title: Mitochondrial disorders in children: toward development of small-molecule treatment strategies.
abstract: This review presents our current understanding of the pathophysiology and potential treatment strategies with respect to mitochondrial disease in children. We focus on pathologies due to mutations in nuclear DNA-encoded structural and assembly factors of the mitochondrial oxidative phosphorylation (OXPHOS) system, with a particular emphasis on isolated mitochondrial complex I deficiency. Following a brief introduction into mitochondrial disease and OXPHOS function, an overview is provided of the diagnostic process in children with mitochondrial disorders. This includes the impact of whole-exome sequencing and relevance of cellular complementation studies. Next, we briefly present how OXPHOS mutations can affect cellular parameters, primarily based on studies in patient-derived fibroblasts, and how this information can be used for the rational design of small-molecule treatment strategies. Finally, we discuss clinical trial design and provide an overview of small molecules that are currently being developed for treatment of mitochondrial disease.
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands Centre for Systems Biology and Bioenergetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Werner Jh
authors.initials: WJ
authors.lastname: Koopman
authors.affiliation: Khondrion BV, Nijmegen, The Netherlands.
authors.forename: Julien
authors.initials: J
authors.lastname: Beyrath
authors.affiliation: Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong.
authors.forename: Cheuk-Wing
authors.initials: CW
authors.lastname: Fung
authors.affiliation: Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Koene
authors.affiliation: Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands Centre for Systems Biology and Bioenergetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Peter Hgm
authors.initials: PH
authors.lastname: Willems
authors.affiliation: Centre for Systems Biology and Bioenergetics, Radboud University Medical Center, Nijmegen, The Netherlands Khondrion BV, Nijmegen, The Netherlands Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Jan.Smeitink@Radboudumc.nl.
authors.forename: Jan Am
authors.initials: JA
authors.lastname: Smeitink
mesh_terms: D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D055808:Drug Discovery / Q000639:trends*; D042967:Electron Transport Complex I / Q000172:deficiency; D006801:Humans; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*
chemical_list: D042967:Electron Transport Complex I
keywords: children; clinical trial; drug development; mitochondria; outcome measures