Journal News

JBC: What makes organelles connect?

Sasha Mushegian
December 01, 2017

Inside every cell is a complex infrastructure of organelles carrying out different functions. Organelles must exchange signals and materials to make the cell operate correctly. Researchers are using new technologies to see and understand the networks that connect these organelles, allowing them to build maps of the trade routes that exist within a cell. A recent article in the Journal of Biological Chemistry reports the use of an emerging method to identify proteins that allows two organelles, the mitochondria and the endoplasmic reticulum, to attach to each other.

Live-imaged HeLa cells with the endoplasmic reticulum labeled red and mitochondria labeled green.courtesy of Ginam Cho

Jeffrey Golden, a professor at Brigham and Women’s Hospital and Harvard Medical School, oversaw the work. “Think of (an organelle) like a ferry docking at one site, unloading and loading passengers and cars, and then going to another site and doing the same thing,” Golden said. “Their ability to dock, load and unload cargo requires guides or ramps of specific widths and heights that connect the boat and land, or they cannot freely load and unload.”

Contact points between the endoplasmic reticulum, or ER, and mitochondria are the “ramps” and “guides” that enable these contacts. They permit important activities like signaling, exchange of calcium and lipids, and control of mitochondrial physiology. Faulty connections between the ER and mitochondria have been implicated in several neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s disease. The proteins that connect and bridge the ER and mitochondria are well-studied in yeast, but the connections between these organelles in multicellular organisms like mammals are more complex and less understood.

Golden’s collaborator Ginam Cho and research fellow Il-Taeg Cho had the idea to search for proteins important for ER–mitochondrial contact using a method recently developed to show contact between proteins. The method takes advantage of an enzyme called ascorbate peroxidase, or APEX, which can attach biotin to proteins nearby. The team engineered cells to produce mitochondria that had APEX attached to their outer membranes and then added biotin to the cells for the APEX to use to label nearby proteins.

The team then isolated parts of the cell that contained the ER, purified those proteins that had biotin attached and identified the ones found in the ER using mass spectrometry. Because the APEX was attached to mitochondria, only those proteins that came into close proximity to the mitochondria could have had biotin attached. Thus, the biotin served as a kind of passport stamp that indicated which proteins had been involved in the ER-mitochondria contact.

“It was previously feasible to only look at one molecule at a time to assess what it interacted with,” Golden said. “The method we have used is more rapid and allows an unbiased look at a whole system and what’s happening at that organelle’s interface.”

Using this screening method, the researchers zeroed in on an ER protein called RTN1a, which previously was known to contribute to the ER’s shape. In follow-up experiments, they confirmed that this protein also helped mitochondria to attach to the ER.

This study raises the possibility that defects in RTN1a could contribute to the problems experienced by patients with neurodegenerative diseases, but the researchers won’t know for sure until they conduct additional experiments, including similar studies in neural cells.

Golden speculates that the proteins important for ER–mitochondrial contact might be different in different cell types.

“Does the liver use the same proteins to control these kinds of interactions that neural cells do? Is one (protein) more important for calcium exchange and another set of proteins more important for lipid exchange?” Golden asked. “I think there’s a lot of cell biology that we just don’t know and could be answered.” The team now is using the APEX-mass spectrometry method to compare proteins involved in ER–mitochondrial contacts between normal and patient-derived neural cells.

“There are a lot of interesting things we can do,” Il-Taeg Cho said.

Sasha Mushegian

Sasha Mushegian is a postdoctoral fellow at Georgetown University. Follow her on Twitter.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

Ocean virus hijacks carbon-storing bacteria
Journal News

Ocean virus hijacks carbon-storing bacteria

July 07, 2020

A Journal of Biological Chemistry paper reports that these minuscule interactions could have ripple effects on global carbon dioxide levels.

CRISPR nanoparticles are the next big hope in Alzheimer’s disease treatments
News

CRISPR nanoparticles are the next big hope in Alzheimer’s disease treatments

July 04, 2020

Nearly 6 million Americans live with Alzheimer’s disease without solid treatment options.

Summer food science
Stroopwafels

Summer food science

July 02, 2020

For those of you bound for a summertime holiday weekend, we dug into recent research on the yummy foods you might serve at a socially distant picnic.

How lipid droplets stay in shape
Journal News

How lipid droplets stay in shape

June 30, 2020

Andrew Greenberg and colleagues discovered that the protein perilipin is involved in storage and hydrolysis of neutral lipids within these key structures in cells.

The bat-virus détente
News

The bat-virus détente

June 28, 2020

Bats cope with myriad viruses, including the one causing Covid-19, with few ill effects. Scientists are probing their immune systems to fathom how they do it. The answers might help infected people, too.

Organizing fat: Mechanisms of creating and organizing cellular lipid stores
Lipid News

Organizing fat: Mechanisms of creating and organizing cellular lipid stores

June 23, 2020

Mike Henne, a cell biologist at UT Southwestern, summarizes recent findings about the highly regulated production and turnover of lipid droplets.