Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases

Daniela Strobbe, Leonardo Caporali, Luisa Iommarini, Alessandra Maresca, Monica Montopoli, Andrea Martinuzzi, Alessandro Achilli, Anna Olivieri, Antonio Torroni, Valerio Carelli, Anna Ghelli

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)129-139
Number of pages11
JournalNeurobiology of Disease
Volume114
DOIs
Publication statusPublished - Jun 2018

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Rotenone
Mitochondrial DNA
Pesticides
Leber's Hereditary Optic Atrophy
Parkinson Disease
Cell Respiration
Electron Transport Complex I
Penetrance
Hybrid Cells
Oxidative Phosphorylation
Galactose
Population
Culture Media
Reactive Oxygen Species
Cell Survival
Adenosine Triphosphate
Pathology
Health

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Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone : Relevance for human diseases. / Strobbe, Daniela; Caporali, Leonardo; Iommarini, Luisa; Maresca, Alessandra; Montopoli, Monica; Martinuzzi, Andrea; Achilli, Alessandro; Olivieri, Anna; Torroni, Antonio; Carelli, Valerio; Ghelli, Anna.

In: Neurobiology of Disease, Vol. 114, 06.2018, p. 129-139.

Research output: Contribution to journalArticle

Strobbe, D, Caporali, L, Iommarini, L, Maresca, A, Montopoli, M, Martinuzzi, A, Achilli, A, Olivieri, A, Torroni, A, Carelli, V & Ghelli, A 2018, 'Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases', Neurobiology of Disease, vol. 114, pp. 129-139. https://doi.org/10.1016/j.nbd.2018.02.010
Strobbe, Daniela ; Caporali, Leonardo ; Iommarini, Luisa ; Maresca, Alessandra ; Montopoli, Monica ; Martinuzzi, Andrea ; Achilli, Alessandro ; Olivieri, Anna ; Torroni, Antonio ; Carelli, Valerio ; Ghelli, Anna. / Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone : Relevance for human diseases. In: Neurobiology of Disease. 2018 ; Vol. 114. pp. 129-139.
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