a contributor in many diseases. The kidney is an organ enriched in mitochondria and with high energy demand in the human body. Recent studies have been focusing on how mitochondrial dysfunction contributes to the pathogenesis of different forms of kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD). AKI has been linked to an increased risk of developing CKD. AKI and CKD have a broad clinical syndrome and a substantial impact on morbidity and mortality, encompassing various etiologies and representing important challenges for global public health. Renal mitochondrial disorders are a common feature of diverse forms of AKI and CKD, which result from defects in mitochondrial structure, dynamics, and biogenesis as well as crosstalk of mitochondria with other organelles. Persistent dysregulation of mitochondrial homeostasis in AKI and CKD affects diverse cellular pathways, leading to an increase in renal microvascular loss, oxidative stress, apoptosis, and eventually renal failure. It is important to understand the cellular and molecular events that govern mitochondria functions and pathophysiology in AKI and CKD, which should facilitate the development of novel therapeutic strategies. This review provides an overview of the molecular insights of the mitochondria and the specific pathogenic mechanisms of mitochondrial dysfunction in the progression of AKI, CKD, and AKI to CKD transition. We also discuss the possible beneficial effects of mitochondrial-targeted therapeutic agents for the treatment of mitochondrial dysfunction-mediated AKI and CKD, which may translate into therapeutic options to ameliorate renal injury and delay the progression of these kidney diseases.
Highlights
Acute kidney injury (AKI), formerly called acute kidney failure, is defined as kidneys suddenly stopping working properly, ranging from minor loss of kidney function to complete kidney failure and can occur within a few hours or a few days [1]
In IRI-AKI, treatment with SIRT1 activator SRT1720 restores the expression of PGC-1α in kidneys, leading to enhanced mitochondria biogenesis characterized by the increase of mitochondrial mass and adenosine triphosphate (ATP) levels, and improved renal function [103]
Mitochondrial dysfunction in renal cells plays a critical role in the pathophysiology of AKI and Chronic kidney disease (CKD) as well as AKI to CKD transition
Summary
Acute kidney injury (AKI), formerly called acute kidney failure, is defined as kidneys suddenly stopping working properly, ranging from minor loss of kidney function to complete kidney failure and can occur within a few hours or a few days [1]. The causes of CKD vary globally, and could include diabetes, hypertension, primary glomerulonephritis, chronic tubulointerstitial nephritis, hereditary or cystic diseases, heart diseases, and stroke [4,5]. Understanding the molecular mechanisms underlying AKI and CKD is crucial for drug development and the generation of novel therapeutic strategies for these kidney diseases. The kidney is one of the most energy-demanding organs in human and has the second highest mitochondrial content and oxygen consumption after the heart. Accumulating evidence suggests that various acute and chronic injuries may lead to mitochondrial respiratory chain-derived oxidative stress, ultrastructural defects, abnormal activation of the mitochondrial pathway of apoptosis, unstable mitochondrial DNA (mtDNA), and defective clearance of damaged mitochondria. A better understanding of the cellular and molecular events that govern mitochondria functions in kidney diseases should facilitate the development of improved therapeutic strategies. This review provides an overview of the molecular insights of the roles of mitochondria in the progression of AKI, CKD, and the transition from AKI to CKD
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