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Yeast NDI1 expression prevents the unfolded protein response and reconfigures metabolism to restore neuronal function in mitochondrial complex I deficiency

Lucy Granat, Daniel Ranson, Emma Hamer, Ram Prosad Chakrabarty, Francesca Mattedi, Laura Fort-Aznar, Frank Hirth, Sean T. Sweeney, View ORCID ProfileAlessio Vagnoni, Navdeep S. Chandel, View ORCID ProfileJoseph M. Bateman
doi: https://doi.org/10.1101/2022.09.22.509020
Lucy Granat
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 125 Coldharbour lane, London, SE5 9NU, UK
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Daniel Ranson
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 125 Coldharbour lane, London, SE5 9NU, UK
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Emma Hamer
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 125 Coldharbour lane, London, SE5 9NU, UK
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Ram Prosad Chakrabarty
2Department of Medicine and Biochemistry & Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Francesca Mattedi
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 125 Coldharbour lane, London, SE5 9NU, UK
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Laura Fort-Aznar
3Department of Biology and York Biomedical Research Institute, University of York, Wentworth Way, Heslington, York, YO10 5DD, UK
4Alzheimer’s disease and other cognitive disorders Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, 08009, Spain
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Frank Hirth
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 125 Coldharbour lane, London, SE5 9NU, UK
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Sean T. Sweeney
3Department of Biology and York Biomedical Research Institute, University of York, Wentworth Way, Heslington, York, YO10 5DD, UK
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Alessio Vagnoni
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 125 Coldharbour lane, London, SE5 9NU, UK
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  • ORCID record for Alessio Vagnoni
Navdeep S. Chandel
2Department of Medicine and Biochemistry & Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Joseph M. Bateman
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 125 Coldharbour lane, London, SE5 9NU, UK
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  • ORCID record for Joseph M. Bateman
  • For correspondence: joseph_matthew.bateman@kcl.ac.uk
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Abstract

Mutations in mitochondrial complex I cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The mechanisms underlying complex I deficiency pathogenesis remain poorly understood, and as a result there are currently no available treatments. To better understand the causes of neuronal dysfunction in complex I deficiency, we modelled complex I deficiency in Drosophila by knocking down the mitochondrial complex I subunit ND-75 (NDUFS1) specifically in neurons. Neuronal complex I deficiency causes locomotor defects, seizures and reduced lifespan. At the cellular level, complex I deficiency leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Remarkably, we find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1 in neurons, which couples NADH oxidation to transfer of electrons into the respiratory chain, reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Metabolomic analysis shows that NDI1 expression also reconfigures neuronal metabolism and implicates increased GABA levels as a contributor to the neurological manifestations of complex I deficiency. Together, these data indicate that NDI1 abrogates UPR signalling and reprogrammes metabolism to alleviate neuronal dysfunction caused by neuronal complex I deficiency.

Competing Interest Statement

The authors have declared no competing interest.

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Posted September 23, 2022.
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Yeast NDI1 expression prevents the unfolded protein response and reconfigures metabolism to restore neuronal function in mitochondrial complex I deficiency
Lucy Granat, Daniel Ranson, Emma Hamer, Ram Prosad Chakrabarty, Francesca Mattedi, Laura Fort-Aznar, Frank Hirth, Sean T. Sweeney, Alessio Vagnoni, Navdeep S. Chandel, Joseph M. Bateman
bioRxiv 2022.09.22.509020; doi: https://doi.org/10.1101/2022.09.22.509020
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Yeast NDI1 expression prevents the unfolded protein response and reconfigures metabolism to restore neuronal function in mitochondrial complex I deficiency
Lucy Granat, Daniel Ranson, Emma Hamer, Ram Prosad Chakrabarty, Francesca Mattedi, Laura Fort-Aznar, Frank Hirth, Sean T. Sweeney, Alessio Vagnoni, Navdeep S. Chandel, Joseph M. Bateman
bioRxiv 2022.09.22.509020; doi: https://doi.org/10.1101/2022.09.22.509020

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