Advancements in mitochondrial-targeted antioxidants: Organelle-specific drug delivery for disease management
Nazmun Nahar, Md. Shihab Uddin Sohag
Abstract
• Reactive Oxygen Species (ROS) are a "necessary evil," vital for cellular signaling, apoptosis, and immune responses, yet responsible for oxidative damage leading to diverse diseases. • ROS are mitigated by mitochondria-targeted antioxidants (MTAs), including lipophilic cation-linked, amino acid and peptide-based, metallo-complex-based, and nanoparticle-based MTAs (Nano-MTAs), which are specifically localized to mitochondria. • MTAs reveal therapeutic efficacy in more than 20 types of diseases associated with reactive free radicals. • Nano-MTAs enhance mitochondrial delivery, bioavailability, stability, and therapeutic efficacy. • Recent studies have explored mitochondrial-targeted antioxidants improve quality and function of sperm and oocyte thereby enhancing fertility. Mitochondria, a crucial subcellular organelle, serve as the primary generator of reactive oxygen species (producing around 90% of total ROS), utilizing over 98% of cellular oxygen for ATP synthesis while converting 1–2% into ROS. Excess reactive oxygen species disrupt redox homeostasis, inducing oxidative stress, resulting in mitochondrial dysfunction and damage. Furthermore, defective or impaired mitochondria might intensify ROS production. This "necessary evil" serves dual functions: regulating signaling, apoptosis, proliferation, differentiation, autophagy, and immunological responses while simultaneously inflicting oxidative damage on lipids, proteins, and DNA, hence contributing to numerous diseases. Thus, the targeted suppression of mitochondrial ROS-induced oxidative damage and dysfunction by mitochondria-targeted antioxidants (MTAs) represents a precise therapeutic strategy that has attracted growing interest and offers substantial opportunities for clinical application by directly alleviating oxidative stress at its origin within affected cells. Lipophilic cation-linked MTAs, amino acid- and peptide-based MTAs, metallo-complex-based MTAs, and nanoparticle-based MTAs (Nano-MTAs) can selectively localize to mitochondria and diminish excessive mitochondrial ROS. Incorporating these MTAs into precision medicine facilitates tailored therapies based on individual mitochondrial dysfunction characteristics and disease-specific redox imbalances. This review classifies current mitochondria-targeted antioxidants according to the characteristics of their targeting moieties and examines their composition and antioxidant efficacy. We also evaluate nanoparticle-based MTAs, including liposomes, DQAsomes, solid lipid nanoparticles, MITO-Porters, micelles, dendrimers, nanoemulsions, metal nanoparticles, quantum dots, and nanopolyplexes. Furthermore, we summarize recent experimental findings regarding MTAs across diverse disease models including cancer, neurological disorders (e.g., Alzheimer’s, Huntington’s, Parkinson’s, ataxia, TBI, and epilepsy); cardiovascular diseases; asthma; COPD; auditory impairments; diabetic complications; ocular, renal, hepatic, and inflammatory disorders; sepsis; infertility; aging-longevity; and their potential as antibiotics to clarify the evidence supporting their therapeutic efficacy.