Yeast Mitochondrial Protein–Protein Interactions Reveal Diverse Complexes and Disease-Relevant Functional Relationships

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.