AI Networking Cookbook: Practical recipes for AI-assisted network automation and development
TL;DR
Gene therapy targeting mecciRNAs and mt-dsRNAs combined with mitochondrial delivery represents a promising strategy for HF treatment.
This review examines mitochondrial pathology as the central orchestrator of SIC progression and integrates mitochondrial biology, immunometabolism, and translational medicine to identify promising directions for improving patient outcomes.
Oxidative stress and mitochondrial dysfunction were intimately linked processes driving aging and numerous human diseases. Mitochondria generating reactive oxygen species (ROS) during energy metabolism; physiological ROS levels are vital for cell signaling and adaptation. However, excessive ROS damage mitochondrial DNA (mtDNA), respiratory proteins, and membrane lipids, reducing ATP production, disturbing calcium balance, and impairing organelle function. In turn, damaged mitochondria produce more ROS and release mtDNA, activating inflammatory pathways such as cGAS-STING and NLRP3. Mitochondrial quality control mechanisms—fusion, fission, mitophagy, proteostasis, and PGC-1α-driven biogenesis—are essential for homeostasis. This review discusses the biochemical links between oxidative stress and mitochondrial dysfunction and their roles in cardiovascular disease, type 2 diabetes, neurodegeneration, metabolic liver disease, cancer, and aging. We summarize widely used biomarkers (F2-isoprostanes, oxidized nucleic acids, mitochondrial respiration, multi-omics) and current therapeutic strategies, including exercise-induced mitohormesis, NRF2 activation, mitochondria-targeted antioxidants (MitoQ), cardiolipin-targeting peptides (elamipretide), NAD⁺ restoration, and mitophagy enhancers (urolithin A). Although several approaches show biological promise, clinical outcomes remain variable. Future therapies must prioritize restoring mitochondrial quality and redox balance over simplistic ROS scavenging.
This Review summarizes mitochondrial pathological mechanisms in neurodegenerative diseases and discusses emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges.
Chronic kidney disease (CKD) represents a major global health challenge, affecting more than 10% of the population and contributing substantially to morbidity and premature mortality. Growing evidence identifies oxidative stress and mitochondrial dysfunction as central drivers of renal injury and disease progression across diverse etiologies. The kidney is one of the most mitochondria-rich organs in the body, reflecting the high bioenergetic demands required for tubular reabsorption and metabolic homeostasis. Disruption of mitochondrial oxidative phosphorylation, excessive production of reactive oxygen species (ROS), and impaired mitochondrial quality control mechanisms promote tubular injury, inflammation, and fibrosis. In particular, dysfunction of the electron transport chain, activation of NADPH oxidase isoforms—especially NOX4—and alterations in mitochondrial dynamics create a vicious cycle of oxidative damage and bioenergetic failure. Emerging evidence highlights the importance of mitochondrial quality control pathways, including fusion–fission balance, PINK1/Parkin-mediated mitophagy, and mitochondrial biogenesis regulated by PGC-1α and TFAM. Additional mechanisms include ferroptosis, epigenetic regulation, mitochondrial DNA-mediated innate immune activation, and Na+/K+-ATPase-linked redox signaling. At the translational level, redox and mitochondrial biomarkers and targeted therapies are biologically compelling, but the evidence is uneven: most candidate biomarkers remain insufficiently standardized, and direct mitochondria-targeted interventions are supported predominantly by preclinical studies or small human proof-of-concept trials. This review therefore emphasizes not only mechanistic advances but also conflicting findings, model limitations, and the barriers that currently separate experimental efficacy from clinically meaningful CKD outcomes.
Metabolic diseases are jointly driven by insulin resistance, chronic inflammation, lipotoxicity, and disrupted organelle homeostasis arising from sustained nutrient overload. These disorders substantially increase the risk of cardiovascular, renal, and other multi-organ complications and have become a major global public health burden. Mitochondria are central organelles that integrate energy metabolism with stress signaling. They participate in fatty acid β-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation, while also regulating reactive oxygen species generation, mitochondrial DNA-related inflammatory signaling, calcium homeostasis, and cell death. Under chronic metabolic stress, the mitochondrial quality control (MQC) system shifts from adaptive repair toward decompensation, characterized by impaired mitochondrial biogenesis, abnormal mitochondrial dynamics, defective mitophagy, disrupted proteostasis and mitochondrial unfolded protein response, increased oxidative stress, and impaired metabolic reprogramming. Natural small molecules possess structural diversity and multi-target, multi-pathway regulatory properties. They can modulate multiple MQC processes and improve mitochondrial function and metabolic phenotypes in preclinical models. Novel formulations, structural optimization, and mitochondria-targeted delivery can further improve their solubility, bioavailability, tissue exposure, and subcellular localization, thereby enhancing therapeutic efficacy and translational potential. This review systematically summarizes the mechanisms of MQC dysregulation in metabolic diseases, the evidence supporting natural small-molecule interventions, and strategies for formulation and delivery optimization. Future studies should strengthen causal validation of MQC, quantify intramitochondrial drug exposure, and incorporate clinically relevant endpoints to facilitate the translation of natural small-molecule MQC modulators.
Doxorubicin (DOX) is a broad-spectrum anthracycline chemotherapeutic agent, and its clinical application is severely limited by dose-dependent cardiotoxicity (DIC), for which there are currently no effective clinical interventions. Mitochondria are the central organelles regulating myocardial energy metabolism and cell survival, and mitochondrial dysfunction is considered the initiating and core mechanism underlying DIC. DOX disrupts the mitochondrial quality control (MQC) system and induces mitochondrial metabolic reprogramming, thereby leading to mitochondrial dysfunction. This results in excessive production of mitochondrial reactive oxygen species (mROS) and leakage of mitochondrial DNA (mtDNA), ultimately inducing PANoptosis. PANoptosis is a newly defined inflammatory programmed cell death pathway that integrates key features of apoptosis, pyroptosis, and necroptosis. This review delves into the molecular mechanisms by which mitochondrial dysfunction triggers PANoptosis in DIC, focusing on key aspects such as impaired mitochondrial protein homeostasis, mitochondrial dynamics imbalance, suppressed mitochondrial biogenesis, inhibited mitophagy, and mitochondrial metabolic reprogramming. It systematically discusses DIC-targeted intervention strategies against mitochondrial homeostasis and PANoptosis, including mitochondrial-targeted antioxidants, mitochondrial dynamics regulators, mitophagy activators, mitochondrial biogenesis promoters, mitochondrial transplantation, PANoptosis inhibitors, nanomedicine delivery systems, and gene/cell therapy. The aim is to balance the antitumor efficacy of DOX and reduce its cardiac adverse effects, thereby providing a new theoretical basis and potential therapeutic targets for the clinical prevention and treatment of DIC.
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