Potential Therapeutic Benefits of Strategies Directed to Mitochondria

The mitochondrion is the most important organelle in determining continued cell survival and cell death. Mitochondrial dysfunction leads to many human maladies, including cardiovascular diseases, neurodegenerative disease, and cancer. These mitochondria-related pathologies range from early infancy to senescence. The central premise of this review is that if mitochondrial abnormalities contribute to the pathological state, alleviating the mitochondrial dysfunction would contribute to attenuating the severity or progression of the disease. Therefore, this review will examine the role of mitochondria in the etiology and progression of several diseases and explore potential therapeutic benefits of targeting mitochondria in mitigating the disease processes. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate and manipulate mitochondrial function and genomics for therapeutic benefit. These approaches to treat mitochondrial dysfunction rationally could lead to selective protection of cells in different tissues and various disease states. However, most of these approaches are in their infancy. Antioxid. Redox Signal. 13, 279–347. Introduction and Topics Reviewed Anatomy and Function of Mitochondrial Membranes Outer mitochondrial membrane and its potential role as therapeutic target Inner mitochondrial membrane and its potential role as therapeutic target Mitochondrial permeability transition pore Electron Transport Chain and Oxidative Phosphorylation: Modulation by Mitochondrial Ion Channels and Exchangers Mitochondrial ROS and RNS Mitochondria and reactive oxygen species Mitochondria and reactive nitrogen species Mitochondrial ROS Scavenging and Its Potential Therapeutic Value Manganese superoxide dismutase Glutathione thioredoxin, and peroxiredoxin systems Catalase and glutathione peroxidase Cytochrome c Mitochondria as scavengers of cytosolic O2•− Uncoupling Proteins in Modulation of Mitochondrial Function: Physiological and Pharmacologic Relevance Mitochondrial DNA-Related Pathologies and a Potential Therapeutic Target Mitochondrial Interaction with other Organelles: Therapeutic Implications Mitochondrion—mitochondrion interaction Mitochondrion—nucleus interaction Mitochondria—endoplasmic/sarcoplasmic reticulum interaction Mitochondria-Related Diseases and Cell Injury Mitochondria and cardiac ischemia and reperfusion injury Mitochondria and the failing heart Mitochondria and diabetes Mitochondria and hypertension Mitochondria and neurodegenerative diseases Alzheimer's disease Parkinson's disease Amyotrophic lateral sclerosis Friedreich's ataxia Neoplastic diseases Other mitochondria-related diseases Mitochondria and psychiatric disorders Mitochondria and migraine headache Mitochondrial Pharmacology and Therapeutic Potential Strategies for drug delivery to mitochondria Mitochondria-targeted drugs Approaches to improve mitochondrial function during ischemia and reperfusion Preconditioning Postconditioning Other Mitochondrial Therapeutic Approaches Lipid replacement therapy Transactivator of transcription proteins and mitochondrial therapy Molecular genetics approaches Mitochondria and caloric restriction Mitochondria and dietary supplements Mitochondria Age and Lifespan Mitochondria and age-associated diseases Mitochondrial p66shc and lifespan Caveats and Potential Limitations in Mitochondrial Drug Targeting Conclusion and Perspectives