Wednesday, November 09, 2022

A “door” into the mitochondrial membrane

Amazing stuff!

"Proteins on the outer membrane of mitochondria are especially important; they allow the mitochondria to communicate with the rest of the cell, and play a role in immune functions and a type of programmed cell death called apoptosis. Over the course of evolution, cells evolved a specific mechanism by which to insert these proteins — which are made in the cell’s cytoplasm — into the mitochondrial membrane. But what that mechanism was, and what cellular players were involved, has long been a mystery. 
A new paper ... reveals that a protein called mitochondrial carrier homolog 2, or MTCH2 for short, which has been linked to many cellular processes and even diseases such as cancer and Alzheimer’s, is responsible for acting as a “door” for a variety of proteins to access the mitochondrial membrane. ..."

"How mitochondria handle helical proteins
The essential roles of mitochondria in metabolism and signaling depend on a functionally and structurally diverse class of alpha-helical proteins embedded in the outer mitochondrial membrane. Guna et al. identified the mitochondrial outer membrane protein MTCH2 (mitochondrial carrier homolog 2) and found that it is both necessary and sufficient for the insertion of mitochondrial alpha-helical proteins. MTCH2 is the defining member of a broadly conserved class of insertases that exploit a diverged ancestral solute transporter fold to mediate membrane protein insertion. MTCH2’s role as a gatekeeper for outer mitochondrial membrane biogenesis rationalizes its pleotropic phenotypes and association with human disease."

From the abstract:
"In the mitochondrial outer membrane, α-helical transmembrane proteins play critical roles in cytoplasmic-mitochondrial communication. Using genome-wide CRISPR screens, we identified mitochondrial carrier homolog 2 (MTCH2), and its paralog MTCH1, and showed that it is required for insertion of biophysically diverse tail-anchored (TA), signal-anchored, and multipass proteins, but not outer membrane β-barrel proteins. Purified MTCH2 was sufficient to mediate insertion into reconstituted proteoliposomes. Functional and mutational studies suggested that MTCH2 has evolved from a solute carrier transporter. MTCH2 uses membrane-embedded hydrophilic residues to function as a gatekeeper for the outer membrane, controlling mislocalization of TAs into the endoplasmic reticulum and modulating the sensitivity of leukemia cells to apoptosis. Our identification of MTCH2 as an insertase provides a mechanistic explanation for the diverse phenotypes and disease states associated with MTCH2 dysfunction."

A “door” into the mitochondrial membrane | MIT News | Massachusetts Institute of Technology Study finds the protein MTCH2 is responsible for shuttling various other proteins into the membrane of mitochondria. The finding could have implications for cancer treatments and MTCH2-linked conditions.

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