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Annu Rev Pathol. 2018 Jan 24;13:163-191. doi: 10.1146/annurev-pathol-020117-043644. Epub 2017 Nov 3.

Nutritional Interventions for Mitochondrial OXPHOS Deficiencies: Mechanisms and Model Systems.

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Office of Dietary Supplements, National Institutes of Health, Bethesda, Maryland 20852, USA; email:
Division of Cancer Biology, National Cancer Institute, Rockville, Maryland 20850, USA; email:
Department of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; email:
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06510-8023, USA; email:
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; email:
Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06520-8023, USA; email:
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA; email:
Department of Pediatrics, Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; email:


Multisystem metabolic disorders caused by defects in oxidative phosphorylation (OXPHOS) are severe, often lethal, conditions. Inborn errors of OXPHOS function are termed primary mitochondrial disorders (PMDs), and the use of nutritional interventions is routine in their supportive management. However, detailed mechanistic understanding and evidence for efficacy and safety of these interventions are limited. Preclinical cellular and animal model systems are important tools to investigate PMD metabolic mechanisms and therapeutic strategies. This review assesses the mechanistic rationale and experimental evidence for nutritional interventions commonly used in PMDs, including micronutrients, metabolic agents, signaling modifiers, and dietary regulation, while highlighting important knowledge gaps and impediments for randomized controlled trials. Cellular and animal model systems that recapitulate mutations and clinical manifestations of specific PMDs are evaluated for their potential in determining pathological mechanisms, elucidating therapeutic health outcomes, and investigating the value of nutritional interventions for mitochondrial disease conditions.


electron transport chain; metabolism; nutritional interventions; primary mitochondrial OXPHOS disorders

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