Abstract
Mitochondrial diseases are a clinically heterogenous group of disorders caused by respiratory chain dysfunction and associated with progressive, multi-systemic phenotype. There is no effective treatment or cure, and no FDA-approved drug for treating mitochondrial disease. To identify and characterize potential therapeutic compounds, we developed an in vitro screening assay and identified a group of direct AMP-activated protein kinase (AMPK) activators originally developed for the treatment of diabetes and metabolic syndrome. Unlike previously investigated AMPK agonists such as AICAR, these compounds allosterically activate AMPK in an AMP-independent manner, thereby increasing specificity and decreasing pleiotropic effects. The direct AMPK activator PT1 significantly improved mitochondrial function in assays of cellular respiration, energy status, and cellular redox. PT1 also protected against retinal degeneration in a mouse model of photoreceptor degeneration associated with mitochondrial dysfunction and oxidative stress, further supporting the therapeutic potential of AMP-independent AMPK agonists in the treatment of mitochondrial disease.
Highlights
Primary mitochondrial diseases encompass a clinically heterogeneous group arising from inherited deficiencies in the mitochondrial electron transport chain (ETC)
PT1 protected against retinal degeneration in a mouse model of photoreceptor degeneration associated with mitochondrial dysfunction and oxidative stress, further supporting the therapeutic potential of AMP-independent AMPK agonists in the treatment of mitochondrial disease
We show that this is accompanied by Activator of AMPK for treatment of mitochondrial disorders increased oxygen consumption and ATP concentration, reduced oxidative stress, and activation of AMPK downstream targets involved in mitochondrial biogenesis and oxidative stress response, and extend these findings to the sodium iodate (SI) mouse model of photoreceptor degeneration caused by oxidative stress
Summary
Primary mitochondrial diseases encompass a clinically heterogeneous group arising from inherited deficiencies in the mitochondrial electron transport chain (ETC). These disorders commonly involve multiple organ systems and are characterized by prominent neurologic and myopathic features but can affect a single tissue such as eye or muscle [1, 2]. Molecular defects underlying mitochondrial disorders include pathogenic variants in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) affecting the expression, replication or maintenance of mtDNA, as well as the function and formation of ETC complexes. Regardless of genetic etiology, respiratory chain abnormalities impair the transfer of electrons to molecular oxygen, leading to overproduction of reactive oxygen species (ROS) and decreased ATP synthesis [3]. The resulting imbalances disrupt signaling mechanisms responsible for metabolic homeostasis and lead to cellular damage, necrosis and apoptosis, and to the overt signs and symptoms of mitochondrial disease
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