In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions

S. R. Burstein, F. Valsecchi, H. Kawamata, M. Bourens, R. Zeng, A. Zuberi, T. A. Milner, S. M. Cloonan, C. Lutz, Antonio Barrientos, G. Manfredi

Research output: Contribution to journalArticle

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Abstract

Mutations in coiled-coil-helix-coiled-coil-helix-domain containing 10 (CHCHD10), a mitochondrial twin CX9C protein whose function is still unknown, cause myopathy, motor neuron disease, frontotemporal dementia, and Parkinson's disease. Here, we investigate CHCHD10 topology and its protein interactome, as well as the effects of CHCHD10 depletion or expression of disease-associated mutations in wild-type cells. We find that CHCHD10 associates with membranes in the mitochondrial intermembrane space, where it interacts with a closely related protein, CHCHD2. Furthermore, both CHCHD10 and CHCHD2 interact with p32/GC1QR, a protein with various intra and extra-mitochondrial functions. CHCHD10 and CHCHD2 have short half-lives, suggesting regulatory rather than structural functions. Cell lines with CHCHD10 knockdown do not display bioenergetic defects, but, unexpectedly, accumulate excessive intramitochondrial iron. In mice, CHCHD10 is expressed in many tissues, most abundantly in heart, skeletal muscle, liver, and in specific CNS regions, notably the dopaminergic neurons of the substantia nigra and spinal cord neurons, which is consistent with the pathology associated with CHCHD10 mutations. Homozygote CHCHD10 knockout mice are viable, have no gross phenotypes, no bioenergetic defects or ultrastructural mitochondrial abnormalities in brain, heart or skeletal muscle, indicating that functional redundancy or compensatory mechanisms for CHCHD10 loss occur in vivo. Instead, cells expressing S59L or R15L mutant versions of CHCHD10, but not WT, have impaired mitochondrial energy metabolism. Taken together, the evidence obtained from our in vitro and in vivo studies suggest that CHCHD10 mutants cause disease through a gain of toxic function mechanism, rather than a loss of function.

Original languageEnglish (US)
Pages (from-to)160-177
Number of pages18
JournalHuman Molecular Genetics
Volume27
Issue number1
DOIs
StatePublished - Jan 1 2018

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Frontotemporal Lobar Degeneration
Mitochondrial Proteins
Energy Metabolism
Mutation
Myocardium
Skeletal Muscle
Proteins
Frontotemporal Dementia
Motor Neuron Disease
Poisons
Dopaminergic Neurons
Homozygote
Mitochondrial Membranes
Muscular Diseases
Substantia Nigra
Knockout Mice
Parkinson Disease
Spinal Cord
Iron
Pathology

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Burstein, S. R., Valsecchi, F., Kawamata, H., Bourens, M., Zeng, R., Zuberi, A., ... Manfredi, G. (2018). In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions. Human Molecular Genetics, 27(1), 160-177. https://doi.org/10.1093/hmg/ddx397

In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions. / Burstein, S. R.; Valsecchi, F.; Kawamata, H.; Bourens, M.; Zeng, R.; Zuberi, A.; Milner, T. A.; Cloonan, S. M.; Lutz, C.; Barrientos, Antonio; Manfredi, G.

In: Human Molecular Genetics, Vol. 27, No. 1, 01.01.2018, p. 160-177.

Research output: Contribution to journalArticle

Burstein, SR, Valsecchi, F, Kawamata, H, Bourens, M, Zeng, R, Zuberi, A, Milner, TA, Cloonan, SM, Lutz, C, Barrientos, A & Manfredi, G 2018, 'In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions', Human Molecular Genetics, vol. 27, no. 1, pp. 160-177. https://doi.org/10.1093/hmg/ddx397
Burstein, S. R. ; Valsecchi, F. ; Kawamata, H. ; Bourens, M. ; Zeng, R. ; Zuberi, A. ; Milner, T. A. ; Cloonan, S. M. ; Lutz, C. ; Barrientos, Antonio ; Manfredi, G. / In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 1. pp. 160-177.
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