Passively-targeted mitochondrial tungsten-based nanodots for efficient acute kidney injury treatment
Qiong HuangYuqi YangTianjiao ZhaoQiaohui ChenMin LiuShuting JiYan ZhuYunrong YangJinping ZhangHaixin ZhaoYayun NanKelong Ai
58
Citation
61
Reference
10
Related Paper
Citation Trend
Abstract:
Acute kidney injury (AKI) can lead to loss of kidney function and a substantial increase in mortality. The burst of reactive oxygen species (ROS) plays a key role in the pathological progression of AKI. Mitochondrial-targeted antioxidant therapy is very promising because mitochondria are the main source of ROS in AKI. Antioxidant nanodrugs with actively targeted mitochondria have achieved encouraging success in many oxidative stress-induced diseases. However, most strategies to actively target mitochondria make the size of nanodrugs too large to pass through the glomerular system to reach the renal tubules, the main damage site of AKI. Here, an ultra-small Tungsten-based nanodots (TWNDs) with strong ROS scavenging can be very effective for treatment of AKI. TWNDs can reach the tubular site after crossing the glomerular barrier, and enter the mitochondria of the renal tubule without resorting to complex active targeting strategies. To our knowledge, this is the first time that ultra-small negatively charged nanodots can be used to passively target mitochondrial therapy for AKI. Through in-depth study of the therapeutic mechanism, such passive mitochondria-targeted TWNDs are highly effective in protecting mitochondria by reducing mitochondrial ROS and increasing mitophagy. In addition, TWNDs can also reduce the infiltration of inflammatory cells. This work provides a new way to passively target mitochondria for AKI, and give inspiration for the treatment of many major diseases closely related to mitochondria, such as myocardial infarction and cerebral infarction.Keywords:
Mitochondrial ROS
Objective High levels of reactive oxygen species (ROS) are intricately linked to obesity and associated pathologies, notably insulin resistance and type 2 diabetes. However, ROS are also thought to be important in intracellular signaling, which may paradoxically be required for insulin sensitivity. Many theories have been developed to explain this apparent paradox, which have broadened our understanding of these important small molecules. While many sites for intracellular ROS production have been described, mitochondrial generated ROS remain a major contributor in most cell types. Mitochondrial ROS generation is controlled by a number of factors described in this review. Moreover, these studies have established both a demand for novel sensitive approaches to measure ROS, as well as a need to standardize and review their suitability for different applications. Methods To properly assess levels of ROS and mitochondrial ROS in the development of obesity and its complications, a growing number of tools have been developed. This paper reviews many of the common methods for the investigation of ROS in mitochondria, cell, animal, and human models. Results Available approaches can be generally divided into those that measure ROS‐induced damage (e.g., DNA, lipid, and protein damage); those that measure antioxidant levels and redox ratios; and those that use novel biosensors and probes for a more direct measure of different forms of ROS (e.g., 2′,7′‐di‐chlorofluorescein (DCF), dihydroethidium (DHE) and its mitochondrial targeted form (MitoSOX), Amplex Red, roGFP, HyPer, mt‐cpYFP, ratiometric H 2 O 2 probes, and their derivatives). Moreover, this review provides caveats and strengths for the use of these techniques in different models. Conclusions Advances in these techniques will undoubtedly advance the understanding of ROS in obesity and may help resolve unanswered questions in the field.
Mitochondrial ROS
Cite
Citations (220)
Mitochondrial ROS
Cite
Citations (1,289)
Mitophagy is a degradative process that adapts the quantity and quality of mitochondria to the cellular needs. Mitochondria destined for degradation are marked by specific receptors that recruit the core autophagic machinery to the organellar surface. The organelle is then enclosed by a phagophore (PG) which fuses with the lysosome or vacuole where the mitochondrion is degraded. In spite of significant progress in recent years, several parts of the molecular machinery of mitophagy remain unknown. We used yeast as a model organism to screen for novel components and identified the mitochondria-ER tether ERMES (ER-mitochondria encounter structure) as a major player contributing to mitophagy and formation of mitophagosomes. Tethering of mitochondria to the ER appears to be important to supply the growing PG with lipids synthesized in the ER.
