Pathophysiological Role of Organelle Stress/Crosstalk in AKI-to-CKD Transition

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected syndromes that represent a global public health challenge. Organelles play essential roles in a vast range of cell functions, and their damage is related to several kidney diseases. Organelles launch the stress signal or trigger the stress response, and organelles interact with each other through a phenomenon termed organelle crosstalk. The endoplasmic reticulum (ER) is a major organelle that controls protein synthesis, folding, and degradation via the unfolded protein response pathway. Renal pathogenic conditions, such as chronic hypoxia, induce a maladaptive unfolded protein response pathway (ER stress) in the kidney, leading to progression of AKI and CKD. Mitochondria have an essential role in producing adenosine triphosphate for maintaining the cellular/organelle functions, including protein homeostasis in the ER. Thus, mitochondrial dysfunction also can induce ER stress (altered protein homeostasis) and subsequent cellular damage. Recent evidence has shown that ER or mitochondrial dysfunction disrupts the organelle crosstalk between mitochondria and ER in the kidney. Such alterations of ER-mitochondria crosstalk might contribute to the progression of AKI to CKD. Mitochondrial injury induces aberrant tubular inflammation, which is one of the major fibrotic processes. We recently found that a novel tubular inflammatory pathway that is activated specifically by the interaction of mitochondrial DNA with the ER membrane molecule triggers the progression of tubular inflammation in AKI. Thus, there is accumulating evidence for the pathophysiologic importance of organelle crosstalk, especially mitochondria-ER crosstalk. Organelle stress and crosstalk can serve as potential therapeutic targets for the prevention of AKI-to-CKD transition.