CRISPR interference screening reveals mitochondrial door linked to Alzheimer's, cancer

By Nick Paul Taylor, The Science Advisory Board contributing writer

October 21, 2022 -- Using CRISPR interference screening, scientists at the nonprofit research center the Whitehead Institute have uncovered the gene that serves as a doorway to the mitochondrial membrane, providing a molecular basis for understanding its role in cancer and Alzheimer's disease.

Earlier work revealed that the removal of the protein expressed by the gene mitochondrial carrier homolog 2 (MTCH2) affects a range of processes in the cell, including pathways involved in diseases such as cancer and Alzheimer's. However, the mechanisms through which MTCH2 exerted its effects on the cell were unknown.

Whitehead researchers hit upon a solution to the mystery when they tried to show how proteins from the cytoplasm are inserted into the outer membranes of mitochondria. Proteins on the outer mitochondrial membrane allow the organelle to communicate with the rest of the cell and play a role in immune function and apoptosis. As with MTCH2, the mechanism used to insert proteins into the membrane was unknown.

Writing in an October 20 article in the journal Science, the Whitehead scientists describe how CRISPR interference screening cleared up both of the mysteries. The CRISPR screen enabled the team to systematically remove genes and analyze what happened. After removing MTCH2, the researchers saw a decrease in protein in the mitochondrial membrane, leading them to speculate that the gene acts as a doorway to the organelle.

In confirmatory experiments, the researchers saw that MTCH2 was needed for tail-anchored membrane proteins to move from the cytoplasm into the mitochondrial membrane. Then, the scientists predicted the structure of the protein using AlphaFold, the artificial intelligence (AI) system that DeepMind, a sibling company of Google, created with EMBL-EBI. The AI found that the protein is hydrophobic, enabling insertion into the oily membrane, but has a single hydrophilic groove that could allow other proteins to enter.

Mutating the gene, and thereby altering the structure of the protein, resulted in forms that were more and less active. The research points to novel ways to treat disease, as Alina Guna, a Whitehead Lab postdoctoral researcher and first author of the study, explained in a statement.

"We can make leukemia cells more sensitive to a cancer treatment by giving them a mutation that changes the activity of MTCH2," Guna said. "The mutation makes MTCH2 act more 'greedy' and insert more things into the membrane, and some of those things that have inserts are like pro apoptotic factors, so then those cells are more likely to die which is fantastic in the context of a cancer treatment."

Gene editing advances continue a pace, but progress is still early: panel
With the first-ever approval of a CRISPR gene editing therapy expected in 2023, companies at last week’s Cell & Gene Meeting on the Mesa say they are...
CRISPR-Cas9 screen uncovers chance to repurpose drugs to treat sickle cell disease
A CRISPR-Cas9 screen has generated insights into the switch from fetal to adult hemoglobin that suggest a new approach for treating beta hemoglobinopathies...
CRISPR-Cas9 variant enables DNA cutting at ‘practically any sequence’
Massachusetts General Hospital researchers have engineered a CRISPR-Cas9 variant that overcomes a previous restriction on the locations that DNA can be...
Spherical nucleic acids 'dramatically' expand CRISPR delivery options
Researchers at Northwestern University contend that by combining nanostructures called spherical nucleic acids with CRISPR-Cas9 systems, the types of...
Penn State-led team develops more efficient system for delivering CRISPR to stem cells
Modified mRNA (modRNA)-based CRISPR systems improve on the transfection and knockout efficiency of plasmid-based systems in human pluripotent stem cells...
CRISPR reveals way to enhance the function, persistence of CAR T-cell therapies
The use of CRISPR knockout screens have uncovered a new regulator of immunity that could enhance the function and persistence of anticancer T-cell therapies,...

Copyright © 2022

Science Advisory Board on LinkedIn
Science Advisory Board on Facebook
Science Advisory Board on Twitter