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

Neurobiology of Disease
Daniela StrobbeA M Ghelli

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 penetranc...Continue Reading

Citations

Apr 2, 2020·Cells·Andrea Dalmao-FernándezMercedes Fernández-Moreno
May 27, 2020·Biochemical Society Transactions·Sophie L PenmanAmy E Chadwick
Feb 6, 2020·Human Molecular Genetics·Nicolás Gutiérrez CortésChristophe Rocher
Apr 4, 2021·Biomolecules·Alessandra Maresca, Valerio Carelli
Sep 7, 2021·Frontiers in Genetics·Samantha W JonesAna Alfirevic

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