Damaged mitochondria release harmful molecules, such as ROS, DNA, and cardiolipin, which can activate NOD-like receptors (NLR) and elevate the levels of proinflammatory cytokines and chemokines, such as IL-18 and IL-1β, to induce persistent renal injury 
). The innate immune system has been implicated in both AKI and CKD and persistent inflammation after AKI prevents tissue repair and tubular apoptosis. On one hand, inflammation plays a critical role in the initiation and progression of renal fibrosis, when mitochondrial damage persists long after ischemia to sustain chronic inflammasome activation, leading to persistent endothelial injury, podocyte damage, microvascular rarefaction, and ultimately, progressive glomerular and interstitial fibrosis. On the other hand, upon kidney injury, oxidant stress, abundant cytokines, or hypoxia, deteriorate the mitochondrial membrane potential by excreting ROS and releasing pro-apoptotic factors, such as cytochrome c and apoptosis-inducing factor (AIF), which promote caspase dependent and independent apoptosis. In this perspective, persistent mitochondrial dysfunction result in persistent tubular damage, which may affect renal recovery from AKI and further progression to CKD. In a study with AKI to CKD transition experimental model, the investigators performed a long (nine months) follow-up, exploring the role of mitochondria in rats 
. They confirmed that AKI is not merely an acute phenomenon but results in long-lasting morphologic and functional consequences. AKI induced peritubular and glomerular capillary loss, podocyte damage, and increased profibrotic and proinflammatory cytokines from one to nine months, leading to progressive glomerular and interstitial fibrosis. Transmission electron microscopy revealed major alterations of mitochondria including loss of cristae and matrix density in endothelial cells, podocytes, and tubular cells up to nine months after the injury. Similar data was also presented in the Lan et al. study 
, which showed that persistence in mitochondrial morphologic alterations and significant reductions in mitochondrial number and metabolic dysfunctions at 14 days after IRI plays a key role in the development of renal tubular atrophy and the transition to CKD after AKI. Studies have also focused on the role and mechanisms of impaired protein kinase B (PKB/AKT1) signaling, which works together with mitochondrial proteins, in the regulation of ATP production and oxidative phosphorylation in renal tubular epithelial cells. Mitochondrial AKT1 inhibition led to activation of caspases and tubular cell death, and renal fibrosis after ischemia-reperfusion injury 
. Altogether, these studies suggest long-term mitochondrial damage may affect the pathophysiology and recovery from AKI and result in the gradual progression to CKD.
In addition, studies show that mitochondrial dysfunction disrupts the crosstalk between mitochondria and ER, leading to tubular inflammation and fibrosis as well as the AKI to CKD transition. ER is a major organelle that controls protein synthesis, folding, and degradation via the unfolded protein response (UPR) pathway. The UPR promotes cellular survival by restoring ER and mitochondrial homeostasis through distinct signaling networks, but if unsuccessful, the UPR induces cell death 
. UPR pathways is regulated by three distinctive transmembrane sensors: activating transcription factor 6 (ATF6), PRKR-like ER kinase (PERK), and inositol-requiring enzyme 1 (IRE1), which can be activated under ER stress 
). Various types of kidney damage are associated with dysfunction of the ER and the activation of the UPR. In cisplatin-induced AKI model, cisplatin-induced mitochondrial damage and mtDNA leakage into the cytosol in renal tubular cells, and damaged mtDNA subsequently increased the activation of cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway, resulting in the activation of UPR response and then renal inflammation and AKI progression 
. The activation of ATF6α caused by pathogenic conditions significantly reduces mitochondrial fatty acid β-oxidation activity through suppressing the expression of peroxisome proliferator–activated receptor-α (PPARα) and thereby induced tubular inflammation and fibrosis after acute kidney injury induced by lipotoxicity 
. Furthermore, activated ATF6 can be translocated to the Golgi apparatus for cleavage to form an active fragment (ATF6 p50). The activation of IRE1 and PERK induces the splicing of the X-box binding protein 1 (XBP1) mRNA and phosphorylates eIF2α, which promotes the translation of activating transcription factor 4 (ATF4) and suppresses the translation of other mRNAs to reduce unfolded proteins, respectively. ATF6 p50, spliced XBP1, and ATF4 could induce the transcription of various UPR target genes that regulate inflammation and apoptosis (Figure 1
. These findings suggest that alterations in ER–mitochondria crosstalk may contribute to the progression of AKI to CKD transition.