Abstract
ATP synthase or complex V (cV) of the oxidative phosphorylation system is responsible for the production of ATP, dissipating the electrochemical gradient generated by the mitochondrial respiratory chain. In addition to maternally transmitted cV dysfunction caused by mutations in mtDNA genes (MT-ATP6 or MT-ATP8), encoding cV subunits, recessive mutations in the nuclear TMEM70 are the most frequent cause of ATP synthase deficiency.
We report on a cohort of ten Italian patients presenting with neonatal lactic acidosis, respiratory distress, hypotonia, cardiomyopathy and psychomotor delay and harbouring mutations in TMEM70, including the common splice mutation and four novel variants. TMEM70 protein was virtually absent in all tested TMEM70 patients’ specimens.
The exact function of TMEM70 is not known, but it is considered to impact on cV assembly since TMEM70 mutations have been associated with isolated cV activity reduction. We detected a clear cV biochemical defect in TMEM70 patients’ fibroblasts, whereas the assay was not reliable in frozen muscle. Nevertheless, the evaluation of the amount of holocomplexes in patients with TMEM70 mutations showed a nearly absent cV in muscles and a strong decrease of cV with accumulation of sub-assembly species in fibroblasts. In our cohort we found not only cV deficiencies but also impairment of other OXPHOS complexes. By ultrastructural analysis of muscle tissue from one patient with isolated cV deficiency, we found a severely impaired mitochondrial morphology with loss of the cristae. These findings indicate that cV impairment could indirectly alter other respiratory chain complex activities by disrupting the mitochondrial cristae structure.
Competing interests: None declared
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Acknowledgements
We thank Rosalba Carrozzo for the generous gift of anti-TMEM70 antibody. This work was supported by the Italian Ministry of Health (GR2010–2316392); Fondazione Telethon grants GGP11011 and GPP10005; CARIPLO grant 2011/0526; the Pierfranco and Luisa Mariani Foundation of Italy; and the Italian Association of Mitochondrial Disease Patients and Families (Mitocon). H.P. was supported by the Impulse and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society (HA-215) and the German Federal Ministry of Education and Research (BMBF) funded German Center for Diabetes Research (DZD e.V.) and Systems Biology of Metabotypes grant (SysMBo #0315494A), the grant RF-INN-2007-634163 of the Italian Ministry of Health, the BMBF funded German Network for Mitochondrial Disorders (mitoNET #01GM1113C/D) and the E-Rare project GENOMIT (01GM1207 and FWF I 920-B13). We acknowledge the “Cell lines and DNA Bank of Paediatric Movement Disorders and Neurodegenerative Diseases” of the Telethon Network of Genetic Biobanks (grant GTB12001J) and the EuroBioBank Network.
The authors declare that they have no conflict of interest.
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Communicated by: Garry Brown
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Sentence Take-Home Message
TMEM70 patients present with a mitochondrial cardiomyopathy with early-onset hypotonia, respiratory distress and psychomotor delay, irrespective of the biochemical defect.
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Daria Diodato, Federica Invernizzi, Eleonora Lamantea, Gigliola Fagiolari, Rossella Parini, Francesca Menni, Giancarlo Parenti, Lina Bollani, Maria A.Donati, Denise Cassandrini, Elisabetta Pasquini, Filippo M. Santorelli, Tobias B. Haack, Holger Prokisch, Daniele Ghezzi, Costanza Lamperti and Massimo Zeviani declare that they have no conflict of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki (1975), as revised in 2000. Informed consent was obtained from all patients for being included in the study.
Details of the Contributions of Individual Authors
DD, DG, CL and MZ designed the study; DD, FI, EL, GF, EP, FMS, TBH, HP, DG, CL and MZ performed experiments, collected and analysed data. RP, FM, GP, LB, MAD, DC, FMS and CL evaluated the patients and wrote case reports. DD, DG, CL and MZ wrote the manuscript. FI, EL, GF, RP, FM, GP, LB, MAD, DC, EP, FMS, TBH and HP critically revised the manuscript for important intellectual content.
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Diodato, D. et al. (2014). Common and Novel TMEM70 Mutations in a Cohort of Italian Patients with Mitochondrial Encephalocardiomyopathy. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports, Volume 15. JIMD Reports, vol 15. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_300
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DOI: https://doi.org/10.1007/8904_2014_300
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