Mitochondrial quality control in health and disease: mechanisms and therapeutic targets

Mitochondria in health and disease: cellular powerhouses, signaling centers, and drivers of dysfunction

Although the mitochondria are known as the cellular powerhouse, their function is beyond energy generation. These organelles regulate cellular metabolism, yet maintains a tightly regulated reactive oxygen species (ROS) generation and optimal redox state. In addition, mitochondria serve as mediators of physiological and pathological processes, such as maintenance of calcium balance, and control of apoptosis and mitophagy. All these make the mitochondria a major factor in both cellular and organismal regulation. However, mitochondria dysfunction may occur through many processes, including genetic mutations, increased production of ROS, metabolic failure from impaired electron transport chain activity, and dysregulated dynamics or mitophagy. Several self-perpetuating damages accumulate from these processes and influence clinical pathologies, such as aging, metabolic syndrome, cancer, neurodegeneration, and reproductive disorders. Recent studies demonstrate promising therapeutic targets for mitochondrial dysfunction. Examples include targeted antioxidants, such as MitoQ and SkQ1, to selectively neutralize mitochondrial ROS, pharmacological modulators to enhance mitochondrial biogenesis and to restore NAD + homeostasis via PGC-1α activation, gene-editing technologies, such as mitoTALENs and mtZFNs to selectively eliminate pathogenic mitochondrial DNA mutations, and mitochondrial transplantation as a new technique to replace damaged organelles. Together, these novel approaches highlight the need for research in mitochondrial function to change the therapeutic landscape in the management of mitochondrial dysfunction-associated diseases.

A Function-Centric Framework for Mitochondrial Quality Control

Mitochondrial quality control (QC) comprises interconnected pathways that preserve organelle function by detecting damage and mediating repair, remodelling, or elimination of defective components. Although many sub-organellar QC mechanisms are well characterised, stress is often sensed first at the level of mitochondrial function rather than at individual molecular targets. Functional domains such as oxidative folding, bioenergetics, redox balance, pH, and thermogenesis act as sensory portals that detect perturbations and trigger adaptive reprogramming of mitochondrial activity. In this perspective, we provide a conceptual perspective for mitochondrial QC as a mechanistically integrated network, emphasising how changes in these functional states couple diverse QC modules—including proteases, antioxidant systems, mitochondrial dynamics, mitophagy, and mitochondrial-derived vesicles—into a unified surveillance system. We propose that primary stressors, such as redox imbalance, are progressively converted into secondary stress signals, including reactive oxygen species accumulation, membrane depolarisation, metabolite redistribution, and altered lipid or nucleic-acid structure. These secondary signals propagate across mitochondrial and cytosolic compartments, amplifying QC by coordinating the engagement of repair, remodelling, and organelle-elimination pathways. This cascading transformation of stress signals not only limits the impact of the initial insult but also enhances adaptive capacity by driving synergistic deployment of QC processes across multiple mechanistic layers.

Targeting mitochondria for the treatment of neurodegenerative diseases

Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.

Mitochondria-targeted natural products with potential for the treatment of mitochondria-related diseases.

Mitochondria are indispensable organelles that serve as the powerhouses of cells, playing a crucial role in maintaining cellular energy homeostasis. Consequently, mitochondrial dysfunction is recognized as a key pathogenic factor in a wide range of common diseases, including cardiovascular diseases, neurodegenerative disorders, metabolic syndromes and cancers. Due to their multitarget properties and favorable safety profiles, natural products have shown significant potential for regulating key mitochondrial biological processes, including mitobiogenesis, mitophagy, mitochondrial dynamics (fusion and fission), oxidative phosphorylation, and mitochondria-mediated apoptosis. Therefore, they have become an important resource for mitochondria-targeted therapy. Despite significant progress in mechanistic studies in vitro, translating these findings into clinical applications remains a major challenge. This translational gap is primarily due to unfavorable pharmaceutical properties, such as low bioavailability, poor targeted delivery, and rapid metabolic clearance. Additionally, the precise mechanisms governing mitochondria remain to be fully elucidated. In this review, we systematically summarize the specific mitochondrial pathological phenotypes in various diseases and provide a comprehensive overview of natural products that correspond to these phenotypes, along with their mechanisms of action. We also analyze common challenges associated with the absorption, distribution, metabolism, and excretion of these products. By bridging the gap between basic research and clinical application, this review aims to accelerate the development of novel therapeutic strategies for mitochondria-related diseases.

Research progress on VDAC2 in mitochondrial dysfunction-related diseases

Mitochondrial dynamics and metabolic regulation in cellular inflammation: From mechanisms to precision therapeutics.

This treatise evaluates the pharmacological potential of modulating mitochondrial dynamics-ranging from direct Drp1 inhibitors and unfractionated heparin to metabolic stabilizers (e.g., GLP-1 receptor agonists), multi-pronged disruptors (e.g., Antimycin A), targeted nanomedicine, and communication-driven mitochondrial transplantation-positioning this axis as a promising frontier for precision pharmacology.