Opening Up The Gateway To A Cell’s Batteries

How do large, complex molecules enter the mitochondria from the cytosol? Real time atomic-resolution images now reveal the architecture of the gateway proteins involved.

AsianScientist (Oct. 5, 2015) – Researchers have shown how large molecules manage cross the mitochondrial membrane, visualizing the process with atomic-resolution imaging, in real time. Their findings have been published in Science.

Mitochondria are often referred to as the powerhouses of our cells, because they generate chemical energy similar to that obtained from a battery. Whether it’s a brain, muscle or plant cell, nano-sized gateways control the activity of the mitochondrial battery, by carefully allowing certain proteins and other molecules to enter into our mitochondria.

Some of these proteins are large and complex molecules, yet they are essentially ‘spirited’ into from the cytoplasm into the mitochondria, while the mitochondrial membrane remains water-tight and intact. How this happens has confounded science for decades.

According to the lead researcher, Professor Trevor Lithgow, from the newly launched Biomedicine Discovery Institute (BDI) at Monash University, the discovery means that scientists can now use the technology to determine how any molecule passes through any membrane.

“How large molecules like proteins get in and out of membranes has long been a mystery. We have shown that this technology can be applied to solve the atomic scale details for all sorts of fundamental pathways going on in cells, opening the way to direct applications for medical research,” he said.

The researchers used a novel technology that enables the systematic expansion of the genetic codes of living organisms to include unnatural amino acids beyond the common twenty. The technology had been used in a handful of labs outside of Australia.

Lithgow and lead researcher Dr. Takuya Shiota from the BDI focused on the TOM protein complex, a large, complicated set of molecules embedded in the mitochondrial membrane in ways that have long confounded researchers. According to Lithgow, TOM 40 has resisted all attempts to unlock its transport secrets, including x-ray crystallography and other standard techniques in structural biology.

The Lithgow lab, working with colleagues from Nagoya University, Kyoto Sangyo University and the National Institute of Advanced Industrial Science and Technology in Tokyo, ramped up scale of the technology making literally hundreds of re-coded TOM 40 complexes, each one with a novel additional 21st amino acid.

What they ended up with was a Rubik’s Cube of three dimensional data, which in the end had a unique solution that explained the structure of the TOM 40 protein complex and precisely how it operates as the gateway for entry into mitochondria.

Having shown the technology works, Lithgow believes other labs working on diverse processes in human cell biology will mimic these experiments to determine how their chosen nanomachines operate. This includes processes from DNA damage and repair, to regulation events in metabolic disorders and cancer.

“This new technology has revealed what has been a major unknown in biology, and other cellular mysteries are now ripe for the picking,” he said.

The article can be found at: Shiota et al. (2015) Molecular Architecture of the Active Mitochondrial Protein Gate.

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Source: Monash University; Photo: NICHD/Flickr/CC.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

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