Organelle
Cite
Citations (32)
Reactive oxygen species (ROS) have been implicated as a signal for general autophagy. Both mitochondrial-produced and exogenous ROS induce autophagosome formation. However, it is unclear whether ROS are required for the selective autophagic degradation of mitochondria, a process called mitophagy. Recent work using carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial-uncoupling reagent, has been shown to induce mitophagy. However, CCCP treatment may not be biologically relevant since it causes the depolarization of the entire mitochondrial network. Since mitochondria are the main ROS production sites in mammalian cells, we propose that short bursts of ROS produced within mitochondria may be involved in the signaling for mitophagy. To test this hypothesis, we induced an acute burst of ROS within mitochondria using a mitochondrial-targeted photosensitizer, mitochondrial KillerRed (mtKR). Using mtKR, we increased ROS levels in the mitochondrial matrix, which resulted in the loss of membrane potential and the subsequent activation of PARK2-dependent mitophagy. Importantly, we showed that overexpression of the mitochondrial antioxidant protein, superoxide dismutase-2, can squelch mtKR-induced mitophagy, demonstrating that mitochondrial ROS are responsible for mitophagy activation. Using this assay, we examined the impact of mitochondrial morphology on mitophagy. It was shown recently that elongated mitochondria are more resistant to mitophagy through unknown mechanisms. Here, we show that elongated mitochondria are more resistant to ROS-induced damage and mitophagy compared with fragmented mitochondria, suggesting that mitochondrial morphology has an important role in regulating ROS and mitophagy. Together, our results suggest that ROS-induced mitochondrial damage may be an important upstream activator of mitophagy.
Mitochondrial ROS
PINK1
Cite
Citations (386)
Oxidative stress is considered a major contributor to the etiology of both “normal” senescence and severe pathologies with serious public health implications. Several cellular sources, including mitochondria, are known to produce significant amounts of reactive oxygen species (ROS) that may contribute to intracellular oxidative stress. Mitochondria possess at least 10 known sites that are capable of generating ROS, but they also feature a sophisticated multilayered ROS defense system that is much less studied. This review summarizes the current knowledge about major components involved in mitochondrial ROS metabolism and factors that regulate ROS generation and removal at the level of mitochondria. An integrative systemic approach is applied to analysis of mitochondrial ROS metabolism, which is “dissected” into ROS generation, ROS emission, and ROS scavenging. The in vitro ROS‐producing capacity of several mitochondrial sites is compared in the metabolic context and the role of mitochondria in ROS‐dependent intracellular signaling is discussed.
Mitochondrial ROS
Cite
Citations (778)
Mitochondrial dysfunction has severe cellular consequences and is linked with neurodegenerative diseases and aging. Maintaining a healthy population of mitochondria is thus essential for proper cellular homeostasis. Several strategies have evolved to prevent and limit mitochondria damage, and macroautophagy plays a role in degrading superfluous or severely damaged mitochondria. Selective removal of mitochondria by autophagy (termed mitophagy) has been extensively studied recently in both yeast and mammalian cells. In this review, we summarize our current knowledge of mitophagy. We also compare the molecular process of mitophagy with other types of specific autophagic pathways and discuss its biological importance.
Cite
Citations (377)
Mitochondrial ROS
Cite
Citations (250)
Amyloid-β (Aβ) peptide is accumulated in the mitochondria and has been shown to play a central role in the development of Alzheimer's disease (AD). It has been shown that exposure of neurons to aggregated Aβ can result in damaged mitochondria and dysregulated mitophagy, indicating that changes in the Aβ content of mitochondria may affect the levels of mitophagy and interfere with the progression of AD. However, the direct influence of mitochondrial Aβ on mitophagy has not been elucidated. In the present study, the effect of the mitochondria-specific Aβ was assessed following a direct change of Aβ content in the mitochondria. We directly change mitochondrial Aβ by transfecting cells with mitochondria-associated plasmids, including the mitochondrial outer membrane protein translocase 22 (TOMM22) and 40 (TOMM40) or presequence protease (PreP) overexpression plasmids. The changes in the levels of mitophagy were assessed by TEM, Western blot, mito-Keima construct, organelle tracker, and probe JC-1 assay. We demonstrated that increased mitochondrial Aβ content enhance mitophagy levels; overexpression of PreP could reverse the mitochondrial Aβ-induced mitophagy levels in vivo and in vitro by reversing the levels of reactive oxygen species (ROS) and the mitochondrial membrane potential. The data provide novel insight into the role of mitochondria-specific Aβ in the progression of AD pathophysiology.
Translocase
Cite
Citations (9)
PINK1
Cite
Citations (107)
Many vital metabolic pathways take place in mitochondria, but some of the associated processes generate toxic substances including reactive oxygen species that can damage proteins and DNA. Therefore, it is critical to maintain normally functioning mitochondria to achieve proper cellular homeostasis. Along these lines, mitochondrial dysfunction is associated with numerous diseases, and mitochondria quality control is essential for cell survival. The maintenance of functioning mitochondria is particularly important in aging cells, and there is a strong relationship between cellular aging and dysfunctional mitochondria. The best characterized pathway that is responsible for the elimination of damaged mitochondria is mitophagy, a selective type of autophagy. In yeast, mitophagy requires the mitochondrial protein Atg32 to serve as a receptor for recognition and sequestration by a phagophore. Although conventional mitophagy has been extensively studied, recent research suggests that an unconventional pathway, which is independent of Atg32, contributes to the removal of mitochondria.
Cite
Citations (11)