Mitochondrial pharmacology

Abstract

Mitochondria are being recognized as key factors in many unexpected areas of biomedical science. In addition to their well-known roles in oxidative phosphorylation and metabolism, it is now clear that mitochondria are also central to cell death, neoplasia, cell differentiation, the innate immune system, oxygen and hypoxia sensing, and calcium metabolism. Disruption to these processes contributes to a range of human pathologies, making mitochondria a potentially important, but currently seemingly neglected, therapeutic target. Mitochondrial dysfunction is often associated with oxidative damage, calcium dyshomeostasis, defective ATP synthesis, or induction of the permeability transition pore. Consequently, therapies designed to prevent these types of damage are beneficial and can be used to treat many diverse and apparently unrelated indications. Here we outline the biological properties that make mitochondria important determinants of health and disease, and describe the pharmacological strategies being developed to address mitochondrial dysfunction.

Assessing the Delivery of Molecules to the Mitochondrial Matrix Using Click Chemistry

“…Considerable efforts are ongoing to develop molecules that alter mtDNA function in a sequence specific way, either as probes or as potential therapies 2. These agents include DNA‐mimetic oligomers, such as peptide nucleic acids (PNAs), that bind selectively to complementary DNA sequences 11.…”

Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo

“…Mitochondrial targeting has emerged as a therapeutic approach for several disorders involving mitochondrial oxidative stress (Edeas and Weissig, 2013;Fulda et al, 2010;Smith et al, 2012). Although accumulating evidence points towards mitochondrial dysfunction in psychiatric disorders (Manji et al, 2012), the therapeutic potential of mitochondrial targeting has only been recently highlighted for bipolar disorder (de Sousa et al, 2014) and autism (Ghanizadeh et al, 2013) and has never been tested in vivo.…”

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

“…The advent of genetic linkage and next-generation sequencing (NGS) technologies has led to significant insights into the role of mitochondrial mutations in driving disease processes [3,4]. Mitochondrial disorders can be subdivided into three classes: (i) primary mitochondrial disorders caused by mutations in mitochondrial genes; (ii) disorders with mutations in nuclear genes involved in mitochondrial function; and (iii) secondary disorders that arise from the accumulation of mitochondrial damage over time frequently involving neurodegenerative pathologies [5][6][7][8]. Tissues such as retina, brain, and muscle, which have enormous energy requirements, are particularly vulnerable to variations in mitochondrial function.…”

“…Although great diversity exists in the nuclear and mtDNA mutations causative of mitochondrial diseases, at times there is a perturbation of common pathways, including ROS production, ATP synthesis, calcium homeostasis, regulation of the permeability transition pore (PTP), and mitochondrial biogenesis, suggesting the possibility of developing common therapies for these conditions [5,6]. Although it is well established that somatic mtDNA mutations accumulate and mitochondrial function attenuates in ageing animals, the relative impact of ROS production, OXPHOS capacity, mtDNA replication errors, and mitochondrial biogenesis remains ill defined [34].…”

“…The approach was used to deliver the antioxidant MitoQ in animal models, prompting its evaluation in clinical studies [65,66]. Peptides, including mitochondrial-penetrating and Szeto-Schiller peptides, have been tested for their ability to direct delivery to mitochondria [6]. Indeed, water-soluble Szeto-Schiller peptides, which target the inner mitochondrial membrane (IMM), have antioxidant properties themselves, and are in preclinical and clinical development for several indications [67].…”