title: Yeast mitochondrial protein-protein interactions reveal diverse complexes and disease-relevant functional relationships.
abstract: Although detailed, focused, and mechanistic analyses of associations among mitochondrial proteins (MPs) have identified their importance in varied biological processes, a systematic understanding of how MPs function in concert both with one another and with extra-mitochondrial proteins remains incomplete. Consequently, many questions regarding the role of mitochondrial dysfunction in the development of human disease remain unanswered. To address this, we compiled all existing mitochondrial physical interaction data for over 1200 experimentally defined yeast MPs and, through bioinformatic analysis, identified hundreds of heteromeric MP complexes having extensive associations both within and outside the mitochondria. We provide support for these complexes through structure prediction analysis, morphological comparisons of deletion strains, and protein co-immunoprecipitation. The integration of these MP complexes with reported genetic interaction data reveals substantial crosstalk between MPs and non-MPs and identifies novel factors in endoplasmic reticulum-mitochondrial organization, membrane structure, and mitochondrial lipid homeostasis. More than one-third of these MP complexes are conserved in humans, with many containing members linked to clinical pathologies, enabling us to identify genes with putative disease function through guilt-by-association. Although still remaining incomplete, existing mitochondrial interaction data suggests that the relevant molecular machinery is modular, yet highly integrated with non-mitochondrial processes.
authors.affiliation: Terrence Donnelly Centre, University of Toronto , Toronto, Ontario M5S 3E1, Canada.
authors.forename: Ke
authors.initials: K
authors.lastname: Jin
authors.forename: Gabriel
authors.initials: G
authors.lastname: Musso
authors.forename: James
authors.initials: J
authors.lastname: Vlasblom
authors.forename: Matthew
authors.initials: M
authors.lastname: Jessulat
authors.forename: Viktor
authors.initials: V
authors.lastname: Deineko
authors.forename: Jacopo
authors.initials: J
authors.lastname: Negroni
authors.forename: Roberto
authors.initials: R
authors.lastname: Mosca
authors.forename: Ramy
authors.initials: R
authors.lastname: Malty
authors.forename: Diem-Hang
authors.initials: DH
authors.lastname: Nguyen-Tran
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aoki
authors.forename: Zoran
authors.initials: Z
authors.lastname: Minic
authors.forename: Tanya
authors.initials: T
authors.lastname: Freywald
authors.forename: Sadhna
authors.initials: S
authors.lastname: Phanse
authors.forename: Qian
authors.initials: Q
authors.lastname: Xiang
authors.forename: Andrew
authors.initials: A
authors.lastname: Freywald
authors.forename: Patrick
authors.initials: P
authors.lastname: Aloy
authors.forename: Zhaolei
authors.initials: Z
authors.lastname: Zhang
authors.forename: Mohan
authors.initials: M
authors.lastname: Babu
mesh_terms: D024101:Mitochondrial Proteins / Q000378:metabolism*; D011485:Protein Binding; D015003:Yeasts / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins
keywords: Budding yeast; disease; genetic interactions; mass spectrometry; mitochondria; network; pathway crosstalk; protein complex; protein interactions