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Unravelling the Effects of the Mutation m.3571insC/MT-ND1 on Respiratory Complexes Structural Organization

Iommarini, Luisa, Ghelli, Anna, Tropeano, Concetta, Kurelac, Ivana, Leone, Giulia, Vidoni, Sara, Lombes, Anne, Zeviani, Massimo, Gasparre, Giuseppe, Porcelli, Anna·2018·International Journal of Molecular Sciences
DOI 10.3390/ijms19030764PMC PMC5877625
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Abstract

Mammalian respiratory complex I (CI) biogenesis requires both nuclear and mitochondria-encoded proteins and is mostly organized in respiratory supercomplexes. Among the CI proteins encoded by the mitochondrial DNA, NADH-ubiquinone oxidoreductase chain 1 (ND1) is a core subunit, evolutionary conserved from bacteria to mammals. Recently, ND1 has been recognized as a pivotal subunit in maintaining the structural and functional interaction among the hydrophilic and hydrophobic CI arms. A critical role of human ND1 both in CI biogenesis and in the dynamic organization of supercomplexes has been depicted, although the proof of concept is still missing and the critical amount of ND1 protein necessary for a proper assembly of both CI and supercomplexes is not defined. By exploiting a unique model in which human ND1 is allotopically re-expressed in cells lacking the endogenous protein, we demonstrated that the lack of this protein induces a stall in the multi-step process of CI biogenesis, as well as the alteration of supramolecular organization of respiratory complexes. We also defined a mutation threshold for the m.3571insC truncative mutation in mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1), below which CI and its supramolecular organization is recovered, strengthening the notion that a certain amount of human ND1 is required for CI and supercomplexes biogenesis.

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  • Protein import and complex incorporation of oND1 were notably more robust when expressed in ND1 cybrids with partial reversion of the mutation (ND1m/+) than in homoplasmic ND1m cells.

    “we also found protein import and complex incorporation to be notably more robust when expressed in ND1 cybrids with partial reversion of the mutation (ND1m/+), that is, some wild-type ND1 present [34].”

    From Codon optimization is an essential parameter for the efficient allotopic expression of mtDNA genes (2020) · cites this paper as [34]

  • In the absence of wild-type ND1, Complex I fails to assemble, resulting in impaired oxidative metabolism and failure to grow in galactose media.

    “In the absence of wild-type ND1, Complex I fails to assemble, resulting in impaired oxidative metabolism and failure to grow in galactose media [34,80].”

    From Codon optimization is an essential parameter for the efficient allotopic expression of mtDNA genes (2020) · cites this paper as [34]

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Metadata

Authors
Iommarini, L., Ghelli, A., Tropeano, C., Kurelac, I., Leone, G., Vidoni, S., Lombes, A., Zeviani, M., Gasparre, G., & Porcelli, A.
Affiliations
  • Dipartimento di Farmacia e Biotecnologie (FABIT), Università di Bologna, Via Francesco Selmi 3, 40126 Bologna, Italy
  • Dipartimento Scienze Mediche e Chirurgiche (DIMEC), U.O. Genetica Medica, Pol. Universitario S. Orsola-Malpighi, Università di Bologna, via Massarenti 9, 40138 Bologna, Italy
  • Medical Research Council, Mitochondrial Biology Unit, Cambridge CB2 0XY, UK
  • Inserm U1016, Institut Cochin, F-75014 Paris, France
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2018-03-07
Volume
19
Issue
3
Pages
764
ISSN
1422-0067
DOI
10.3390/ijms19030764
PMC
PMC5877625
Cited by
16
References
2
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • FP7 People: Marie-Curie Actions (MEET-317433)
  • Associazione Italiana per la Ricerca sul Cancro (JANEUTICS - IG14242)
  • Centro Studi della Barbariga

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