Cnm1 mediates nucleus–mitochondria contact site formation in response to phospholipid levels

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.

Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

“…Mitochondria are also known to make contact with the nuclear membrane, forming nucleus-associated mitochondria (NAM; Desai et al, 2020 ; Eisenberg-Bord et al, 2021 ). As a part of the retrograde signaling response that links mitochondria homeostasis to the activation of adaptative response from transcriptional control within the nucleus, NAM participate in the regulation of many cellular processes such as cell proliferation, stress adaptation, metabolic switch, autophagy, and mitochondrial biogenesis ( Strobbe et al, 2021 ).…”

“…This might suggest a specific removal of a subset of mitochondrial population, maintaining those in proximity to the nucleus despite the total reduced number of these structures. NAM were first described 50 years ago ( McCully and Robinow, 1971 ; Franke et al, 1973 ) and they were speculated to participate in several functions as yeast fission and heme and phospholipid traffic in yeast ( McCully and Robinow, 1971 ; Franke et al, 1973 ; Martinez-Guzman et al, 2020 ; Eisenberg-Bord et al, 2021 ). They are described to regulate the localization of transcription factors and consequently controls cellular adaptation to stress by retro-communicating with the nucleus ( Jazwinski, 2014 ; Desai et al, 2020 ; Strobbe et al, 2021 ).…”

Mitochondrialand: What Will Come Next?

“…Very recently, Eisenberg-Bord et al . 2 identified, in Saccharomyces cerevisiae , the uncharacterized protein Ybr063c (named Cnm1, contact nucleus mitochondria 1) as the tethering molecule between mitochondria and the nuclear membrane. Cnm1 is an integral nuclear membrane protein which needs the outer mitochondrial membrane protein Tom70 to tether mitochondria to the nucleus.…”

The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology

“…While many types of mitochondrial contacts have been documented [e.g. lysosomes ( Peng et al, 2020 ), the nucleus ( Eisenberg-Bord et al, 2021 ), lipid droplets ( Kilwein and Welte, 2019 ), the plasma membrane ( Meschede et al, 2020 ) and peroxisomes ( Sargsyan and Thoms, 2020 )], the most well-studied mitochondrial contact is with the endoplasmic reticulum (ER), which we will refer to here as mitochondrial-ER contacts (MERCs).…”