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

Lucy Granat; Daniel Ranson; Debbra Knorr; Emma Hamer; Ram Prosad  Chakrabarty; Francesca Mattedi; Laura Fort-Aznar; Frank Hirth; Sean Sweeney; Alessio Vagnoni; Navdeep S. Chandel; Joseph Bateman

doi:https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010793

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

Lucy Granat, Daniel Ranson, Debbra Knorr, Emma Hamer, Ram Prosad Chakrabarty, Francesca Mattedi, Laura Fort-Aznar, Frank Hirth, Sean Sweeney, Alessio Vagnoni, Navdeep S. Chandel, Joseph Bateman

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available treatments. To better understand the underlying mechanisms, we modelled complex I deficiency in Drosophila using knockdown of 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 does not affect ATP levels but leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Multi-omic analysis shows that complex I deficiency dramatically perturbs mitochondrial metabolism in the brain. We find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1, which reinstates mitochondrial NADH oxidation but not ATP production, restores levels of several key metabolites in the brain in complex I deficiency. Remarkably, NDI1 expression also reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Together, these data show that metabolic disruption due to loss of neuronal NADH dehydrogenase activity cause UPR activation and drive pathogenesis in complex I deficiency.

Original language	English
Article number	e1010793
Journal	PLoS genetics
Volume	19
Issue number	7
DOIs	https://doi.org/https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010793 https://doi.org/10.1371/journal.pgen.1010793
Publication status	Published - 3 Jul 2023

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Granat, L., Ranson, D., Knorr, D., Hamer, E., Chakrabarty, R. P., Mattedi, F., Fort-Aznar, L., Hirth, F., Sweeney, S., Vagnoni, A., Chandel, N. S., & Bateman, J. (2023). Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency. PLoS genetics, 19(7), Article e1010793. https://doi.org/https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010793, https://doi.org/10.1371/journal.pgen.1010793

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title = "Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency",

abstract = "Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available treatments. To better understand the underlying mechanisms, we modelled complex I deficiency in Drosophila using knockdown of 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 does not affect ATP levels but leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Multi-omic analysis shows that complex I deficiency dramatically perturbs mitochondrial metabolism in the brain. We find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1, which reinstates mitochondrial NADH oxidation but not ATP production, restores levels of several key metabolites in the brain in complex I deficiency. Remarkably, NDI1 expression also reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Together, these data show that metabolic disruption due to loss of neuronal NADH dehydrogenase activity cause UPR activation and drive pathogenesis in complex I deficiency. ",

author = "Lucy Granat and Daniel Ranson and Debbra Knorr and Emma Hamer and Chakrabarty, {Ram Prosad} and Francesca Mattedi and Laura Fort-Aznar and Frank Hirth and Sean Sweeney and Alessio Vagnoni and Chandel, {Navdeep S.} and Joseph Bateman",

note = "Publisher Copyright: Copyright: {\textcopyright} 2023 Granat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2023",

month = jul,

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doi = "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010793",

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Granat, L , Ranson, D , Knorr, D , Hamer, E, Chakrabarty, RP, Mattedi, F, Fort-Aznar, L, Hirth, F, Sweeney, S, Vagnoni, A, Chandel, NS & Bateman, J 2023, 'Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency', PLoS genetics, vol. 19, no. 7, e1010793. https://doi.org/https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010793, https://doi.org/10.1371/journal.pgen.1010793

TY - JOUR

T1 - Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency

AU - Granat, Lucy

AU - Ranson, Daniel

AU - Knorr, Debbra

AU - Hamer, Emma

AU - Chakrabarty, Ram Prosad

AU - Mattedi, Francesca

AU - Fort-Aznar, Laura

AU - Hirth, Frank

AU - Sweeney, Sean

AU - Vagnoni, Alessio

AU - Chandel, Navdeep S.

AU - Bateman, Joseph

N1 - Publisher Copyright: Copyright: © 2023 Granat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2023/7/3

Y1 - 2023/7/3

N2 - Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available treatments. To better understand the underlying mechanisms, we modelled complex I deficiency in Drosophila using knockdown of 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 does not affect ATP levels but leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Multi-omic analysis shows that complex I deficiency dramatically perturbs mitochondrial metabolism in the brain. We find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1, which reinstates mitochondrial NADH oxidation but not ATP production, restores levels of several key metabolites in the brain in complex I deficiency. Remarkably, NDI1 expression also reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Together, these data show that metabolic disruption due to loss of neuronal NADH dehydrogenase activity cause UPR activation and drive pathogenesis in complex I deficiency.

AB - Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available treatments. To better understand the underlying mechanisms, we modelled complex I deficiency in Drosophila using knockdown of 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 does not affect ATP levels but leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Multi-omic analysis shows that complex I deficiency dramatically perturbs mitochondrial metabolism in the brain. We find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1, which reinstates mitochondrial NADH oxidation but not ATP production, restores levels of several key metabolites in the brain in complex I deficiency. Remarkably, NDI1 expression also reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Together, these data show that metabolic disruption due to loss of neuronal NADH dehydrogenase activity cause UPR activation and drive pathogenesis in complex I deficiency.

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U2 - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010793

DO - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010793

M3 - Article

SN - 1553-7390

VL - 19

JO - PLoS genetics

JF - PLoS genetics

IS - 7

M1 - e1010793

ER -

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

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