Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases
There is growing evidence that the sequence variation of mitochondrial DNA (mtDNA), which clusters in population- and/or geographic-specific haplogroups, may result in functional effects that, in turn, become relevant in disease predisposition or protection, interaction with environmental factors an...
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doaj-74a86fe31c9448708bfdbbc605ee1c3d2021-03-22T12:46:18ZengElsevierNeurobiology of Disease1095-953X2018-06-01114129139Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseasesDaniela Strobbe0Leonardo Caporali1Luisa Iommarini2Alessandra Maresca3Monica Montopoli4Andrea Martinuzzi5Alessandro Achilli6Anna Olivieri7Antonio Torroni8Valerio Carelli9Anna Ghelli10Department of Pharmaceutical and Pharmacological Sciences, School of Medicine-University of Padua, ItalyIRCCS Institute of Neurological Sciences of Bologna, Bologna, ItalyDepartment of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, ItalyIRCCS Institute of Neurological Sciences of Bologna, Bologna, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, School of Medicine-University of Padua, ItalyIRCCS “E. Medea” Scientific Institute Conegliano-Pieve di Soligo Research Center, Pieve di Soligo, ItalyDipartimento di Biologia e Biotecnologie “L. Spallanzani”, University of Pavia, Pavia, ItalyDipartimento di Biologia e Biotecnologie “L. Spallanzani”, University of Pavia, Pavia, ItalyDipartimento di Biologia e Biotecnologie “L. Spallanzani”, University of Pavia, Pavia, ItalyIRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy; Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy; Correspondence to: V. Carelli, IRCCS Institute of Neurological Sciences of Bologna (ISNB), Bellaria Hospital, Neurology Unit, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Altura 3, 40139 Bologna, Italy.Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy; Correspondence to: A. Ghelli, Dipartimento di Farmacia e Biotecnologie (FABIT), Università degli studi di Bologna, Via Selmi 3, 40126 Bologna, Italy.There is growing evidence that the sequence variation of mitochondrial DNA (mtDNA), which clusters in population- and/or geographic-specific haplogroups, may result in functional effects that, in turn, become relevant in disease predisposition or protection, interaction with environmental factors and ultimately in modulating longevity.To unravel functional differences between mtDNA haplogroups we here employed transmitochondrial cytoplasmic hybrid cells (cybrids) grown in galactose medium, a culture condition that forces oxidative phosphorylation, and in the presence of rotenone, the classic inhibitor of respiratory Complex I. Under this experimental paradigm we assessed functional parameters such as cell viability and respiration, ATP synthesis, reactive oxygen species production and mtDNA copy number.Our analyses show that haplogroup J1, which is common in western Eurasian populations, is the most sensitive to rotenone, whereas K1 mitogenomes orchestrate the best compensation, possibly because of the haplogroup-specific missense variants impinging on Complex I function. Remarkably, haplogroups J1 and K1 fit the genetic associations previously established with Leber's hereditary optic neuropathy (LHON) for J1, as a penetrance enhancer, and with Parkinson's disease (PD) for K1, as a protective background.Our findings provide functional evidences supporting previous well-established genetic associations of specific haplogroups with two neurodegenerative pathologies, LHON and PD. Our experimental paradigm is instrumental to highlighting the subtle functional differences characterizing mtDNA haplogroups, which will be increasingly needed to dissect the role of mtDNA genetic variation in health, disease and longevity.http://www.sciencedirect.com/science/article/pii/S0969996118300421RotenoneCybridsMitochondrial DNAHaplogroupsComplex I |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Daniela Strobbe Leonardo Caporali Luisa Iommarini Alessandra Maresca Monica Montopoli Andrea Martinuzzi Alessandro Achilli Anna Olivieri Antonio Torroni Valerio Carelli Anna Ghelli |
spellingShingle |
Daniela Strobbe Leonardo Caporali Luisa Iommarini Alessandra Maresca Monica Montopoli Andrea Martinuzzi Alessandro Achilli Anna Olivieri Antonio Torroni Valerio Carelli Anna Ghelli Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases Neurobiology of Disease Rotenone Cybrids Mitochondrial DNA Haplogroups Complex I |
author_facet |
Daniela Strobbe Leonardo Caporali Luisa Iommarini Alessandra Maresca Monica Montopoli Andrea Martinuzzi Alessandro Achilli Anna Olivieri Antonio Torroni Valerio Carelli Anna Ghelli |
author_sort |
Daniela Strobbe |
title |
Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases |
title_short |
Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases |
title_full |
Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases |
title_fullStr |
Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases |
title_full_unstemmed |
Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases |
title_sort |
haplogroup j mitogenomes are the most sensitive to the pesticide rotenone: relevance for human diseases |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2018-06-01 |
description |
There is growing evidence that the sequence variation of mitochondrial DNA (mtDNA), which clusters in population- and/or geographic-specific haplogroups, may result in functional effects that, in turn, become relevant in disease predisposition or protection, interaction with environmental factors and ultimately in modulating longevity.To unravel functional differences between mtDNA haplogroups we here employed transmitochondrial cytoplasmic hybrid cells (cybrids) grown in galactose medium, a culture condition that forces oxidative phosphorylation, and in the presence of rotenone, the classic inhibitor of respiratory Complex I. Under this experimental paradigm we assessed functional parameters such as cell viability and respiration, ATP synthesis, reactive oxygen species production and mtDNA copy number.Our analyses show that haplogroup J1, which is common in western Eurasian populations, is the most sensitive to rotenone, whereas K1 mitogenomes orchestrate the best compensation, possibly because of the haplogroup-specific missense variants impinging on Complex I function. Remarkably, haplogroups J1 and K1 fit the genetic associations previously established with Leber's hereditary optic neuropathy (LHON) for J1, as a penetrance enhancer, and with Parkinson's disease (PD) for K1, as a protective background.Our findings provide functional evidences supporting previous well-established genetic associations of specific haplogroups with two neurodegenerative pathologies, LHON and PD. Our experimental paradigm is instrumental to highlighting the subtle functional differences characterizing mtDNA haplogroups, which will be increasingly needed to dissect the role of mtDNA genetic variation in health, disease and longevity. |
topic |
Rotenone Cybrids Mitochondrial DNA Haplogroups Complex I |
url |
http://www.sciencedirect.com/science/article/pii/S0969996118300421 |
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