Abstract
Mitochondrial functions are tightly regulated by nuclear activity, requiring extensive communication between these organelles. One way by which organelles can communicate is through contact sites, areas of close apposition held together by tethering molecules. While many contacts have been characterized in yeast, the contact between the nucleus and mitochondria was not previously identified. Using fluorescence and electron microscopy in S. cerevisiae, we demonstrate specific areas of contact between the two organelles. Using a high-throughput screen, we uncover a role for the uncharacterized protein Ybr063c, which we have named Cnm1 (contact nucleus mitochondria 1), as a molecular tether on the nuclear membrane. We show that Cnm1 mediates contact by interacting with Tom70 on mitochondria. Moreover, Cnm1 abundance is regulated by phosphatidylcholine, enabling the coupling of phospholipid homeostasis with contact extent. The discovery of a molecular mechanism that allows mitochondrial crosstalk with the nucleus sets the ground for better understanding of mitochondrial functions in health and disease.
Highlights
During the evolution of eukaryotes, an α-proteobacterium integrated into its archaeal host cell, giving rise to the mitochondrial organelle (Dyall et al, 2004)
Mitochondria form ER–mitochondria encounter structure (ERMES)-independent contact sites with the nuclear ER EM images of yeast cells demonstrates three distinct types of contact sites between mitochondria and the ER: those with cortical ER, those with tubular ER, and some with the nuclear ER
At contact sites, where the two membranes are in proximity, the Venus fragments interact, the full Venus protein is formed, and the resulting fluorescence enables imaging by a fluorescent microscope
Summary
During the evolution of eukaryotes, an α-proteobacterium integrated into its archaeal host cell, giving rise to the mitochondrial organelle (Dyall et al, 2004). As mitochondrial genes transferred to the nuclear genome, the response to mitochondrial stress became nuclear transcribed, and mitochondria number and function had to become coordinated with cellular needs and cell division. This increased dependence on the nucleus required that the two organelles evolve methods of communication. The importance of this communication is evident by how its breakdown contributes to a number of diseases, such as various forms of cancer (Mello et al, 2019; Xia et al, 2019; Yi, 2019), fatty liver disease (Yi, 2019), insulin resistance and obesity (Lee et al, 2015), and physiological conditions such as aging (Mohrin et al, 2015; Reynolds et al, 2020). More direct forms of communication between the two organelles, such as through contact sites, were less explored
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