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Ant1 mutant mice bridge the mitochondrial and serotonergic dysfunctions in bipolar disorder

Molecular Psychiatry volume 25, pages 2203–2204 (2020)Cite this article

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In the issue of Molecular Psychiatry published on June 11, 2018, Kato and colleagues reported that by sequencing the mitochondrial adenine nucleotide translocator 1 (ANT1) in 324 probands of bipolar disorder (BD) pedigrees, two patients carrying heterozygous loss-of-function mutations were identified [1]. By engineering mice harboring Ant1 mutations only in the brain, hyperexcitability in dorsal raphe neurons along with enhanced serotonin turnover in the nucleus accumbens was evident, likely accounting for the selective diminution in delay discounting, a hallmark of BD. Mitochondria obtained from the brains of homozygous Ant1 cKO mice exhibited a decrease in calcium retention capacity (CRC) compared to heterozygous and wild-type mice.

On the basis of the results obtained from mitochondrial CRC, the authors suggested that the mitochondria of homozygous Ant1 cKO mice are vulnerable to opening of the permeability transition pore (PTP), a channel triggered by calcium allowing the passage of solutes and metabolites with a molecular weight of <1500 Da leading to mitochondrial demise [2]. According to the authors, the connection between Ant1 and PTP is based on the discovery of modulation of the latter by the former [3,4,5]. The importance of ‘mitochondrial dysfunction’ causing serotonergic hyperactivity is so central to the work by Kato and colleagues [1], that lead to the extrapolation that faulty mitochondria increase the risk of someone becoming a patient suffering from BD. This work sits atop mounting evidence indicating that mitochondrial abnormalities are plausible risk factors of psychiatric disorders, including bipolar disorder [6]. Most importantly though, Kato and colleagues identify a molecule (Ant1) solely responsible for disease manifestation, thus revealing a potential target amenable to therapeutic manipulation.

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References

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  1. Department of Medical Biochemistry, Semmelweis University, Budapest, Tuzolto st. 37-47, 1094, Hungary

    Christos Chinopoulos

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Correspondence to Christos Chinopoulos.

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Chinopoulos, C. Ant1 mutant mice bridge the mitochondrial and serotonergic dysfunctions in bipolar disorder. Mol Psychiatry 25, 2203–2204 (2020). https://doi.org/10.1038/s41380-018-0251-x

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