title: Mitochondrial Dysfunction in the Pathogenesis of Rett Syndrome: Implications for Mitochondria-Targeted Therapies.
abstract: First described over 50 years ago, Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by mutations of the X-linkedMECP2gene. RTT affects predominantly females, and has a prevalence of roughly 1 in every 10,000 female births. Prior to the discovery that mutations ofMECP2are the leading cause of RTT, there were suggestions that RTT could be a mitochondrial disease. In fact, several reports documented altered mitochondrial structure, and deficiencies in mitochondrial enzyme activity in different cells or tissues derived from RTT patients. With the identification ofMECP2as the causal gene, interest largely shifted toward defining the normal function of MeCP2 in the brain, and how its absence affects the neurodevelopment and neurophysiology. Recently, though, interest in studying mitochondrial function in RTT has been reignited, at least in part due to observations suggesting systemic oxidative stress does play a contributing role in RTT pathogenesis. Here we review data relating to mitochondrial alterations at the structural and functional levels in RTT patients and model systems, and present a hypothesis for how the absence of MeCP2 could lead to altered mitochondrial function and elevated levels of cellular oxidative stress. Finally, we discuss the prospects for treating RTT using interventions that target specific aspects of mitochondrial dysfunction and/or oxidative stress.
authors.affiliation: Division of Genetics and Development, Krembil Research Institute, University Health NetworkToronto, ON, Canada; Department of Physiology, University of TorontoToronto, ON, Canada.
authors.forename: Natalya
authors.initials: N
authors.lastname: Shulyakova
authors.affiliation: Department of Pharmacology, University of Toronto Toronto, ON, Canada.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Andreazza
authors.affiliation: Department of Physiology, University of Toronto Toronto, ON, Canada.
authors.forename: Linda R
authors.initials: LR
authors.lastname: Mills
authors.affiliation: Division of Genetics and Development, Krembil Research Institute, University Health NetworkToronto, ON, Canada; Department of Physiology, University of TorontoToronto, ON, Canada; Institute of Medical Sciences, University of TorontoToronto, ON, Canada; Department of Surgery (Neurosurgery), University of TorontoToronto, ON, Canada.
authors.forename: James H
authors.initials: JH
authors.lastname: Eubanks
keywords: MECP2; Rett syndrome; mitochondrial dysfunction; oxidative stress