bims-cytox1 2017-11-12 papers

J Med Genet. 2017 Nov 03. pii: jmedgenet-2017-104891. [Epub ahead of print]

Phenotype-genotype correlations in Leigh syndrome: new insights from a multicentre study of 96 patients.

Kalliopi Sofou, Irenaeus F M de Coo, Elsebet Ostergaard, Pirjo Isohanni, Karin Naess, Linda De Meirleir, Charalampos Tzoulis, Johanna Uusimaa, Tuula Lönnqvist, Laurence Albert Bindoff, Már Tulinius, Niklas Darin.

BACKGROUND: Leigh syndrome is a phenotypically and genetically heterogeneous mitochondrial disorder. While some genetic defects are associated with well-described phenotypes, phenotype-genotype correlations in Leigh syndrome are not fully explored.
OBJECTIVE: We aimed to identify phenotype-genotype correlations in Leigh syndrome in a large cohort of systematically evaluated patients.
METHODS: We studied 96 patients with genetically confirmed Leigh syndrome diagnosed and followed in eight European centres specialising in mitochondrial diseases.
RESULTS: We found that ataxia, ophthalmoplegia and cardiomyopathy were more prevalent among patients with mitochondrial DNA defects. Patients with mutations in MT-ND and NDUF genes with complex I deficiency shared common phenotypic features, such as early development of central nervous system disease, followed by high occurrence of cardiac and ocular manifestations. The cerebral cortex was affected in patients with NDUF mutations significantly more often than the rest of the cohort. Patients with the m.8993T>G mutation in MT-ATP6 gene had more severe clinical and radiological manifestations and poorer disease outcome compared with patients with the m.8993T>C mutation.
CONCLUSION: Our study provides new insights into phenotype-genotype correlations in Leigh syndrome and particularly in patients with complex I deficiency and with defects in the mitochondrial ATP synthase.

Keywords: Leigh syndrome; MRI; complex I; genetic; mitochondrial DNA

DOI: https://doi.org/10.1136/jmedgenet-2017-104891

Sci Rep. 2017 Nov 03. 7(1): 14488

Cyclophilin D regulates the dynamic assembly of mitochondrial ATP synthase into synthasomes.

Gisela Beutner, Ryan E Alanzalon, George A Porter.

Mitochondrial electron transport is essential for oxidative phosphorylation (OXPHOS). Electron transport chain (ETC) activity generates an electrochemical gradient that is used by the ATP synthase to make ATP. ATP synthase is organized into supramolecular units called synthasomes that increase the efficiency of ATP production, while within ATP synthase is the cyclophilin D (CypD) regulated mitochondrial permeability transition pore (PTP). We investigated whether synthasomes are dynamic structures that respond to metabolic demands and whether CypD regulates this dynamic. Isolated heart mitochondria from wild-type (WT) and CypD knockout (KO) mice were treated to either stimulate OXPHOS or open the PTP. The presence and dynamics of mitochondrial synthasomes were investigated by native electrophoresis, immunoprecipitation, and sucrose density centrifugation. We show that stimulation of OXPHOS, inhibition of the PTP, or deletion of CypD increased high order synthasome assembly. In contrast, OXPHOS inhibition or PTP opening increased synthasome disassembly in WT, but not in CypD KO heart mitochondria. CypD activity also correlated with synthasome assembly in other tissues, such as liver and brain. We conclude that CypD not only regulates the PTP, but also regulates the dynamics of synthasome assembly depending on the bioenergetic state of the mitochondria.

DOI: https://doi.org/10.1038/s41598-017-14795-x

Annu Rev Pathol. 2017 Nov 03.

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

Adam J Kuszak, Michael Graham Espey, Marni J Falk, Marissa A Holmbeck, Giovanni Manfredi, Gerald S Shadel, Hilary J Vernon, Zarazuela Zolkipli-Cunningham.

Multisystem metabolic disorders caused by defects in oxidative phosphorylation (OXPHOS) are severe and 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 patterns, 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. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 13 is January 24, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-pathol-020117-043644