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

• Published in: Neurobiology of disease Vol. 114; pp. 129 - 139
• Main Authors: Strobbe, Daniela, Caporali, Leonardo, Iommarini, Luisa, Maresca, Alessandra, Montopoli, Monica, Martinuzzi, Andrea, Achilli, Alessandro, Olivieri, Anna, Torroni, Antonio, Carelli, Valerio, Ghelli, Anna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2018; Elsevier
• Subjects: Cell Survival - drug effects; Cell Survival - genetics; Complex I; Cybrids; DNA, Mitochondrial - chemistry; DNA, Mitochondrial - genetics; Fibroblasts - drug effects; Fibroblasts - physiology; Genome, Mitochondrial - drug effects; Genome, Mitochondrial - genetics; Haplogroups; Haplotypes - drug effects; Haplotypes - genetics; Humans; Mitochondrial DNA; Oxygen Consumption - drug effects; Oxygen Consumption - physiology; Parkinson Disease, Secondary - chemically induced; Parkinson Disease, Secondary - genetics; Pesticides - toxicity; Phylogeny; Protein Structure, Secondary; Rotenone; Rotenone - toxicity; Haplogroups; Mitochondrial DNA; Complex I; Cybrids; Rotenone
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2018.02.010

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.
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•Sequence variation of mitochondrial DNA (haplogroups) is investigated as modifier factor in neurodegenerative diseases.•Haplogroup J1, which increases LHON penetrance, is the most sensitive to rotenone toxic effect in cells.•Haplogroup K1, associated with a protective role in PD, shows rotenone resistance and mitochondrial DNA copy number increase in cells.•Mitochondrial DNA haplogroups may influence disease predisposition or protection, sensitivity to environmental factors and longevity.