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

ABSTRACT: 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.

SUBMITTER: Kuszak AJ

PROVIDER: S-EPMC5911915 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Kuszak Adam J AJ Espey Michael Graham MG Falk Marni J MJ Holmbeck Marissa A MA Manfredi Giovanni G Shadel Gerald S GS Vernon Hilary J HJ Zolkipli-Cunningham Zarazuela Z

Annual review of pathology 20171103

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 meta ...[more]

PMID: 29099651

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Project description:In December 2014, a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD.

Project description:Background Literature has shown a tendency of inadequate dietary intake among youth, consequently, nutritional interventions are required. The transtheoretical model (TTM) classifies individuals based on their readiness to change. This model is widely used for health education interventions with proven efficacy. Purpose This review aimed to weigh the strength of evidence about the TTM usage in nutritional interventions for adolescents and its effectiveness regarding dietary intake. Methods This study followed the PRISMA guidelines. Eligible studies were input into Mendeley software. The Adolec, Google Scholar, LILACS, PsycINFO, PubMed, Science Direct and Web of Science databases were searched. Only full original articles written in English, Spanish or Portuguese on randomized controlled trials and quasi-experimental designs that applied the TTM in the design of nutritional interventions targeting adolescents were included, with no restrictions on publication date. The quality and risk of bias was evaluated with the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies. Results The initial search yielded 3779 results. Three studies were rated as strong, six as moderate and five as weak. The final sample of 14 articles included adolescents that were mostly recruited from schools, with interventions ranging from one month to three years. The TTM was used alone or combined with other behavior-change theories and most of the interventions involved digital technology. The nutritional topics covered included fruit and vegetable consumption, low-fat diet, and cooking skills. Four studies presented improvement in fruit and vegetable consumption and four progressed through stages of change. Participants from two interventions reduced fat intake. At the end of one intervention, all the participants were in action and maintenance stages. Conclusion The TTM seems to be a successful strategy for nutritional intervention aiming at improving dietary intake in adolescents. Its application in different contexts shows that the TTM is flexible and possible to be implemented in many settings. The use of the model is shown to be restricted to the stage of change’ construct. Further studies should use all constructs of the TTM in the design and compare the TTM with other behavior-change theories to better understand its effectiveness.

Project description:The five macromolecular complexes that jointly mediate oxidative phosphorylation (OXPHOS) in mitochondria consist of many more subunits than those of bacteria, yet, it remains unclear by which evolutionary mechanism(s) these novel subunits were recruited. Even less well understood is the structural evolution of mitochondrial ribosomes (mitoribosomes): while it was long thought that their exceptionally high protein content would physically compensate for their uniquely low amount of ribosomal RNA (rRNA), this hypothesis has been refuted by structural studies. Here, we present a cryo-electron microscopy structure of the 73S mitoribosome from Neurospora crassa, together with genomic and proteomic analyses of mitoribosome composition across the eukaryotic domain. Surprisingly, our findings reveal that both structurally and compositionally, mitoribosomes have evolved very similarly to mitochondrial OXPHOS complexes via two distinct phases: A constructive phase that mainly acted early in eukaryote evolution, resulting in the recruitment of altogether approximately 75 novel subunits, and a reductive phase that acted during metazoan evolution, resulting in gradual length-reduction of mitochondrially encoded rRNAs and OXPHOS proteins. Both phases can be well explained by the accumulation of (slightly) deleterious mutations and deletions, respectively, in mitochondrially encoded rRNAs and OXPHOS proteins. We argue that the main role of the newly recruited (nuclear encoded) ribosomal- and OXPHOS proteins is to provide structural compensation to the mutationally destabilized mitochondrially encoded components. While the newly recruited proteins probably provide a selective advantage owing to their compensatory nature, and while their presence may have opened evolutionary pathways toward novel mitochondrion-specific functions, we emphasize that the initial events that resulted in their recruitment was nonadaptive in nature. Our framework is supported by population genetic studies, and it can explain the complete structural evolution of mitochondrial ribosomes and OXPHOS complexes, as well as many observed functions of individual proteins.

Dataset Information

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

Publications

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

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