Threshold of heteroplasmic truncating MT-ATP6 mutation in reprogramming, Notch hyperactivation and motor neuron metabolism
Open Access
- 12 October 2021
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 31 (6), 958-974
- https://doi.org/10.1093/hmg/ddab299
Abstract
Mutations in mitochondrial DNA encoded subunit of ATP synthase, MT-ATP6, are frequent causes of neurological mitochondrial diseases with a range of phenotypes from Leigh syndrome and NARP to ataxias and neuropathies. Here we investigated the functional consequences of an unusual heteroplasmic truncating mutation m.9154C>T in MT-ATP6, which caused peripheral neuropathy, ataxia and IgA nephropathy. ATP synthase not only generates cellular ATP, but its dimerization is required for mitochondrial cristae formation. Accordingly, the MT-ATP6 truncating mutation impaired the assembly of ATP synthase and disrupted cristae morphology, supporting our molecular dynamics simulations that predicted destabilized a/c subunit subcomplex. Next, we modeled the effects of the truncating mutation using patient-specific induced pluripotent stem cells. Unexpectedly, depending on mutation heteroplasmy level, the truncation showed multiple threshold effects in cellular reprogramming, neurogenesis and in metabolism of mature motor neurons (MN). Interestingly, MN differentiation beyond progenitor stage was impaired by Notch hyperactivation in the MT-ATP6 mutant, but not by rotenone-induced inhibition of mitochondrial respiration, suggesting that altered mitochondrial morphology contributed to Notch hyperactivation. Finally, we also identified a lower mutation threshold for a metabolic shift in mature MN, affecting lactate utilization, which may be relevant for understanding the mechanisms of mitochondrial involvement in peripheral motor neuropathies. These results establish a critical and disease-relevant role for ATP synthase in human cell fate decisions and neuronal metabolism.Funding Information
- Academy of Finland
- University of Helsinki
- Magnus Ehrnrooth Foundation
- Sigrid Juselius Foundation
- Emil Aaltonen Foundation
- University of Eastern Finland Doctoral Program in Molecular Medicine
This publication has 70 references indexed in Scilit:
- Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth diseaseNeurology, 2012
- Adult-onset spinocerebellar ataxia syndromes due toMTATP6mutationsJournal of Neurology, Neurosurgery & Psychiatry, 2012
- UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cellsThe EMBO Journal, 2011
- A more efficient method to generate integration-free human iPS cellsNature Methods, 2011
- Difference Tracker: ImageJ plugins for fully automated analysis of multiple axonal transport parametersJournal of Neuroscience Methods, 2010
- Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid TypesThe Journal of Physical Chemistry B, 2010
- The ATP synthase is involved in generating mitochondrial cristae morphologyThe EMBO Journal, 2002
- All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of ProteinsThe Journal of Physical Chemistry B, 1998
- Assembly of mitochondrial ATP synthase in cultured human cells: implications for mitochondrial diseasesBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1995
- Molecular dynamics with coupling to an external bathThe Journal of Chemical Physics, 1984