Loss of Parkinson’s disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c

Hongrui Meng, Chikara Yamashita, Kahori Shiba-Fukushima, Tsuyoshi Inoshita, Manabu Funayama, Shigeto Sato, Tomohisa Hatta, Tohru Natsume, Masataka Umitsu, Junichi Takagi, Yuzuru Imai () and Nobutaka Hattori ()
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Hongrui Meng: Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine
Chikara Yamashita: Juntendo University Graduate School of Medicine
Kahori Shiba-Fukushima: Juntendo University Graduate School of Medicine
Tsuyoshi Inoshita: Juntendo University Graduate School of Medicine
Manabu Funayama: Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine
Shigeto Sato: Juntendo University Graduate School of Medicine
Tomohisa Hatta: Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology
Tohru Natsume: Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology
Masataka Umitsu: Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University
Junichi Takagi: Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University
Yuzuru Imai: Juntendo University Graduate School of Medicine
Nobutaka Hattori: Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract Mutations in CHCHD2 have been identified in some Parkinson’s disease (PD) cases. To understand the physiological and pathological roles of CHCHD2, we manipulated the expression of CHCHD2 in Drosophila and mammalian cells. The loss of CHCHD2 in Drosophila causes abnormal matrix structures and impaired oxygen respiration in mitochondria, leading to oxidative stress, dopaminergic neuron loss and motor dysfunction with age. These PD-associated phenotypes are rescued by the overexpression of the translation inhibitor 4E-BP and by the introduction of human CHCHD2 but not its PD-associated mutants. CHCHD2 is upregulated by various mitochondrial stresses, including the destabilization of mitochondrial genomes and unfolded protein stress, in Drosophila. CHCHD2 binds to cytochrome c along with a member of the Bax inhibitor-1 superfamily, MICS1, and modulated cell death signalling, suggesting that CHCHD2 dynamically regulates the functions of cytochrome c in both oxidative phosphorylation and cell death in response to mitochondrial stress.

Date: 2017
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DOI: 10.1038/ncomms15500

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