Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration

Abstract Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson’s disease, Huntington’s disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1-methyl-4-phenylpyridinium (MPP+) and 3-nitrop...

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Autores principales:	Sathyanarayanan Ranganayaki, Neema Jamshidi, Mohamad Aiyaz, Santhosh-Kumar Rashmi, Narayanappa Gayathri, Pulleri Kandi Harsha, Balasundaram Padmanabhan, Muchukunte Mukunda Srinivas Bharath
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/509a1a41dea843ee9b5ffad39e1ca7da
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spelling	oai:doaj.org-article:509a1a41dea843ee9b5ffad39e1ca7da2021-12-02T14:01:33ZInhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration10.1038/s41598-020-79339-22045-2322https://doaj.org/article/509a1a41dea843ee9b5ffad39e1ca7da2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79339-2https://doaj.org/toc/2045-2322Abstract Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson’s disease, Huntington’s disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1-methyl-4-phenylpyridinium (MPP+) and 3-nitropropionic acid (3-NPA) respectively, induced degenerative changes noted in such neurodegenerative diseases. We aimed to unravel the down-stream pathways associated with CII inhibition and compared with CI inhibition and the Manganese (Mn) neurotoxicity. Genome-wide transcriptomics of N27 neuronal cells exposed to 3-NPA, compared with MPP+ and Mn revealed varied transcriptomic profile. Along with mitochondrial and synaptic pathways, Autophagy was the predominant pathway differentially regulated in the 3-NPA model with implications for neuronal survival. This pathway was unique to 3-NPA, as substantiated by in silico modelling of the three toxins. Morphological and biochemical validation of autophagy markers in the cell model of 3-NPA revealed incomplete autophagy mediated by mechanistic Target of Rapamycin Complex 2 (mTORC2) pathway. Interestingly, Brain Derived Neurotrophic Factor (BDNF), which was elevated in the 3-NPA model could confer neuroprotection against 3-NPA. We propose that, different downstream events are activated upon neurotoxin-dependent CII inhibition compared to other neurotoxins, with implications for movement disorders and regulation of autophagy could potentially offer neuroprotection.Sathyanarayanan RanganayakiNeema JamshidiMohamad AiyazSanthosh-Kumar RashmiNarayanappa GayathriPulleri Kandi HarshaBalasundaram PadmanabhanMuchukunte Mukunda Srinivas BharathNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-23 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sathyanarayanan Ranganayaki Neema Jamshidi Mohamad Aiyaz Santhosh-Kumar Rashmi Narayanappa Gayathri Pulleri Kandi Harsha Balasundaram Padmanabhan Muchukunte Mukunda Srinivas Bharath Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration
description	Abstract Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson’s disease, Huntington’s disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1-methyl-4-phenylpyridinium (MPP+) and 3-nitropropionic acid (3-NPA) respectively, induced degenerative changes noted in such neurodegenerative diseases. We aimed to unravel the down-stream pathways associated with CII inhibition and compared with CI inhibition and the Manganese (Mn) neurotoxicity. Genome-wide transcriptomics of N27 neuronal cells exposed to 3-NPA, compared with MPP+ and Mn revealed varied transcriptomic profile. Along with mitochondrial and synaptic pathways, Autophagy was the predominant pathway differentially regulated in the 3-NPA model with implications for neuronal survival. This pathway was unique to 3-NPA, as substantiated by in silico modelling of the three toxins. Morphological and biochemical validation of autophagy markers in the cell model of 3-NPA revealed incomplete autophagy mediated by mechanistic Target of Rapamycin Complex 2 (mTORC2) pathway. Interestingly, Brain Derived Neurotrophic Factor (BDNF), which was elevated in the 3-NPA model could confer neuroprotection against 3-NPA. We propose that, different downstream events are activated upon neurotoxin-dependent CII inhibition compared to other neurotoxins, with implications for movement disorders and regulation of autophagy could potentially offer neuroprotection.
format	article
author	Sathyanarayanan Ranganayaki Neema Jamshidi Mohamad Aiyaz Santhosh-Kumar Rashmi Narayanappa Gayathri Pulleri Kandi Harsha Balasundaram Padmanabhan Muchukunte Mukunda Srinivas Bharath
author_facet	Sathyanarayanan Ranganayaki Neema Jamshidi Mohamad Aiyaz Santhosh-Kumar Rashmi Narayanappa Gayathri Pulleri Kandi Harsha Balasundaram Padmanabhan Muchukunte Mukunda Srinivas Bharath
author_sort	Sathyanarayanan Ranganayaki
title	Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration
title_short	Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration
title_full	Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration
title_fullStr	Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration
title_full_unstemmed	Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration
title_sort	inhibition of mitochondrial complex ii in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/509a1a41dea843ee9b5ffad39e1ca7da
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Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration

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